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www.unamur
This booklet « Cancerology » has been implemented by the Research Administrations
of the Académie universitaire Louvain (FUCAM, FUNDP and UCL) with the precious
help of a reading committee composed of Professors O. Feron (UCL - Angiogenesis
and Cancer Research Laboratory, IREC - Institute of Experimental and Clinical
Research), B. Flamion (FUNDP - College of Medicine), B. Gallez (UCL - Laboratory of
Biomedical Magnetic Resonance, LDRI - Louvain Drug Research Institute), M. Hamoir
(UCL - St Luc Cancer Center) and C. Michiels (FUNDP - Cellular Biology Unit).
With the contribution of M. Brion (UCL), J. Colin (UCL), A. D’Antonio (FUCAM), M. Dubuisson (UCL),
F. Roussel (FUNDP), A. Tondeur (FUCAM).
Cover: human chromosomes, National Cancer Institute - The Cancer Genome Atlas. http://cancergenome.nih.gov
2 0 1 0
Cancerology
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Foreword
The main objective of this document is to highlight the excellent level of research in cancerology within the Académie universitaire
Louvain in order to promote synergies, to enrich existing partnerships and generate new ones. It also aims at supporting industrial
innovation by raising industrial awareness of university competencies in cancerology and, in fine, improving the quality of health
care.
In addition to being an important public health issue, cancer is a complex pathology the study of which requires the collaboration
of all scientific disciplines. The approach to cancer diseases involves multidisciplinary teams to deal with complex sequences of
research and care: diagnostic, surgery, drug therapy, radiotherapy, rehabilitation, psychological support…
The level of international cooperation already in place in the research teams within the Académie universitaire Louvain will be
obvious from this booklet, which presents their research topics, recent achievements and current developments. These topics are
classified in ten categories, according to the main scientific or technological approach.
The last part gathers different research centers and non-profit organizations established within the Académie universitaire Louvain
and devoted to cancer research.
u Prevention
and epidemiology
u Mechanisms
u Diagnostic
of cancer
– Imaging
u Immunology
– Genetics
u Biomarker
u Clinical
study
u Anti-cancer
treatment
u Surgery
u Radiotherapy
u Psycho-oncology
u Research
centers and non-profit organizations
3
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Content
A. PREVENTION AND EPIDEMIOLOGY
B.5 - Genetic and Epigenetic Alterations of the
Genome
A.1 - Fertility preservation for cancer patients:
21
A. DECOTTIGNIES, C. DE SMET
Cryobanking and transplantation of reproductive
tissues
B.6 - Identification of genes involved in hypoxia-
9
induced metastasis, using statistical and
J. DONNEZ, C. WYNS, M.-M. DOLMANS, J.-L. SQUIFFLET, P. JADOUL,
C. Pirard, D. DEMYLLE, C. AMORIM, A. VAN LANGENDONCKT
bioinformatics analysis of DNA array data, and
confirmation of their differential expression in in
A.2 - Methodological support in epidemiology and
vitro et in vivo models
biostatistics applied to research in cancer
E. DEPIEREUX, C. MICHIELS
11
23
A. ROBERT
B.7 - Mechanisms of p53-dependent apoptosis
25
P. DUMONT
B. MECHANISMS OF CANCER
B.8 - Hyaluronan metabolism in cancer stem cells
B. FLAMION
B.1 - Study of the endoplasmic stress response
mechanisms in multiple myeloma
13
B.9 - Role of intracellular calcium homeostasis in
T. ARNOULD, M. RAES
B.2 - Oxidative stress and cancer cell death
apoptosis of cancer cells
29
P. GAILLY, N. TAJEDDINE
15
P. BUC CALDERON, J. VERRAX
B.10 - Hox transcription factors and cancer
31
R. REZSOHAZY
B.3 - Pathologic activation of tyrosine kinases in
leukemia and myeloproliferative neoplasms
27
17
S. N. CONSTANTINESCU, J.-C. RENAULD, J.-B. DEMOULIN
C. DIAGNOSTICS-IMAGING
B.4 - Are type I MAGE genes involved in
tumorigenesis ?
19
C.1 - Semi-automatic delineation, non-rigid
registration and dose accumulation for adaptive
O. DE BACKER
treatment in radiotherapy and proton therapy
A. BOL, X. GEETS, V. GREGOIRE, J. LEE, B. MACQ, V. NICOLAS
5
33
C.2 - Functional magnetic resonance (NMR, EPR)
spectroscopy and imaging in tumors
D.4 - Intracellular processing of tumor antigens
recognized by cytolytic T lymphocytes : role of the
35
proteasome and other cytosolic proteases
B. GALLEZ, B. JORDAN
47
B. VAN DEN EYNDE, V. STroobant
C.3 - Intuitive And Standardized Annotation For
Cancer Prevention And Diagnosis
D.5 - Regulation of T lymphocyte function in
37
tumors
B. MACQ, V. NICOLAS, P.-Y. SCHOBBENS
49
P. VAN DER BRUGGEN, D. COLAU, N. DEMOTTE, D. GODELAINE
C.4 - Impact of intra-operative MRI at 3 Tesla on
the degree of tumor resection and long-term
survival rate in patients with intracranial glioma,
E. BIOMARKERS
and development of neuronavigation on intraoperative images
39
E.1 - Gene profiling, prognosis and diagnosis
C. RAFTOPOULOS, J. G. VAZ, E. FOMEKONG
51
P. DUPONT
E.2 - Study of the seric and serological proteomes
D. IMMUNOLOGY-GENETICS
of cancer patients to identify and validate
predictive / prognostic / monitoring biomarkers
D.1 - Genetic analysis of T lymphocytes infitrating
human tumors
53
O. FERON, F. DEFRESNE
41
P. COULIE, P. VAN DER BRUGGEN, S. LUCAS
F. CLINICAL STUDIES
D.2 - Therapeutic vaccination of cancer patients
with tumor specific antigens
43
F.1 - New treatments of cancer : Immunotherapy
N. VAN BAREN, J.-F. BAURAIN, T. BOON
and targeted therapies
J.-F. BAURAIN, J.-P. MACHIELS
D.3 - Mechanisms of tumor resistance to the
immune system and development of a mouse
model of inducible melanoma
55
F.2 - Clinical studies in hematology
45
A. FERRANT, L. KNOOPS, L. MICHAUX, E. VAN DEN NESTE,
M.-Ch. VEKEMANS
B. Van den eynde, C. Uyttenhove, D. COLAU, V. stroobant
6
57
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
F.3 - Lung cancer - mesothelioma - clinical research in
G.7 - Mechanisms involved in cancer cell resistance
diagnosis - active treatment - supportive care
to apoptosis and/or autophagy induced by
59
chemotherapeutic drugs under hypoxia
D. RODENSTEIN, P. COLLARD, G. LIISTRO, T. PIETERS
73
C. MICHIELS, T. ARNOULD
G.8 - Active and passive targeting of anticancer
G. ANTI-CANCER TREATMENT
nanomedicine
V. PREAT, O. FERON, J. MARCHAND
G.1 - Mechanisms of ovarian toxicity of
chemotherapeutic agents used in breast cancer
61
G.9 - Isolation and structure determination of
M. BERLIERE, E. MARBAIX, Ch. GALANT, J.-P. MACHIELS
G.2 - Nucleoside analogues in leukaemia
75
cytotoxic, anticancer or anti-angiogenic compounds
from plants
77
63
J. QUETIN-LECLERCQ, G. CHATAIGNE
F. BONTEMPS, E. VAN DEN NESTE
G.10 - Treatment of skin carcinoma using
G.3 - Screening of synthetic and natural compounds
for anti-tumor and anti-angiogenic activity
phototherapy
79
65
M. RAES
O. FERON, R. BOIDOT
G.11 - Design, synthesis, and biological evaluation
G.4 - Influence of the tumor microenvironment
of mixed DNA methyl transferase and Histone
including tumor hypoxia and metabolism on cancer
progression and metastases
Deacetylase inhibitors as epigenetic regulators
81
67
J. WOUTERS, D. LAMBERT
O. FERON, P. SONVEAUX
G.5 - Prevention and treatment of hepatocellular
carcinoma
H. SURGERY
69
Y. HORSMANS, P. STÄRKEL, I. BORBATH
H.1 - Limb salvage in tumor surgery with massive
G.6 - Anti-cancer drug discovery and synthesis
bone allografts (Bone Bank)
71
C. DELLOYE, O. CORNU, X. BANSE, P.-L. DOCQUIER
B. MASEREEL, J. WOUTERS
7
83
I. RADIOTHERAPY
K.2 - Head and Neck Oncology Program – Cancer
Center
I.1 - Molecular imaging of cancer and experimental
radiotherapy
97
V. GREGOIRE, M. HAMOIR, H. REYCHLER, E. COCHE , G. COSNARD,
T. DUPREZ, B. LENGELE, M. LONNEUX, J.-P. MACHIELS, E. MARBAIX,
B. WEYNAND, J.-Ch. DEGOLS, J.-. GERARD, M. MAGREMANNE,
P. MAHY, S. SCHMITZ
85
V. GREGOIRE, F. JAMAR, B. KRUG, M. LONNEUX, S. PAUWELS,
V. ROELANTS, P. SCALLIET, T. VANDER BORGHT, X. GEETS, A. BOL,
J.-M. DENIS, J. GEORGE, H. MEURISSE, S. VYNCKIER, S. WALRAND,
T. DOUMONT, J. GILLART, D. LABAR
K.3 - The Brussels Branch of the Ludwig Institute
for Cancer Research
99
I.2 - Study of the effects of direct irradiation or
K.4 - The European CanCer Organisation – ECCO
using targeted nanoparticles containing several
101
radioactive atoms on the interactions between
tumor cells and endothelial cells
K.5 - European Organisation for Research and
87
Treatment of Cancer-EORTC
S. LUCAS, C. MICHIELS, B. MASEREEL
103
K.6 - European Society Of Surgical Oncology – ESSO
J. PSYCHO-ONCOLOGY
105
K.7 - European Society for Therapeutic Radiology
J.1 - Psycho-oncology
and Oncology-ESTRO
89
107
D. OGEZ, M. COLMANT
K.8 - The U.S. National Cancer Institute Liaison
Office - NCI L.O.
K. RESEARCH CENTERS AND NONPROFIT ASSOCIATIONS
K.1 - Cancer Center at UCL and Saint Luc academic
hospital
93
8
109
A 1
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Fertility preservation for cancer patients:
Cryobanking and transplantation of reproductive tissues
Senior scientists :
u Jacques DONNEZ
u Christine WYNS
u Marie-Madeleine DOLMANS
u Jean-Luc SQUIFFLET
u Pascale JADOUL
u Céline Pirard
u Dominique DEMYLLE
u Christiani AMORIM
u Anne VAN LANGENDONCKT
Research Field and Subjects
spermatogonia and somatic cells. In order to evaluate tissue and
cell functionality after freezing and thawing, we developed an
orthotopic xenografting model in immunodeficient mice and an
in vitro culture system for testicular explants. The xenografting
model will be implemented to optimize transplantation conditions for human immature testicular tissue with a view to clinical
implementation of autografting of stored tissue.
CRYOPRESERVATION AND TRANSPLANTATION OF OVARIAN TISSUE
For women who are to undergo chemotherapy or radiotherapy,
the loss of ovarian function will result in premature menopause
and loss of fertility. The storage of ovarian tissue provides a
means of restoring long-term fertility in such patients. We performed the first successful transplantation of cryopreserved
ovarian tissue in a women who had previously received chemotherapy for Hodgkin’s disease.
Representative References
During the last ten years, we have set up a bank including ovarian tissue from 340 patients undergoing treatment that may
irreversibly damage the oocyte population.
After thawing, primordial follicles enclosed in ovarian tissue
need to reach the antral stage in order to obtain mature oocytes
that can be fertilized. Two approaches are implemented in our
laboratory to achieve this maturation step: in vitro culture of
ovarian tissue and transplantation of human ovarian cortical
slices or isolated follicles.
Three main projects are currently under way:
1. The aim of our first project is to optimize grafting conditions for human ovarian tissue. For this purpose, an experimental model was set up in immunodeficient mice allowing us to
test the site of transplantation, the size of the graft, the factors
promoting the revascularization of the graft and the treatment
required to sustain follicle growth after transplantation.
2. Our second project is designed to optimize cryopreservation
protocols for ovarian fragments and entire ovaries.
3. Another main project consists in the development of a scaffold for the grafting of isolated human follicles and the support
of their growth.
u J.
Donnez, M.M. Dolmans, D. Demylle, P. Jadoul, C. Pirard,
J. Squifflet, B. Martinez-Madrid, A. Van Langendonckt. Livebirth
after orthotopic transplantation of cryopreserved ovarian tissue.
Lancet 364, 1405-10, 2004.
u B. Martinez-Madrid, A. Camboni, M.M. Dolmans, S. Nottola,
A. Van Langendonckt, J. Donnez. Apoptosis and ultrastructural
assessment after cryopreservation of whole human ovaries with
their vascular pedicle. Fertility Sterility 87, 1153-65, 2007.
u M.M. Dolmans, Y.Y. Wu, A. Camboni, A. Torre, A. Van Langendonckt, B. Martinez-Madrid, J. Donnez. Isolated human primordial
follicles can develop to the antral stage after xenografting to
SCID mice. Reproductive Biomedicine Online 16,705-711, 2008.
u J. Donnez, J. Squifflet, A.S. Van Eyck, D. Demylle, P. Jadoul, A. Van
Langendonckt, M.M. Dolmans. Restoration of ovarian function in
orthotopically transplanted cryopreserved ovarian tissue: a pilot
experience. Reproductive Biomedecine Online 16, 694-704, 2008.
u C. Wyns, A. Van Langendonckt. F.X. Wese, J. Donnez, M. Curaba.
Long-term spermatogonial survival in cryopreserved and xenografted immature human testicular tissue. Human Reproduction
23,2402-14, 2008.
u C.A. Amorim, A. Van Langendonckt, A. David, M.M. Dolmans,
J. Donnez. Survival of human pre-antral follicles after cryopreservation of ovarian tissue, follicular isolation and in vitro culture in
a calcium alginate matrix. Human Reproduction 24, 92-9, 2009.
MALE FERTILITY PRESERVATION AFTER GONADOTOXIC TREATMENT
Aggressive chemotherapy and radiotherapy can severely affect
male germ cells and lead to permanent loss of fertility. Cryopreservation of immature testicular tissue either in the form of a cell
suspension or whole pieces of tissue is the only way of preserving
fertility in prepubertal boys. Our experimental project focuses on
the development of an appropriate cryopreservation protocol for
immature testicular tissue, allowing survival and functioning of
Patent
European Patent Apllication n° 07117661.4-1219 : « Scaffolds
for follicle transplantation », C. Andrade Amorim, M.M. Dolmans,
A. Van Langendonckt, J. Donnez
9
Partnership
u Inter-university:
Key Words for R&D
Cryopreservation
Transplantation
Fertility preservation
Post-chemotherapy
Follicle isolation
Artificial ovary
Scaffold
Ovarian tissue
Testicular tissue
Follicle isolation
Ulg, ULB & UCL.
u CERM
Ulg
u VUB : Prof Smitz , Follicle Development Unit
Funding
u Mécénats
u FNRS
u Fondation
Senior Scientists
contre le Cancer, Fondation Saint Luc
Jacques DONNEZ
[email protected]
Tél. : 32(0)2 764 95 01
Main Equipment
Christine WYNS
[email protected]
Tél. : 32(0)2 764 11 01
u Programmable
freezers
nitrogen tanks
u Facilities for cell, follicle and embryo culture
u Tissue chopper
u Liquid
Marie-Madeleine DOLMANS
[email protected]
Tél. : 32(0)2 764 52 47
Jean SQUIFFLET
[email protected]
Tél. : 32(0)2 764 10 71
Products and Services
u Ovarian
and testicular tissue cryobanking
transplantation in nude mice and rats
u Evaluation of neoangiogenesis
Pascale JADOUL
[email protected]
Tél. : 32(0)2 764 17 93
u Experimental
Céline PIRARD
[email protected]
Tél. : 32(0)2 764 10 28
Dominique DEMYLLE
[email protected]
Tél. : 32(0)2 764 10 24
Christiani AMORIM
[email protected]
Tél. : 32(0)2 764 52 47
Anne VAN LANGENDONCKT
[email protected]
Tél. : 32(0)2 764 52 47
Web Site
http://www.isfp-fertility.org/
10
A 2
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Methodological support in epidemiology and biostatistics
applied to research in cancer
Senior Scientist :
u Annie
Research Field and Subjects
ROBERT
agents are however oriented to antitumoral drugs, and consequently call for a new definition of early response to therapy,
taking into account a decrease in the size of cancer lesions or a
stabilization of disease.
“Progression-free survival” and “Time to progression” are valuable alternative definitions of response to treatment, since a
recent harmonization of guidelines has been proposed to assess
the progression of cancer in solid tumors (RECIST Therasse P.
and al. J. Nat. Cancer Inst. 2000, 92:205). Progression-free survival can be estimated using retrospective analyses of phase III
trials, in order to derive P0 and P1 values. Such analysis has
been done for soft tissue sarcomas (Van Glabbeke and al. Eur.
J. Cancer 2002, 38:543-549). We plan to extend those analyses
to other solid tumors such as lung cancers, bladder cancers, or
breast cancers.
Epidemiology and biostatistics can be applied to cancer research
especially in the study of cancer incidence by products or in the
estimation of anticancer drugs efficiency.
u Cancer incidence and mortality among cohorts of pesticides producing workers, etc.
Epidemiological studies are conducted in order to assess if there
is an excess of cancer cases in current and ex-workers from a
plant and to identify workplace exposures which may explain
such a demonstrated excess.
Vital- and cancer status according to the ICD10 codes (international classification of diseases) are established for all workers,
and life table analyses are conducted, using the Belgian mortality and the regional (Flanders, French community) registry of
cancers.
Efficiency and inefficiency estimations derived from such analyses may be sensitive to loss-to-follow data, to left rather than
right censored data, or to variations in the cancer progression
assessment. Sensitivity analyses will be conducted, together
with the consequences on size computations in designing phase
II trials.
Age- and sex standardised mortality (SMR) and incidence (SIR)
ratios are stratified by duration of employment, job title, time
since first employment, and time between the end of the job
at the plant for workers who left the plant. These occupational
data are used as latency- and intensity surrogates for testing
the hypothesis of a relationship between occupational exposure
and cancer development.
u Ultrasound-based cancer detection technique: modelling of raw data and determining its place in clinical management of ovarian cancers
u Progression-free survival in solid tumors: qualities
of estimators of clinical efficiency and inefficiency for
designing Phase II trials.
In Belgium the incidence rate of ovarian cancer in 2002 was
of 20.5 per 100000 (for Western Europe 18.9 per 1000003).
With a mortality rate of ovarian cancer in 2002 of 15.3 per
1000003 (Western Europe 13 per 1000003), it can be seen that
ovarian cancer has high mortality rates. This is merely due to
the anatomical position of the ovaries which often leads to late
detection of the cancer when it has already progressed to an
advanced stage. In addition, the poor survival is leading to an
approach of prudence which results in surgical removal of the
ovaries because of an abnormal image at ultrasound, while in
fact there is no cancer.
Phase II trials play a key role in the development of new potential
anticancer drugs because they are crucial in deciding whether or
not proceeding to a phase III trial.
Phase II trials are conducted in order to assess the clinical efficiency (P1) or the clinical inefficiency (P0) of new treatments. The
number of patients enrolled in a phase II trial closely depends on
P0 and P1 values. An underestimation of P1 can lead to rejection of an active treatment and an overestimation of P0 can lead
to keep a useless treatment. The classical definition of P0 and P1
is based on death rates because mortality is an objective measure of response to therapy. Recent developments in anticancer
Because of its non-invasive and radiation free nature, its relatively low-priced and easy operation, ultrasound imaging may
proof to be a valuable tool for cancer detection.
11
Funding
A new software technology (from a Belgian company) can be
used as an add-on to ultrasound imaging and can improve the
use of ultrasound imaging for diagnosis and detection of softtissue cancers. The new software technology targets women
with symptoms. In this group of women, the software aims
at detecting ovarian cancer. As a consequence, better disease
management is expected.
Ultrasonic acquisition is typically based on the transmission,
and backscattering of ultrasonic pressure waves that propagate
through the human body.The use of the statistics of the backscattered signal for the identification, characterization and classification of different tissues is justified by the random nature of
the ultrasound echoes.
We therefore investigate the ultrasonic backscattered waves.
The statistical nature of the scatterers are considered in terms of
distributions in order to derive a model that might characterize
the data.
Our team also investigates the clinical and economical advantages of using the new software technology as a part of the
existing diagnostic protocols (clinical surveillance method, estimation of the health effects ad resource costs, Model of Natural
history of ovarian cancer, predictions, decision tree and decision
analytical models, and comparison with the analysis of the clinical trials outcomes and date).
u Industry
u Occupational
health services
u Competitive research funds
Partnership
European Organization for Research and Treatment of Cancer
(EORTC).
Key Words for R&D
Applied statistics
Clinical trials
Drug evaluation
Epidemiology
Health- and medical statistics
Occupational medicine
Preventive medicine
Pharmacotherapy
Senior Scientist
Annie ROBERT
[email protected]
Tél. : 32(0)2 764 33 21
Products and Services
Web Site
u Support
for protocol design
u Data analysis and publications of results on a contractual
basis.
http://rch.adre.ucl.ac.be/browse/list_alpha/EPID
Main Equipment
Statistical and Epidemiological softwares: BMDP, The SAS System, SPSS, Splus, EPIinfo, EPICURE.
12
B 1
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Study of the endoplasmic stress response mechanisms
in multiple myeloma
Senior Scientists :
u Thierry ARNOULD
u Martine RAES
Research Field and Subjects
Funding
Using a sensitive proteomic approach, the aim of this project
is to get a molecular signature from multiple myeloma cells
isolated from urine/blood in order to characterize soluble and
membranous proteins and their putative processing such as
« shedding ».
The expected results will help to set up new diagnostic assays to
characterize these cancer cell types according evolution as well
as to determine molecular markers to follow patient treatments.
The study will also evaluate the effects of proteasome inhibitors (Velcade®) or ER stressing molecules on apoptotic and
autophagic multiple myeloma cell responses to better delineate
cell resistance to drug adjustment/adaptation.
Télévie – FNRS
Partnership
Prof. G. Berchem, Dr V. Palissot. RP-Santé Luxembourg
Main Equipment
Proteomics facilities, Imaging technology (Confocal Microscopy)
Products and Services
Representative References
Proteomic analyses, identification of molecular signature
u L.
Mercy, A. De Pauw, L. Payen, S. Tejerina, A. Houbion, C. Demazy,
M. Raes, P. Renard, T. Arnould. Mitochondrial biogenesis in
mtDNA-depleted cells involves a Ca2+-dependent pathway and
a reduced mitochondrial protein import. FEBS J., 272(19):503155, 2005.
u C. Schwartz, V. Palissot, N. Aouali, S. Wack, N. Brons, B. Leners, M. Bosseler, G. Berchem. Valproic acid induces non-apoptotic
cell death mechanisms in multiple myeloma cell lines. Int J
Oncol.,30(3):573-82, 2007.
u I. Hamer, E. Delaive, M. Dieu, F. Abdel-Sater, L. Mercy, M. Jadot,
T. Arnould. Up-regulation of cathepsin B expression and
enhanced secretion in mitochondrial DNA-depleted osteosarcoma cells. Biol Cell., 101(1):31-41, 2009.
u G. Rommelaere, L. Mercy, N. Ninane, C. Demazy, M. Raes,
P. Renard, T. Arnould. Hypersensitivity of mtDNA-depleted cells
to staurosporine-induced apoptosis: role of Bcl-2 downregulation and lysosomal proteases. Biochem. J. Submitted, 2009.
13
Key Words for R&D
Cancerology
Myeloma
Cell death
Signal transduction
Proteomics
Apoptosis
Autophagy
Senior Scientists
Thierry ARNOULD
[email protected]
Tél. : 32(0)81 72 41 25
Martine RAES
[email protected]
Tél. : 32(0)81 72 41 24
Web Site
http://www.fundp.ac.be/facultes/ sciences/departements/biologie/ recherche/centres/urbc/
14
B 2
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Oxidative stress and cancer cell death
Senior Scientists :
u Pedro
u Julien
BUC CALDERON
VERRAX
Research Field and Subjects
Representative References
Due to oncogenic stimulation and high metabolic rates, cancer
cells exhibit high levels of reactive oxygen species (ROS) that
stimulate cell proliferation and promote genetic instability. Such
a biochemical difference between transformed and non-transformed cells represents a redox vulnerability of malignant cells
that can be targeted by chemotherapeutic intervention using
redox modulators. Since cancer cells usually lack antioxidant
enzymes, we hypothesize that their selective exposure to an
oxidative stress, induced by the combination between pharmacologic doses of ascorbate and a redox-active quinone (menadione), will kill tumour cells. Ascorbate plays a key role because
it is preferentially taken up by cancer cells, which favours the
in situ formation of ROS. In addition, such an oxidative stress
affects the chaperoning function of heat shock protein 90
(Hsp90). Since the stability of several proteins (like Bcr-Abl,
Akt, RIP,…) that are essential for malignant transformation, is
made possible by Hsp90, its inhibition represents an interesting
target for cancer therapies. We have recently reported that an
oxidative stress affects hsp90 activity, inducing both degradation of its client proteins and cancer cell death. Given the major
role of hsp90 in cancer cell survival, we anticipate that such an
approach may have potential clinical applications. In addition to
the study about the role of hsp90 cleavage on Bcr-Abl degradation and the subsequent leukemia cell death, two additional
subjects are currently under study. They include:
a) The mechanism involved in the activation of Nrf2 and the
acquisition of cancer cell resistance to chemo-therapy;
b) Calcium homeostasis and ER stress in cell death by autophagy during an oxidant injury.
u J.
Verrax, J. Cadrobbi, C. Marques, H.S. Taper, Y. Habraken,
J. Piette, P. Buc Calderon. Ascorbate potentiates the cytotoxity of
menadione leading to an oxidative stress that kills cancer cells
by a non-apoptotic caspase-3 independent form of cell death.
Apoptosis 9, 223-233, 2004.
u J. Verrax, M. Delvaux, N. Beghein, H.S. Taper, B. Gallez, P. Buc
Calderon. Enhancement of quinone redox cycling by ascorbate
leads to cancer cell death through a caspase-3 independent
pathway. An in vitro comparative study. Free Rad. Res. 39, 649657, 2005.
u J. Verrax, J. Stockis, A. Tison, H. Taper, P. Buc Calderon. Oxidative stress by ascorbate/menadione association kills K562
human chronic myelogenous leukemia cells and inhibits its
tumor growth in nude mice. Biochem. Pharmacol. 72, 671-680,
2006.
u J. Verrax, J. Stockis, S. Vanbever, H. Taper, P. Buc Calderon. Role
of glycolysis inhibition and Poly(ADP-ribose) polymerase activation in necrotic-like cell death caused by ascorbate/menadioneinduced oxidative stress in K562 human chronic myelogenous
leukemic cells. Int. J. Cancer 120, 1192-1197, 2007.
u J. Benites, L. Rojo, J.A. Valderrama, H. Taper, P. Buc Calderon.
Part 1: anticancer activity of two euryfurylbenzo-quinones on
TLT, a murine hepatoma cell line. Role of vitamin C in the mechanism leading to cell death. Eur. J. Med. Chem. 43, 1813-1817,
2008.
u R. Beck, J Verrax, T. Gonze, M. Zappone, R. Curi Pedrosa, H. Taper,
O. Feron, P. Buc Calderon. Hsp90 cleavage by an oxidative stress
leads to Bcr-Abl degradation and leukemia cell death. Biochem.
Pharmacol. 77, 375-383, 2009.
u J. Verrax, P. Buc Calderon. Pharma-cologic concentrations of
ascorbate are achieved by parenteral administration and exhibit
antitumoral effects. Free Rad. Biol. Med. doi:10.1016/j.freeradbiomed. 2009. 02. 016, 2009.
Funding
u FNRS-FRSM-TÉLÉVIE-FRIA
u Région
u FSR
15
Wallonne
Partnership
Key Words for R&D
Apoptosis
Autophagy
Bcr-Abl
Cancer
Cell death
ER stress
Hsp90
Leukemia
Menadione
Oxidative stress
Vitamin C
u Olivier
Feron (FATH/MD/UCL)
u Bernard Gallez (REMA/MD/UCL)
u Laurent Knoops (MEXP/MD/UCL)
u Philippe Gailly (FYMO/MD/UCL)
u Jacques Piette (U. Liège, Belgium)
u Rozangela Curi (U. Santa Catarina, Brazil)
u Julio Benites (U. Arturo Prat, Iquique, Chile)
Main Equipment
Senior Scientists
u Fluorescence
and light microscopes
Pedro BUC CALDERON
[email protected]
Tél. : 32(0)2 764 73 66
u Western
blot
u Cell culture
u Ultracentrifuge
u HPLC
u Luminometer/fluorimeter
Julien VERRAX
[email protected]
Tél. : 32(0)2 764 73 95
Web Site
Products and Services
http://www.uclouvain.be/en-269740.html
Expertise in cell death analysis
16
B 3
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Pathologic activation of tyrosine kinases in leukemia
and myeloproliferative neoplasms
Senior scientists :
u Stefan N. CONSTANTINESCU
u Jean-Christophe RENAULD
u Jean-Baptiste DEMOULIN
Research Field and Subjects
u A.
Dusa, J. Staerk, J. Elliott, C. Pecquet, H.A. Poirel, J.A. JohnsS.N. Constantinescu. Substitution of pseudokinase domain
residue Val-617 by large non-polar amino acids causes activation of JAK2. J Biol Chem. 283:12941-8, 2008.
u F. Toffalini, A. Kallin, L. Michaux, P. Vandenberghe, P. Pierre,
J. Cools and J.B. Demoulin. The fusion proteins TEL-PDGFRβ and
FIP1L1-PDGFRα escape ubiquitination and degradation. Haematologica In press, 2009.
u A. Essaghi, N. Dif, C.Y. Marbehan, P.J. Coffe, J.B. Demoulin.
The transcription of FOXO genes is stimulated by FOXO3 and
repressed by growth factors. J Biol Chem 284:10334-42, 2009.
u T. Hornakova, J. Staerk, Y. Royer, E. Flex, M. Tartaglia, S.N. Constantinescu, L. Knoops, J.C. Renauld. Acute lymphoblastic leukemiaassociated JAK1 mutants activate the Janus kinase/STAT pathway
via interleukin-9 receptor alpha homodimers. J Biol Chem.
284:6773-81. 2009.
ton,
Hematopoietic growth factors bind to receptors which signal
through JAK kinases and STAT transcription factors, leading to
cell survival, proliferation and differentiation. Researchers at the
De Duve Institute have identified a number of alterations of this
pathway that lead to hematopoietic cell transformation. They initially showed that an autocrine loop involving interleukin-9 can
favor the development of lymphoma. They contributed to the discovery of the JAK2 V617F mutation in human myeloproliferative
neoplasms and of mutations in TYK2 or in JAK1, the latter being
involved in adult T cell leukemias. These mutations activate STATs
and other pathways in the absence of receptor ligand interaction.
It was also shown that mutations in cytokine receptors or overexpression of JAK kinases can lead to cell transformation. Chromosomal translocations involving receptor tyrosine kinases, such as
PDGF receptors in myeloproliferative neoplasms, are also studied.
In each case, the detailed mechanisms leading to cell transformation have been analyzed in vitro and in vivo, pointing to the
key role of the STAT factors. The identification of novel alterations is pursued using classical molecular biology, sequencing
and microarrays. These findings are opening new avenues for
the therapy of these diseases.
Awards
u J.-C.
Renauld: Interbrew-Baillet-Latour
Prize, 2000
u Prix Pfizer, 2008
u Health
Funding
Representative References
u FNRS,
Actions de Recherches Concertées, Région Wallonne
contre le Cancer, Fondation Salus Sanguinis
u Ludwig Institute for Cancer Research
u European commission
u NIH
u C.
James, V. Ugo, J.P. Le Couédic, J. Staerk, F. Delhommeau,
C. Lacout, L. Garçon, H. Raslova, R. Berger, A. Bennaceur-Griscelli,
J.L. Villeval, S.N. Constantinescu, N. Casadevall, W. Vainchenker. A
unique clonal JAK2 mutation leading to constitutive signalling
causes polycythaemia vera. Nature 434:1144-8, 2005.
u J. Staerk, C. Lacout, T. Sato, S. O. Smith, W. Vainchenker,
S.N. Constantinescu. An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of
the thrombopoietin receptor. Blood. 107:1864-71, 2006.
u L. Knoops, T. Hornakova, Y. Royer, S.N. Constantinescu,
J.C. Renauld. JAK kinases overexpression promotes in vitro cell
transformation. Oncogene. 27:1511-9, 2008.
u J. Kota, N. Caceres, S.N. Constantinescu. Aberrant signal transduction pathways in myeloproliferative neoplasms. Leukemia.
22:1828-40, 2008.
u Fondation
Partnership
u Ludwig
Institute for Cancer Research
unit, Cliniques universitaires Saint-Luc
u Hematology
Main Equipment
Microarray technology
17
Products and Services
Key Words for R&D
JAK
STAT
Cytokine
Growth factor
Receptors
Signal transduction
Polycythemia vera
Interleukin
u Microarray
hybridization
u Bioinformatics for microarray data analysis
u Identification of novel genetic alterations from patient samples
u Signal transduction assays
Senior Scientists
Stefan N. CONSTANTINESCU
[email protected]
Tél. : 32 (0)2 764 75 40
Jean-Baptiste DEMOULIN
[email protected]
Tél. : 32 (0)2 764 65 29
Jean-Christophe RENAULD
[email protected]
Tél. : 32 (0)2 764 74 64
Web Sites
www.icp.be/mexp
www.deduveinstitute.be
www.bru.licr.org/brussels/research/cii/cii.html
www.bru.licr.org/brussels/research/stg/stg.html
18
B 4
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Are type I MAGE genes involved in tumorigenesis ?
Senior scientist :
u Olivier
Research Field and Subjects
Patents
The MAGE genes of type I have been identified in 1991 by the
team of Thierry Boon at the Brussels’s branch of the Ludwig
Institute for Cancer Research. These genes are well known
because they specify tumor-specific antigens targeted in cancer
immunotherapy. The type I MAGE genes are completely silent
in most somatic tissues, but are ectopically expressed in a significant fraction of tumors of different histotypes (melanomas,
gastro-intestinal, lung, prostate, breast, bladder, neuroblastomas …). However, the function of the MAGE proteins and the
role they could play in tumor development remain largely to be
elucidated. One of our ongoing projects is to unravel the role
of the type I MAGE proteins in tumorigenesis, by forcing their
ectopic expression in transfected cells and in transgenic mice.
u Van
DE BACKER
Den Eynde, De Backer, Boon-Falleur. Isolated peptides
derived from tumor rejection antigens, and their use. US
5,648,226, 1997.
u Van Der Bruggen, Van Den Eynde, De Backer, Boon-Falleur. Isolated peptides derived from the GAGE tumor rejection antigen
precursor and uses thereof. US 5,858,689, 1999.
u De Backer, Van Den Eynde, Boon-Falleur. Isolated, nucleic acid
molecules which code for GAGE tumor rejection antigen, the
tumor rejection antigen, and uses thereof. US 6,013,481, 2000.
Partnership
u B.
Van Den Eynde (Lüdwig Institute for Cancer Research)
Boon-Falleur (UCL)
u P. Van Der Bruggen (UCL)
u T.
Representative References
u S.
Remacle, L. Abbas, O. De Backer, N. Pacico, A. Gavalas, F. GofJ.J. Picard, R. Rezsohazy. Loss of function but no gain of
function caused by amino acid substitutions in the hexapeptide
of Hoxa1 in vivo. Molecular and Cellular Biology 24 8567-75,
2004.
u M. Bertrand, I. Huijbers, P. Chomez, O. De Backer. Comparative
expression analysis of the MAGED genes during embryogenesis
and brain development Developmental Dynamics 230 325-334,
2004.
u M.J.M. Bertrand , R.S. Kenchappa, D. Andrieu, M. Leclercq-Smekens, H. N. T. Nguyen, B. D. Carter, F. Muscatelli, P. A. Barker and
O. De Backer. NRAGE, a p75NTR adaptor protein, is required for
developmental apoptosis in vivo. Cell Death and Differenciation
15 1921-1229, 2008.
u A. Loriot, C. Sterpin, O. De Backer, and C. De Smet. Mouse
embryonic stem cells induce targeted DNA demethylation within
human MAGE-A1 transgenes Epigenetics. 3 38-42, 2008.
Funding
flot,
u FRFC
u FRSM
u FSR
Main Equipment
ABI 3130 Genetic Analyzer
Products and Services
Manipulation of mouse ES cells
19
Key Words for R&D
MAGE gene
ES cells
Transgenic mice
Senior Scientist
Olivier DE BACKER
[email protected]
Tél. : 32(0)81 72 42 77
Web Site
http://www.fundp.ac.be/facultes/medecine/ recherche/centres/urphym/page_view/ presentation.html
20
B 5
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Genetic and Epigenetic Alterations of the Genome
Senior Scientists :
u Anabelle DECOTTIGNIES
u Charles DE SMET
Research Field and Subjects
cells show genome-wide loss of DNA methylation. We have
found that this alteration results in the activation of a set of
genes, which are normally restricted to the germ line. We are
currently investigating the mechanisms targeting DNA demethylation towards these “cancer-germline” genes in tumor cells.
Preservation and regulation of genetic information is essential
for proper cell function. Consequently, cells have evolved mechanisms of telomere maintenance, DNA repair and epigenetic
regulation which defines heritable gene expression patterns.
These processes are functionally linked and converge on chromatin, the complex structure formed by DNA and proteins, in
the nucleus of eukaryotic cells.
Deregulation of these processes contributes to the appearance and progression of cancer cells, which are characterized
by genomic rearrangements and dysregulated gene expression
patterns.
4. Setting of DNA methylation patterns in embryonic stem cells
Embryonic stem cells are characterized by a remarkable epigenetic plasticity. The processes underlying the setting of DNA
methylation patterns in these cells are studied, with a particular
emphasis on cancer-germline gene promoters.
Representative References
1. DNA damage repair in fission yeast S. pombe
DNA repair processes have been well conserved throughout
evolution, and yeast has proven to be a good model for their
study. We use S. pombe to dissect the mechanisms of DNA
double-strand break repair, a type of genetic lesion arising after
exposure to genotoxic agents or during DNA replication. We
focus on improper DSB repair resulting from either deletion or
insertion of nucleotides at the repair junction.
De Smet, A. Loriot and T. Boon. Promoter-dependent mechanism leading to selective hypomethylation within the 5’ region
of gene MAGE-A1 in tumor cells. Mol. Cell. Biol. 24, 47814790, 2004.
u A. Decottignies. Capture of extranuclear DNA at fission yeast
double-strand breaks. Genetics 171, 1535-1548, 2005.
u A. Loriot, E. De Plaen, T. Boon and C. De Smet. Transient downregulation of DNMT1 methyltransferase leads to activation and
stable hypomethylation of MAGE-A1 in melanoma cells. J. Biol.
Chem. 281, 10118-10126, 2006.
u A. Decottignies. Microhomology-mediated end-joining in fission yeast is repressed by pku70 and relies on genes involved in
homologous recombination. Genetics 176, 1403-1415, 2007.
u G. Tilman, M. Mattiussi, F. Brasseur, N. Van Baren and A. Decottignies. Human periostin gene expression in normal tissues,
tumors and melanoma : evidences for periostin production by
both stromal and melanoma cells. Mol. Cancer 6, 80, 2007.
u A. Loriot, C. Sterpin, O. De Backer and C. De Smet. Mouse embryonic stem cells induce targeted DNA demethylation within
human MAGE-A1 transgenes. Epigenetics 3, 38-42, 2008.
u A. Loriot, S. Reister, G.K. Parvizi, P.A. Lysy and C. De Smet. DNA methylation-associated repression of cancer-germline genes in human
embryonic and adult stem cells . Stem Cells 27, 822-824, 2009.
u G. Tilman, A. Loriot, A. Van Beneden, N. Arnoult, J.A. Londono-Vallejo, C. De Smet and A. Decottignies. Subtelomeric DNA
hypomethylation is not required for telomeric sister chromatid
exchanges in A LT cells. Oncogene 28, 1682-1693, 2009.
u C.
2. Mechanisms of telomere maintenance
Telomeres are specialized protein-DNA structures, which prevent
chromosome ends from being recognized as DNA double-strand
breaks. Synthesis of telomeric DNA sequences in replicating cells
requires telomerase. Cancer cells often show an increased level
of telomerase, and this contributes to their unlimited proliferation potential. Certain tumor cells however lack telomerase,
and rely on an alternative mechanism (ALT) to maintain their
telomeres. We are comparing telomerase-positive and -negative
human cell lines to get more insight into the ALT mechanism
and to dissect the “non-canonical” functions of telomerase that
are not directly related to telomere repeat addition but modulate cellular gene expression. We are also interested in studying
the role of subtelomeric DNA methylation in the maintenance
of telomeres.
3. DNA hypomethylation and aberrant gene activation in cancer
DNA methylation is an essential mechanism of epigenetic regulation. It is associated with gene repression. Virtually all tumor
21
Funding
Key Words for R&D
Telomeres
Telomerase and alternative lengthening of telomeres
Genomic stability
Gene expression
DNA repair
DNA methylation
Stem cells
Cancer-germline genes
u Fonds
National de la Recherche Scientifique
u Fondation Contre le Cancer
u Région bruxelloise (Life Science Impulse)
Partnership
“Brubreast: Development of diagnostic and therapeutic tools
for the optimal managment of the individual breast cancer
patient” (Région de Bruxelles-Capitale); C. Sotiriou (IJB-ULB),
F. Fuks (Erasme-ULB), J. De Grève (UZ-VUB)
Senior Scientists
Anabelle DECOTTIGNIES
[email protected]
Tél. : 32(0)2 764 75 74
Charles DE SMET
[email protected]
Tél. : 32(0)2 764 75 23
Products and Services
u DNA
methylation analyses (sodium bisulfite sequencing and
MS-PCR)
u FISH and CO-FISH (detection of telomeric sister chromatid
exchanges) on telomeres
u Detection of telomerase activity in cell extracts by the TRAP
assay
u Extrachromosomal DSB repair assay in yeast
Web Site
http://www.afd-ld.org/~icp/genetic_ epigenetic.php
22
B 6
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Identification of genes involved in hypoxia-induced
metastasis, using statistical and bioinformatics analysis
of DNA array data, and confirmation of their differential
expression in in vitro et in vivo models
Senior scientists :
u Eric DEPIEREUX
u Carine MICHIELS
Research Field and Subjects
protection against etoposide-induced apoptosis: molecular profiling of changes in gene expression and transcription factor
activity. Mol Cancer 7, 27, 2008.
u F. Berger, B. De Hertogh, M. Pierre, A. Gaigneaux and E. Depiereux.
The “Window t-test”: a simple and powerful approach to detect
differentially expressed genes in micro-array datasets. Central
Eur J Biol 3, 327-344, 2008.
One of the major causes of death by cancer is metastasis. Determining mechanisms of production and development of metastases should thus improve diagnostic and therapy. However,
the cellular mechanisms to invade surrounding tissues, detach
from primary tumor, migrate and colonize distant organs are
very complex and regulated by different signalling pathways.
Hypoxia is a key feature of the tumor microenvironment that
greatly influence cancer cell metabolism and aggressiveness.
Moreover, changes in gene expression induced in hypoxia and
leading to a migratory and invasive phenotype of tumor cells
have been highlighted.
In order to define new regulatory pathways that influence
cell migratory and invasive phenotype and to find new genes
induced by hypoxia enabling cancer cells to metastasize, we are
re-analysing several DNA microarray datasets from the public
field, that are related to metastasis and/or hypoxia. Our methodology combines published well-known steps from classical
analysis with new approaches developed in our laboratory to
analyze several datasets at once. The existence of numerous
methods and of an evolving methodology, combined with the
observation of unstable results, offers an attractive challenge
made possible by the emergence of public databases such as
Gene Expression Omnibus (GEO) and ArrayExpress which collects millions of expression data. Datasets can be reanalysed
from scratch with new parameters (e.a. alternative CDFs) and
by combining several datasets relative to a same biological question in a same analysis. Data mining and gene ontology analysis will lead to the identification of candidate genes that may
be involved in regulating cancer cell metastasis under hypoxic
conditions. In vitro validation will be performed, first to confirm
differential expression and then to characterize their role in this
process.
Funding
TÉLÉVIE
Partnership
u BioXpr
u GSK
Main Equipment
u Cell
culture facilities, hypoxic chambers
equipment for biochemical and molecular biology
u General
assays
u Absorbance, fluorescence, luminescence microplate readers
u real-time PCR, equipped for microfluidic cards
u Full proteomic plateform with Maldi and MS-MS mass spectrometers
u Confocal microscope
u Computing cluster
Products and Services
u DNA
microarray data analysis
models for the evaluation of the capacity of drugs to
induce apoptosis and/or autophagy, to influence cell migration
u Proteomic plateform
Representative References
u Cellular
u C. Michiels. Physiological and pathological responses to
hypoxia. Am J Pathol 164, 1875-1882, 2004.
u A. Sermeus, J.P. Cosse, M. Crespin, V. Mainfroid, F. de Longueville,
N. Ninane, M. Raes, J. Remacle and C. Michiels. Hypoxia induces
23
Key Words for R&D
Hypoxia
Chemotherapy
Apoptosis
Microarray
Autophagy
Resistance
Signal transduction
Gene expression
Senior Scientists
Eric DEPIEREUX
[email protected]
Tél. : 32(0)81 72 44 15
Carine MICHIELS
[email protected]
Tél. : 32(0)81 72 41 31
Web Sites
http://www.fundp.ac.be/urbm/
http://www.fundp.ac.be/urbc/
24
B 7
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Mechanisms of p53-dependent apoptosis
Senior Scientist :
u Patrick
Research Field and Subjects
DUMONT
N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1Hbenzo[de]isoquinolin-5-yl}carbamoyl)acetamide (UNBS3157),
a novel nonhematotoxic naphthalimide derivative with potent
antitumor activity. J. Med. Chem. 50, 4122-4134, 2007.
u P. Dumont., L. Ingrassia, S. Rouzeau, F. Ribaucour, S. Thomas,
I. Roland, F. Darro and R. Kiss. The amaryllidaceae isocarbostyril
narciclasine induces apoptosis by activation of the death receptor and/or the mitochondrial pathways in cancer cells but not in
normal fibroblasts. Neoplasia. 9, 766-776, 2007.
u E.C. Pietsch, J. Leu., A. Frank, P. Dumont, D.L. George and
M.E. Murphy. The tetramerization domain of p53 is required
for efficient BAK oligomerization. Cancer Biol. & Ther. 6, 15731583, 2007.
u P. Demetter, N.Nagy, B. Martin, A. Mathieu., P. Dumont, C. Decaestecker and I. Salmon. The galectin family and digestive disease. J.
Pathol. 215, 1-12, 2008.
u P. Dumont, A. Berton, N. Nagy, F. Sandras, S. Tinton, P. Demetter,
F. Mascart, A. Allaoui, C. Decaestecker and I. Salmon. Expression
of galectin-3 in the tumor immune response in colonic cancer.
Lab. Invest. 88, 896-906, 2008.
The tumor suppressor p53 carries the distinction of being the
most frequently mutated gene in human cancer, with an overall mutation rate over 50%. As a transcription factor, p53 has
the ability to induce or repress the expression of a variety of
genes which products have respectively a pro-apoptotic (NOXA,
PUMA, KILLER, …) or a pro-survival (MDR1, SURVIVIN, ...) function. In addition to this well-known role of p53, we and others
have described that, upon apoptosis induction, a fraction of p53
translocates to the mitochondria where it exerts a pro-apoptotic
function by acting analogously to “activating” BH3-only proteins. Mitochondrial p53 is able to interact with BAK, to induce
its oligomerization at the outer mitochondrial membrane and
therefore can trigger the release of the mitochondrial effectors
of apoptosis, such as cytochrome c, from the intermembrane
space into the cytoplasm.
Our main aim is to decipher this pathway of p53-mediated
apoptosis. We are interested at determining what post-translational modifications of p53 are required for or influential to its
mitochondrial trafficking and pro-apoptotic activity at the mitochondria. We are also characterizing new interactions between
p53 and mitochondrial proteins and analyzing their role in this
pathway.
Awards
u The
2000-2001 René de Cooman Award (Belgium)
2002 Edward David Lustbader Award (USA)
u The 2003 FCCC Board of Associates Fellowship (USA)
u The 2004 Edward David Lustbader Award (USA)
u The
Representative References
u J.
Leu., P. Dumont., M. Hafey., M.E. Murphy and D.L. George.
Mitochondrial p53 activates BAK and causes disruption of a
Bak-Mcl1 complex. Nat. Cell Biol. 6, 443-450, 2004.
u X. Li, P. Dumont, A.C. Della Pietra, C. Shetler and M.E. Murphy.
The codon 47 polymorphism in p53 is functionally significant. J.
Biol. Chem. 280, 24245-24251, 2005.
u T. Mijatovic, V. Mathieu, J.F. Gaussin., E. Van Quaquebeke,
P. Dumont, F. Darro and R. Kiss. Cardenolide-induced lysosomal
membrane permeabilization demonstrates therapeutic benefits
in experimental human non-small cell lung cancers. Neoplasia.
8, 402-412, 2006.
u E. Van Quaquebeke E, T. Mahieu, P. Dumont, J. Dewelle, F. Ribaucour, G. Simon, S. Sauvage, J.F. Gaussin, J. Tuti, M. El Yazidi, F. Van
Vynckt, T. Mijatovic, F. Lefranc, F. darro and R. Kiss. 2,2,2-Trichloro-
Partnership
Collaboration with Professor M.E. Murphy, Fox Chase Cancer
Center, Philadelphia, USA
Main Equipment
Regular cellular and molecular biology
25
Products and Services
Key Words for R&D
Tumor suppressor genes
p53
Molecular and cellular biology
Mitochondria
Bcl-2 family members
Apoptosis
Post-translational modifications
u Establishment
of stable (inducible or not) cell lines (overexpression and knock-down)
u Generation of resistant cell lines
u In vitro and cell based models for characterizing the proapoptotic activity of molecules.
Senior Scientist
Patrick DUMONT
[email protected]
Tél. : 32(0)10 47 35 24
Web Site
http://www.uclouvain.be/en-270449.html
26
B 8
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Hyaluronan metabolism in cancer stem cells
Senior scientist :
u Bruno
Research Field and Subjects
FLAMION
Our ultimate goal is to understanding how cancer cells, especially CSC, command­eer their own HA metabolism and that of
stromal cells in order to grow, evade immune rejection, induce
angio­genesis and metastasize.
Hyaluronan or hyaluronic acid (HA) is a ubiquitous high MW
unbranched polymer that is prominent in vertebrate extracellular matrix during embryo­genesis, inflam­mation, and wound
healing, whenever there is rapid tissue turnover and repair,
but particularly in neoplasia. HA is intimately involved in the
cross-talk between cancers and the host peritumor stromal
response. The major receptor for HA, CD44, is expressed on
the surface of virtually all stem cells, including cancer stem
cells (CSC).
Representative References
Flamion, P. Boël, R.A. Kramp, J. Mertens-Strijthagen. Separate
regul­ation of hyaluronan in the kidney cortex and medulla. In :
Hyaluronan, Vol. 2, J.F. Kennedy, Ed., Woodhead Publishing Ltd,
Abington, Cambridge, UK, pp. 201-208, 2002.
u L. Jadin, X. Wu, H. Ding, G.I. Frost, C. Onclinx, B. Triggs-Raine,
B. Flamion. Skeletal and hematological anomalies in HYAL2 deficient mice: a second type of muco­polysaccharidosis IX? FASEB J,
22, 4316-4326, 2008.
u A.E. Declèves, N. Caron, V. Voisin, A. Legrand, N. Bouby, A. Kultti,
M. Tammi, B. Flamion. Sequential hyaluronan accum­ul­ation and
fragmentation in rat kidney ischemia-reperfusion injury. Kidney
Int 2009 (in press).
u C. Duterme, J. Mertens-Strijthagen, B. Flamion. Hyal2 controls
the pericellular coat and CD44-ERM connection. J Biol Chem
2009 (submitted).
u B. Andre, B. Flamion. The hyaluronan coat of breast cancer
stem cells in culture. IMPAKT Breast Cancer Conference, Brussels, 7-9 May 2009.
u B.
CSC can be identified in all tumors and in most cancer cell lines
through specific surface markers such as CD44, a2β1 integrins,
and β-catenin, or functional assays such as dye and drug efflux
via the membrane transporter ABCG2 (this assay defines a “side
population”). Targeting CSC has become one of the major goals
of anticancer chemotherapy.
We have recently shown that MCF7 and Du145 stem/progenitor cells isolated through a cloning technique display a thick
pericellular coat of HA which may help them evade immune
recognition, and prominent membrane protrusions or microvilli
which are involved in their motility.
Our lab has been involved in the study of HA metabolism in various tissues since 1997. We have cloned the first Hyal2 isoform
of the hyaluronidase family and have generated the first Hyal2
knockout mice. These mice display skeletal and haematological anomalies. We have recently shown that hyaluronidases, in
particular Hyal2, play a crucial role in controlling the pericellular
HA coat and CD44 function in various cell types.
Partnership
u Prof.
Armin Buschauer, Institute of Pharmacy, University of
Regensburg, Germany.
u Dr Greg Frost, Halozyme Inc., San Diego, CA, USA.
The aim of this oncology project is to examine the expression
and function of various actors of HA metabolism including
HA synthases, hyaluron­idases, CD44, and the pericellular HArich coat in CSC isolated from cancer cell cultures and human
tumors and to correlate these expressions to the ability of CSC
to generate tumors in nude mice and to respond to various
chemotherapies. The relationship between HA metabolism
and key membrane transporters such as ABCG2 will be examined.
Main Equipment
u Molecular and cellular biology equipment; single-cell realtime RT-PCR; video-microscopy (cooled CCD camera)
27
Products and services
Key Words for R&D
Hyaluronan
Hyaluronic acid
Hyaluronidase
CD44
Cell coat
Glycocalyx
Cancer stem cell
ABCG2
Hyaluronidase-1 and -2 knockout mice
Funding
Institutional funds (FUNDP)
Senior Scientist
Bruno FLAMION
[email protected]
Tél. : 32(0)81 72 43 32
Fax : 32(0)81 72 43 29
Web Site
http://www.fundp.ac.be/facultes/medecine/ recherche/centres/urphym/mmepp
28
B 9
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Role of intracellular calcium homeostasis in apoptosis
of cancer cells
Senior Scientists :
u Philippe GAILLY
u Nicolas TAJEDDINE
Research Field and Subjects
Partnership
Resistance to cytotoxic drugs is an important cause of treatment
failure in advanced cancer and is frequently due to an impairment of the mitochondrial pathway of apoptosis. Several evidences point out the role of calcium in the regulation of apoptosis. Indeed, it seems that calcium content in the endoplasmic
reticulum is a major determinant of sensitivity to apoptosis. The
aim of our studies is to understand the alterations in calcium
homeostasis leading to chemoresistance. More particularly, we
are interested in the role of a specific class of calcium/cationic
channels, so-called TRP, in the control of apoptotic cell death.
We hope that our results will permit to find novel targets and
compounds able to increase chemosensitivity in advanced cancers.
Service d’Urologie, Cliniques universitaires Saint-Luc, Bruxelles,
Belgium
Main Equipment
u Microspectrofluorimetry
for dynamic live cells measurements
u Patch-clamp
u Cell
culture
u Real-time RT PCR
Key Words for R&D
Apoptosis
Calcium
TRP
Endoplasmic reticulum
Mitochondria
Chemoresistance
Representative References
u D. Pigozzi, B. Tombal, T. Ducret, P. Vacher and P. Gailly. Role of
store-dependent influx of Ca2+ and efflux of K+ in apoptosis of
CHO cells. Cell Calcium 36(5), 421-430, 2004.
u N. Tajeddine, J.L. Gala, M. Louis, M. Van Schoor, B. Tombal and
P. Gailly. Tumor-associated antigen preferentially expressed antigen of melanoma (PRAME) induces caspase-independent cell
death in vitro and reduces tumorigenicity in vivo. Cancer Res.
65(16), 7348-7355, 2005.
u D. Pigozzi, T. Ducret, N. Tajeddine, J.L. Gala, B. Tombal and
P. Gailly. Calcium store contents control the expression of
TRPC1, TRPC3 and TRPV6 proteins in LNCaP prostate cancer cell
line. Cell Calcium 39(5), 401-415, 2006.
Senior Scientists
Philippe GAILLY
[email protected]
Tél. : 32(0)2 764 55 42
Nicolas TAJEDDINE
[email protected]
Tél. : 32(0)2 764 55 46
Web Site
http://rch.adre.ucl.ac.be/browse/list_fac/FYCL/ pending
Award
Prix Clément Perdieus et Cécile Petit, 2009
Funding
FNRS – TÉLÉVIE – Action concertée de recherche
29
30
B 10
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Hox transcription factors and cancer
Senior Scientist :
u René
Research Field and Subjects
REZSOHAZY
In the framework of collaborations with the clinic (Prof.
C. Sotiriou, Institut Jules Bordet, Bruxelles), we currently aim to
anchor our data into a better classification of Hox-gene associated cancers as well as into a deeper understanding of their
etiology. The other way around, previous collaborations (Prof.
G. Cornu and Prof. Ch. Verellen-Dumoulin, UCL) allowed us
identifying Hox mutations in patients with lymphoid malignancy
and to demonstrate they corresponded to mild loss-of-function
mutations.
Hox proteins are transcription factors playing crucial roles during
mammalian embryonic development. They contribute to pattern
the central nervous system, the axial skeleton and the limbs, they
control several organogenetic processes and they modulate differentiation pathways. Beside their normal developmental roles,
accumulating data provide evidence that misregulation or mutation of Hox genes is associated with cancerogenesis.
Our research objectives aim at understanding the mode of
action of Hox proteins: what are their functional domains, how
do they govern gene expression programs, what are their target
genes and what are the partner proteins they interact with.
Representative References
u S.
Remacle, L. Abbas, O. De Backer, N. Pacico, A. Gavalas, F. GofJ.J. Picard, and R. Rezsohazy. Loss-of-function but no gain-offunction caused by amino acid substitutions in the hexapeptide
of Hoxa1 in vivo. Mol. Cell. Biol., 24, 8567-8575, 2004.
u V. van Scherpenzeel Thim, S. Remacle, J. Picard, G. Cornu, F. Gofflot, R. Rezsohazy, and C. Verellen-Dumoulin. Mutation analysis
of the HOX paralogous 4-13 genes in children with acute lymphoid malignancies : identification of a novel germline mutation
of HOXD4 leading to a partial loss-of-function. Human Mutation, 25, 384-395, 2005.
u L. Massip, F. Ectors, P. Deprez, M. Maleki, C. Behets, B. Lengelé,
P. Delahaut, J. Picard, and R. Rezsohazy. Expression of Hoxa2 in
cells entering chondrogenesis impairs overall cartilage development. Differentiation, 75, 256-267, 2007.
u C. Matis, F. Oury, X. Lampe, F. Gofflot, J.J. Picard, F.M. Rijli, and
R. Rezsohazy. Identification of Lmo1 as part of a Hox dependent
regulatory network for hindbrain patterning. Dev. Dyn., 236,
2675-2684, 2007.
u X. Lampe, O.A. Samad, A. Guiguen, C. Matis, S. Remacle,
J.J. Picard, F.M. Rijli, and R. Rezsohazy. An ultraconserved Hox-Pbx
responsive element resides in the coding sequence of Hoxa2
and is active in rhombomere 4. Nucleic Acids Res., 36, 32143225, 2008.
u B. Lambert, J. Vandeputte, P.-M. Desmet, S. Remacle, B. Hallet, and
R. Rezsohazy. Pentapeptide insertion mutagenesis of the Hoxa1
protein: mapping of transcription activation and DNA binding
regulatory domains. Submitted, 2009.
flot,
Most of our investigations to date were connected to the developmental functions of Hox proteins. However, we accumulated
data on mutant Hox proteins, target genes and partner proteins, we currently transpose to unravel their involvement in
cancer biology.
For a first pilot study on the mode of action of a Hox protein,
we focused on Hoxa1. Hoxa1 has been shown to play a pivotal
role in certain breast tumors under the influence of autocrine
growth hormone.
We generated series of Hoxa1 mutants that have been screened
for loss or gain of activity. We consequently mapped functional
domains of the protein that are required for transcription activation, DNA binding specificity and interaction with cofactors. We
screened extensive libraries to look for proteins interacting with
Hoxa1 and identified tens of new Hox partners. We identified
and characterized target enhancers of Hoxa1 useful to assay
the activity of the protein, its cofactors and its mutant derivatives. We developed in vitro cell models to address the oncogenic potential of Hoxa1, of its mutant derivatives and of their
combined activity with cofactors. Finally, we generated genetically engineered mice which code for mutant Hoxa1 proteins
to study the impact of specific Hox mutations onto mammary
carcinogenesis. Other recombinant mouse lines are under development with collaborating research teams to develop new in
vivo models to dissect the oncogenic properties of Hox proteins.
31
Funding
Key Words for R&D
Hox
Pbx
Transcription factors
Interactors
Gene regulation
Recombinant mice
Breast cancer
u FNRS,
FRSM
u TÉLÉVIE
u Walloon region, WALEO II programme
Partnership
Senior Scientist
u Member
of the Institut des Sciences de la Vie, UCL, Belgium
u Belgian representative for a European COST action on “Hox
and TALE transcription factors in development and disease”
u Prof. F.M. Rijli, Friedrich Miesscher Institute, Basel, Switzerland
u Prof. M. Vidal, Harvard University, USA
u Prof. A. Noël, University of Liège, Belgium
u Prof. C. Sotiriou, Institut Jules Bordet, Free University of Brussels, Belgium
René REZSOHAZY
[email protected]
Tél. : 32(0)10 47 37 01
Web Site
http://www.uclouvain.be/en-31123.html
Main Equipment
u Cell
culture facilities
equipment for biochemical and molecular biology
u General
assays
u Animal house
Products and Services
u Expression vectors for constitutive or inducible expression of
Hox proteins and cofactors, and mutant versions thereof, for
animal cell models, yeast and bacteria
u Tagged variants of Hox proteins for detection or immunoprecipitation
u Cell lines and in vitro models for carcinogenesis
u Animal models for Hox gene mutations or Hox gene misregulation
32
C 1
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Semi-automatic delineation, non-rigid registration and
dose accumulation for adaptive treatment in radiotherapy
and proton therapy
Senior Scientists :
u Anne BOL
u Xavier GEETS
u Vincent GREGOIRE
u John LEE
u Benoit MACQ
u Vincent NICOLAS
Research Field and Subjects
its course in order to maintain its optimal balance between high
probability of tumor control and minimized adverse effects. Nonrigid registration plays an important part in this application as well.
The efficacy of radiotherapy and protontherapy treatments
relies on accurate localization and delineation of the tumor and
invaded nodes. As the treatment are typically fractionated over
several weeks, with daily dose deliveries, it is of prime importance to maintain this accuracy during the entire course of the
treatment, in order to adapt the dose according to the tumor
shrinkage and other morphological changes (such as weight
loss). In this context, our work has been focused on the development and clinical validation of image processing tools for
improving treatment planning.
All tools developed in the abovementioned projects are integrated in an open source platform called MedicalStudio. It aims
at providing the user with interactivity and advanced 2D/3D
visualization interfaces for medical image processing tasks.
MedicalStudio has been designed by B. Macq’s team and relies
on widely approved software libraries such as the Visualization
Toolkit (VTK) and the Insight Toolkit (ITK).
Representative References
The collaboration between the Center for Molecular Imaging
and Experimental Radiotherapy (V.Gregoire) and the Communications and Remote Sensing Laboratory (B. Macq) intertwines
both technical and medical environments, and has allowed fast
transfers from image processing theory to clinical practice.
u J. Orban De Xivry, G. Janssens, G. Bosmans, M. De Craene, A. Dekker,
J. Bussen, A. Van Baardwijk, D. De Ruysscher, B. Macq. Tumour delineation and cumulative dose computation in radiotherapy based
on deformable registration of respiratory correlated CT images of
lung cancer patients. Radiother Oncol. 85(2): 232-238, 2007.
u X. Geets, J.A. Lee, A. Bol, M. Lonneux, V. Gregoire. A gradientbased method for segmenting FDG-PET images: methodology and validation. European Journal of Nuclear Medicine and
Molecular Imaging, 34: 1427-1438, 2007.
u A. Parraga, A. Susin, J. Petterson, B. Macq, M. De Craene. 3D
Atlas Building in the Context of Head and Neck Radiotherapy
Based on Dense Deformation Fields. Computer Graphics and
Image Processing, 2007.
u X. Geets, M. Tomsej, J.A. Lee, T. Duprez, E. Coche, G. Cosnard,
M. Lonneux, V. Gregoire. Adaptive biological image-guided IMRT
with anatomic and functional imaging in pharyngo-laryngeal
tumors: impact on target volume delineation and dose distribution using helical tomotherapy. Radiother Oncol, 2007.
u P. Castadot, J.A. Lee, A. Parraga, X. Geets, B. Macq, V. Gregoire.
Comparison of 12 deformable registration strategies in adaptive
radiation therapy for the treatment of head and neck tumors.
Radiother Oncol, 89: 1-12, 2008.
u G. Janssens, J. Orban De Xivry, H.J.W. Aerts, G. Bosmans,
A. Dekker, B. Macq. Improving physical behavior in image registration, International Conference on Image Processing. 2008.
u J.A. Lee, X. Geets, V. Gregoire, A. Bol. Edge-preserving filtering
of images with low photon counts. IEEE Transactions on Pattern
Analysis and Machine Intelligence, 30(6): 1014-1027.
The collaboration currently targets three challenges: the automatic segmentation of tumors in PET images, the segmentation
of organs at risk in the head and neck region based on the
nonrigid registration of atlas images, and the development of
adaptive radiotherapyand dose accumulation along treatment
using inter-fraction non-rigid registration.
As to PET segmentation, the most prominent difficulty resides in
the low resolution of the images, which causes a large variability
in the results. In order to improve the delineation accuracy, specific image processings have been developed, such as denoising
and deblurring tools.
The purpose of atlases is twofold. They primarily speed up treatment planning, by automatically contouring some of the volume of interest, such as the organs at risk. Simultaneously, such
an auto-contouring helps reducing the inter-observer variability. Atlases in the head and neck region are challenging for the
registration tools they rely on, and raises many issues as to the
regularization of the deformation fields.
Adaptive radiotherapy attempts to answer two questions. How
can we estimate the cumulative dose deposit after each daily
treatment fraction and how can we adapt the treatment during
33
Patent
u Rigid
J. Marchand, V. Gregoire, O. Josse, D. Labar, (1999) European patent n° 99870172.6 “Methods for preparing perfluorinated [18F]radiolabelled itroimidazole derivatives for cellular hypoxia detection
and non-rigid registration tools
accumulation and treatment planning tools
u MedicalStudio, a 3D visualization platform with integrated
image processing tools
u PET tracers synthesis
Funding
Key Words for R&D
u Dose
Adaptive radiotherapy
Image segmentation
Image registration
Atlases
Dose accumulation.
u Walloon
Region : project PAINTER
u Fond pour la formation à la recherche dans l’industrie et
l’agriculture (FRIA)
u Fonds national de la recherche scientifique (FNRS)
u Fonds de la recherche scientifique médicale (FRSM)
u European Community
u Fonds Joseph Maisin
u Interuniversity Attraction Poles Programme of the Belgian
Federal Science Policy Office
Senior Scientists
Anne BOL
[email protected]
Tél. : 32(0)10 47 29 77
Xavier GEETS
[email protected]
Tél. : 32(0)2 764 47 57
Partnership
Beam Applications S.A., Louvain-la-Neuve, Belgium
u SIMILAR (European Network of Excellence)
u Maastro Clinic, Maastricht, The Netherlands
u Multitel asbl, Mons, Belgium
u Tomotherapy Inc. (Madison, WI, USA)
Vincent GREGOIRE
[email protected]
Tél. : 32(0)2 764 94 43
Main Equipment
Benoit MACQ
[email protected]
Tél. : 32(0)10 47 22 71
u Ion
John LEE
[email protected]
Tél. : 32(0)2 764 47 66
u Software :
MedicalStudio
devices: PET/CT scanner, animal PET, MRI systems,
4D-CT scanner
u Treatment systems: helical tomotherapylinear accelerators
with IMRT capabilities
u Imaging
Vincent NICOLAS
[email protected]
Tél. : 32(0)10 47 85 55
Web Sites
http://www.imre.ucl.ac.be
http://www.tele.ucl.ac.be
http://www.medicalstudio.org
Products and Services
u PET-based
automatic tumor segmentation
atlas-based segmentation
u Anatomical
34
C 2
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Functional magnetic resonance (NMR, EPR) spectroscopy
and imaging in tumors
Senior Scientists :
u Bernard GALLEZ
u Bénédicte JORDAN
Research Field and Subjects
u R.
Ansiaux, C. Baudelet, B.F. Jordan, N. Crokart, P. Martinive,
J. De Wever, V. Grégoire, O. Feron, and B. Gallez. Mechanism of
reoxygenation after anti-angiogenic therapy using SU5416 and
its importance for guiding combined anti-tumor therapy. Cancer Res. 66, 9698-9704, 2006.
u B.F. Jordan, N. Christian, N. Crokart, V. Grégoire, O. Feron and
B. Gallez. Thyroid status is a key modulator of tumor sensitivity to irradiation: Determination of the underlying metabolic
causes. Radiat. Res. 168, 428-432, 2007.
u G.O. Cron, N. Beghein, R. Ansiaux, P. Martinive, O. Feron, and
B. Gallez. 19F NMR in vivo spectroscopy reflects the effectiveness
of perfusion-enhancing vascular modifiers for improving gemcitabine chemotherapy. Magn. Reson. Med.59, 19-27, 2008.
u E. Vanea, N. Charlier, J. Dewever, M. Dinguizli, O. Feron, JF Baurain, And B. Gallez. Molecular EPR Imaging of Melanin in Melanomas: a proof-of-concept. NMR Biomed. 21, 296-300, 2008.
u B.F. Jordan, G.O. Cron, And B. Gallez. Rapid monitoring of
oxygenation by 19F magnetic resonance imaging : simultaneous
comparison with fluorescence quenching. Magn. Reson. Med.
61, 634-638, 2009.
The major theme of the research is to understand how the
tumor microenvironment influences the response to treatments.
Three main areas of research are involved:
1. Development of sensors for monitoring the oxygen in tissues
by EPR
Selection of paramagnetic materials possessing favourable features for oximetry. Microencapsulation of oxygen sensors in biocompatible films to improve their performance in vivo and their
biocompatibility.
2. Applications of MR (EPR and NMR) to characterize the microenvironment in tumors and modulate the response to anti-cancer treatments
Use of combination therapies against cancer (vasoactive
agents + radiotherapy / antiangiogenesis + radiotherapy / …)
to improve the response of tumors to treatments: characterisation of pO2, flow, oxygen consumption, permeability of vessels,
nitric oxide,… and correlation with the tumor growth.
Patents
3. Development of predictive biomarkers of tumor response to
a treatment
NMR spectroscopy in vivo, diffusion imaging, contrast agents
targeted to cell death,…
u G.
Powis, R.J. Gillies, A. Baker, B.F. Jordan, Method of preselecting for anti VEGF, anti-HIF-1 or anti-Thioredoxin Therapy, US
n° 20060104902
u B. Gallez, R. Ansiaux, Methods and compositions for the treatment of cancer, WO/2006/094539, PCT/EP2005/011145
Representative References
u B. Gallez, C. Baudelet, B.F. Jordan. Assessment of tumor oxygenation by EPR oximetry: Principles and applications. NMR
Biomed.17, 240-262, 2004.
u N. Crokart, K. Radermacher, B.F. Jordan, C. Baudelet, G.O. Cron,
V. Grégoire, N. Beghein, C. Bouzin, O. Feron, and B. Gallez. Tumor radiosensitization by anti-inflammatory drugs: evidence for a new mechanism involving the oxygen effect. Cancer Res. 65, 7911-7916, 2005.
u B.F. Jordan, M. Runquist, N. Raghunand, A. Baker, R. Williams,
L. Kirkpatrick, G. Powis, R.J. Gillies. Dynamic contrast-enhanced
and diffusion MRI show rapid and dramatic changes in tumor
microenvironment in response to inhibition of HIF-1alpha using
PX-478. Neoplasia 7, 475-485, 2005.
Awards
u B.
Gallez :
Prix 1995 de la Société Belge des Sciences Pharmaceutiques Prix 1998 des Alumni de la Fondation Universitaire (Section :
Sciences médicales, pharmaceutiques et vétérinaires)
Prix Paul Van de Velde 2000 (Nouveaux outils diagnostiques ou
thérapeutiques)
Young Investigator Award of the International EPR Society 2000
Prix Léopold et Marthe Delsaux-Champy 2004 (Prévention,
traitement ou physiopathologie de maladies cardiovasculaires
ou cancéreuses)
35
Products and Services
Prix du Concours ordinaire de la 5e section de l’Académie Royale
de Médecine de Belgique
Période 2005-2006
u B. Jordan :
Prix Ishango francophone 2003
u EPR:
in vitro (free radicals, spin trapping)
in vivo in small animals
u NMR imaging in small animals
u Oxygen measurements
u Flow measurements
u EPR
Funding
u NCI
Key Words for R&D
(National Cancer Institute, USA)
(FRSM, Télévie, IISN)
Angiogenesis
Biocompatibility
Biomarkers
Biomaterials
Cancer
Chemotherapy
EPR
Free radicals
Functional imaging
Imaging
MRI
NMR
Oxygen
Pharmacology
Radiotherapy
Spectroscopy
Spin trapping
Tumor
u FNRS
u PAI
u ARC
u Fondation
u Fonds
contre le Cancer
Joseph Maisin
u FSR
Partnership
u Pharmacotherapy
Unit (UCL)
Imaging and Experimental Radiotherapy Unit (UCL)
u Gynecology Unit (UCL)
u Experimental Surgery Unit (UCL)
u Organic and Medicinal Chemistry Unit (UCL)
u Dentistry and Stomatology Unit (UCL)
u Pharmaceutical Technology Unit (UCL)
u Vesalius Research Center, VIB-Vlaams
u Instituut voor Biotechnologie (KUL)
u NMR and Molecular Imaging (University of Mons)
u EPR Research Center (Dartmouth Medical School, USA) u Molecular
Senior Scientists
Bernard GALLEZ
[email protected]louvain.be
Tél. : 32(0)2 764 73 91
Bénédicte JORDAN
[email protected]
Tél. : 32(0)2 764 73 64
Main Equipment
u NMR
spectrometer and imaging 11.7 T for small animals
EPR spectrometers (9 GHz, X-Band) for in vitro experiments
u EPR spectrometer (1 GHz, L-Band) for in vivo experiments
u EPR imaging (1GHz and 9GHz)
u OxyLite (pO2 measurements by fluorescence quenching)
u OxyFlo (laser-doppler)
Web Site
u 2
www.uclouvain.be/rema
36
C 3
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Intuitive And Standardized Annotation
For Cancer Prevention And Diagnosis
Senior Scientists :
u Benoît MACQ
u Vincent NICOLAS
u Pierre-Yves SCHOBBENS
Research Field and Subjects
image visualization, 3D rendering, volumetric rendering, image
segmentation, DICOM conformance, etc.
Cancer detection and diagnosis are very complex tasks requiring
inter-domain data management. Image-based detection, as an
example, must deal with a lot of parameters such as morphology, texture or time evolution and can be enhanced by information retrieved from the patient record.
A lot of information is used by our tools and they also produce more information. Such an information management is
achieved by using ontologies. Each ontology describes a specific domain (for instance an ontology based on the BI-RADS
terminology describes the breast cancer domain) and allows us
to face the complexity of biomedical information and its heterogeneity. They are implemented with OWL (Web Ontology
Language) which is recommended by the W3C consortium.
OWL guarantees compatibility between different system and
offers more expressiveness than other languages. It can also be
accompanied with some rule language and query language.
There are a lot of people working on the acquisition and storage of these sparse information. We are working on intelligent
and intuitive presentation and interaction of these in medical
workstations for diagnostic.
One of our tests case is breast cancer detection and diagnosis,
a complex user activity including several specific tasks such as
image screening, lesion detection and description and reporting. Our research efforts undertake to design, implement and
evaluate a breast cancer oriented interactive system which integrates the functionalities of mammogram visualization, annotation, characterization, diagnosis and reporting. Owing to its
high naturalness and mainly to its convenience to satisfy the
annotation requirement, pen-based interaction with a graphic
tablet was chosen as the modality to interact with the system.
The usefulness requirement is ensured by the compliance of
the system with the BI-RADS, which is a quality assurance tool
for breast imaging and reporting, providing an approved and
standardized terminology for describing findings. The usability
requirement is ensured by the development method, combining
user-centered design process together with usability development methods.
Rule language permits the creation of rules used for reasoning about information and then inferring new facts. With these
new facts we can consider the possibility to guide and help the
practitioner during the diagnosis step.
Thanks to query language we can express queries to retrieve
information from the databank built by our tools or to update
it. Combining queries with reasoning provides more effective
results and performances for media (images, videos, texts, etc.)
storage and retrieval than the well known text based querying.
Representative References
u M. Gemo, A. Gouze, B. Debande, A. Grivegnee, B. Macq. A versatile knowledge-based clinical imaging annotation system for
breast cancer screening. The International Society for Optical
Engineering, 2007.
u M. Gemo, S. Kieffer, A. Gouze, L. Lawson, B. Macq, M. Niang,
P-Y. Schobbens, G. Mazy, B. Debande and S.M. Farsy. An intuitive
Annotation Toolbox for Open-source Imaging Diagnosis. In
Proc. IST Africa 2007.
u A. Gouze, S. Kieffer, C. Van Brussel, R. Moncarey, A. Grivegnee
and B. Macq. Interactive Breast Cancer Segmentation based on
Relevance Feedback: from User-Centered Design to Evaluation.
B. In Proc. SPIE Medical Imaging 2009, Orlando (FL), February
9-13, 2009.
Such an approach combining usefulness and naturalness allows
us to design and develop systems that help specialists doing
their tasks while avoiding them to lose time on gathering information. We are applying the same method on other domains
such as pulmonary nodule detection, radiotherapy planning,
etc.
The tools are implemented in a common software platform
called MedicalStudio. Its architecture allows creating generic
components which will be parameterized to create applications
for specific domains. Components currently implemented allow
37
Key Words for R&D
u S.
Kieffer, A. Gouze, R. Moncarey, C. Van Brussel, J-F. De WisF. Kayser and B. Macq. Towards Standardized Pen-Based
Annotation of Breast Cancer Findings. In Proc. HCI International
2009, San Diego (CA), July 19-24, 2009.
Prevention
Diagnostic
Mammography
Usability
Interaction
Segmentation
Ontology
Visualization
User-centered design
Semantics.
pelaere,
Funding
u Brussels
u Walloon
Region : project DIAMANT
Region : project VIGILE
Senior Scientists
Partnership
Benoît MACQ
[email protected]
Tél. : 32(0)10 47 22 71
u Cancer prevention department of Bordet Institute, Brussels,
Belgium
u Radiology department of St-Luc Hospital, Brussels, Belgium
u Radiology department of Mont-Godinne Hospital, Yvoir,
Belgium
Vincent NICOLAS
[email protected]
Tél. : 32(0)10 47 85 55
Pierre-Yves SCHOBBENS
[email protected]
Tél. : 32(0)81 72 49 90
Products and Services
u MedicalStudio : a visualization platform with integrated
image processing tools.
u Mamography image segmentation.
u Ontology based information knowledge
Web Sites http://www.tele.ucl.ac.be
http://www.fundp.ac.be/en/precise/
http://www.medicalstudio.org
38
C 4
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Impact of intra-operative MRI at 3 Tesla on the degree
of tumor resection and long-term survival rate in patients
with intracranial glioma, and development
of neuronavigation on intra-operative images
Senior Scientists :
u Christian RAFTOPOULOS
u Jose Geraldo VAZ
u Edward FOMEKONG
Research Field and Subjects
Main Equipment
Having used the intra-operative MRI suite at 3 Tesla for 3 years,
the aim of our research protocol is to determine its impact on
the rate of complete tumor removal, neurological outcome,
progression free survival and survival in glioma (all WHO grades)
operated patients. We will analyse these items with respect to
data published using other iMRI devices.
Furthermore, we intend to improve the iMRI suite at 3 Tesla
by adding the possibility to use the neuronavigation on the
intra-operative MR images. Currently, if a tumor residue is
observed on the iMRI, the neurosurgeon cannot benefit from
the computer guided neuronagivation to accurately and specifically remove the residue. The upgrading of the existing system
would allow precise and safe removal of the remnant through
the direct injection of iMRI images into the neuronagivation system and through the fusion of both pre-operative and intraoperative images.
u MRI scanner (Achieve 3T; Philips Medical Systems, Best, The
Netherlands)
u VectorVision neuronavigation system (BrainLAB, Munich,
Germany)
u Doro Radiolucent Headrest system with MRI-compatible disposable cranial pins (Pro Med Instruments GmbH, Freiburg, Germany)
Funding
Fond National de la Recherche Scientifique.
Representative references
u C.
Nimsky, O. Ganslandt, K.B. Von, J. Romstock, R. Fahlbusch.
Intraoperative high-field-strength MR imaging: implementation
and experience in 200 patients. Radiology 233:67-78, 2004.
u M.N Pamir, S. Peker, M.M. Ozek, A. Dincer. Intraoperative MR
imaging: preliminary results with 3 tesla MR system. Acta Neurochir Suppl 98:97-100, 2006.
u C.L. Truwit, W.A. Hall. Intraoperative magnetic resonance
imaging-guided neurosurgery at 3-T. Neurosurgery 58:ONS-45,
2006.
u A. Jankovski, F. Francotte, G. Vaz, E. Fomekong, T. Duprez, M. Van
Boven, M.A. Docquier, L. Hermoye, G. Cosnard, C. Raftopoulos.
Intraoperative magnetic resonance imaging at 3-T using a dual
independent operating room-magnetic resonance imaging
suite: development, feasibility, safety, and preliminary experience. Neurosurgery. 63(3):412-24; discussion 424-6, 2008.
u T.P. Duprez, A. Jankovski, C. Grandin, L. Hermoye, G. Cosnard,
C. Raftopoulos. Intraoperative 3T MR imaging for spinal cord
tumor resection: feasibility, timing, and image quality using
a “twin” MR-operating room suite. AJNR Am J Neuroradiol.
29(10):1991-4, 2008.
39
Key Words for R&D
Cerebral tumor
Glioblastoma
Glioma
Intra-operative MRI
MRI 3.0 Tesla
Neuropathology
Neuroradiology
Neurosurgery
Surgery
Surgical medicine
Senior Scientist
Christian RAFTOPOULOS
[email protected]
Tél. : 32(0)2 764 10 87
Web Site
http://www.saintluc.be/services/medicaux/
neurochirurgie/index.php
40
D 1
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Genetic analysis of T lymphocytes infitrating human
tumors
Senior Scientists :
u Pierre COULIE
u Pierre VAN DER
u Sophie LUCAS
BRUGGEN
Research Field and Subjects
Representative References
Vaccination of cancer patients with defined tumor antigens recognized by T lymphocytes, notably cytolytic T lymphocytes, is
followed by tumor regressions in 5-10% of the patients. Our
objective is to increase this proportion. Our immunological
analysis of vaccinated patients indicated that the main limiting
factor to clinical efficacy is not the immunogenicity of the vaccine, but rather a functional impairment of the tumor-specific
lymphocytes when they are localized within the tumors.
u N.
Van Baren, M.C. Bonnet, B. Dreno, A. Khammari, T. Dorval,
S. Piperno-Neumann, D. Lienard, D. Speiser, M. Marchand, V.G. Brichard, B. Escudier, S. Negrier, P.Y. Dietrich, D. Maraninchi, S. Osanto,
R.G. Meyer, G. Ritter, P. Moingeon, J. Tartaglia, P. Van Der Bruggen,
P.G. Coulie, T. Boon. Tumoral and immunologic response after
vaccination of melanoma patients with an ALVAC virus encoding MAGE antigens recognized by T cells. J. Clin. Oncol. 23,
9008-9021, 2005.
u C. Germeau, W. Ma, F. Schiavetti, C. Lurquin, E. Henry, N. Vigneron, F. Brasseur, B. Lethe, E. De Plaen, T. Velu, T. Boon, P.G. Coulie.
High frequency of anti-tumor T cells in the blood of melanoma
patients before and after vaccination with tumor antigens. J.
Exp. Med. 201, 241-248, 2005.
u T. Connerotte, A. Van Pel, D. Godelaine, E. Tartour, B. SchulerThurner, K. Thielemans, G. Schuler, P.G. Coulie. Functions of antiMAGE-T cells induced in melanoma patients under different
vaccination modalities. Cancer Res. 68, 3931-3940, 2008.
u N. Demotte, V. Stroobant, P.J. Courtoy, P. Van Der Smissen,
D. Colau, I.F. Luescher, C. Hivroz, J. Nicaise, J.L. Squifflet, M. Mourad, D. Godelaine, T. Boon, P. Van Der Bruggen. Restoring the association of the T cell receptor with CD8 reverses anergy in human
tumor-infiltrating lymphocytes. Immunity 28, 414-424, 2008.
There are numerous mechanisms of immunosuppression that
have been reported to play a role in the tumor microenvironment, most of them studied in animal models. We wish to
characterize T lymphocytes present within human tumors, to
explain their apparently pacific coexistence with tumor cells.
Our approach consists in a genetic analysis, carried out with
expression microarrays, of small numbers of T lymphocytes
microdissected from human tumors. We usually start from
about 100 cells laser-microdissected from frozen tumor sections. After extraction of RNA and conversion to cDNA, we use
a global cDNA amplification method to obtain enough material
for gene profiling with the Affymetrix technology.
We have compared the gene expression profiles of CD8 T lymphocytes infiltrating cutaneous melanoma metastases, where
they appear to be paralysed, to that of lymphocytes present in
rare primary melanomas showing histological signs of immune
attack. The results provide an unbiaised view of some functional
differences between these T lymphocytes present in the same
tissue, the skin, and at least for some of them recognizing the
same tumor antigens.
Patent
A portfolio of patents covering human tumor antigens recognized by T lymphocytes
41
Awards
Key Words for R&D
Melanoma
Vaccination
Immunotherapy
Expression profiling
u P.
Coulie : 1993 Annual Prize of the « Fondation Maggy &
Robert de Hovre »
u P. Coulie : 1998 Prize of the « Fondation Alexandre et Gaston
Tytgat »
u P. Coulie : 2007 « Mme Veuve Matthys-Bove » Prize
u P. Van Der Bruggen : 1995 Annual Prize of the Fondation
« Maggy et Robert de Hovre »
u P. Van Der Bruggen : 1998 Prize of the « Fondation Alexandre
et Gaston Tytgat »
u P. Van Der Bruggen : 2009 Allard-Janssen Prize
Senior Scientists
Pierre COULIE
[email protected]
Tél. : 32(0)2 764 75 81
Pierre VAN DER BRUGGEN
[email protected]
Tél. : 32(0)2 764 74 31
Funding
Sophie LUCAS
[email protected]
Tél. : 32(0)2 764 74 74
u Commission
Européenne (FP6),
Programme on Interuniversity Poles of Attraction (PAI)
u Région Wallonne (Pôle de compétitivité “Sciences du Vivant”)
u Fonds National de la Recherche Scientifique
u Fondation contre le Cancer, Brussels
u Belgian
Web Sites
http://www.deduveinstitute.be/human_tumor_ immunology.php
http://www.bru.licr.org/brussels/research/rtlf/ rtlf.html
Partnership
Brussels branch of the Ludwig Institute for Cancer Research Ltd.
42
D 2
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Therapeutic vaccination of cancer patients with tumor
specific antigens
Senior Scientists :
u Nicolas VAN BAREN
u Jean-François BAURAIN
u Thierry BOON
Research Field and Subjects
P. van der Bruggen, T. Boon, A.M. Eggermont, M. Marchand. Phase
1/2 study of subcutaneous and intradermal immunization with
a recombinant MAGE-3 protein in patients with detectable metastatic melanoma. International Journal of Cancer, 117 : 596604, 2005.
u N. van Baren, M.C. Bonnet, B. Dreno, A. Khammari, T. Dorval,
S. Piperno-Neumann, D. Lienard, D. Speiser, M. Marchand, V.G. Brichard, B. Escudier, S. Negrier, P.Y. Dietrich, D. Maraninch, S. Osanto,
R.G. Meyer, G. Ritter, P. Moingeon, J. Tartaglia, P. van der Bruggen,
P.G. Coulie, T. Boon. Tumoral and immunologic response after
vaccination of melanoma patients with an ALVAC virus encoding mage antigens recognized by T cells. Journal of Clinical
Oncology, 23 : 9008-21, 2005.
u J. Carrasco, A. Van Pel, B.Neyns, b. Lethé, f. Brasseur, N. Renkvist,
P. van der Bruggen, N. van Baren, R. Paulus, K. Thielemans, T. Boon,
D. Godelaine. Vaccination of a melanoma patient with mature
dendritic cells pulsed with MAGE-3 peptides triggers the activity
of nonvaccine anti-tumor cells. Journal of Immunology, 180 :
3585-93, 2008.
Tumor cells carry antigens such as MAGE antigens that are
absent from normal tissues, and that can be targeted by cytolytic
T lymphocytes (CTL). While it is possible to make such CTL recognize and kill autologous tumor cells in vitro, the precise way
to induce an effective CTL response against a MAGE antigen in
cancer patients is not known yet. In clinical vaccination trials,
patients with a MAGE expressing cancer, often melanoma, are
treated repeatedly with a MAGE vaccine. These trials have two
main objectives. First, the effectiveness of various vaccination
modalities can be assessed by following the clinical evolution of
the tumor, by analyzing whether a specific CTL response to the
vaccine antigen occurred, and by determining whether immunological and clinical responses are correlated. Secondly, T lymphocytes and tumor samples collected at different timepoints
during vaccination can be analyzed in detail, which improves
our understanding on what happens in the minority of patients
who experience regression of metastatic lesions upon vaccination, and which may explain why this does not happen in the
majority of patients, who have overall disease progression. It
seems that most tumors have acquired the capacity to resist
destruction by the immune system. This resistance is selected
during tumor progression in face of spontaneous T lymphocyte responses directed at tumor antigens. Our current work is
focused on the identification of tumor resistance mechanisms,
and on the development of counter-measures against this resistance which, associated with cancer vaccines in new clinical trials, will likely improve the anti-tumoral effects of the vaccines.
Patents
Many patents covering clinical applications of tumor-specific
antigens in cancer immunotherapy
Awards
Prize of the “Fondation Clément Perdieus et Cécile Petit, 2002”
Representative References
Funding
u M.
Marchand, C.J. Punt, S. Aamdal, B. Escudier, W.H. Kruit,
U. Keilholz, L. Hakansson, N. van Baren, Y. Humblet, P. Mulders,
M.F. Avril, A.M. Eggermont, C. Scheibenbogen, J. Uiters, J. Wanders,
M. Delire, T. Boon, G. Stoter. Immunisation of metastatic cancer
patients with MAGE-3 protein combined with adjuvant SBAS-2:
a clinical report. Eur J Cancer; 39 : 70-7 2003.
u W.H. KruiT, H.H. van Ojik, V.G. Brichard, B. Escudier, T. Dorval,
B. Dreno, P. Patel, N. van Baren, M.F. Avril, S. Piperno, A. Khammari,
M. Stas, G. Ritter, B. Lethe, D. Godelaine, F. Brasseur, Y. Zhang,
u Ludwig
Institute for Cancer Research
and TELEVIE
u EU-FP6 program
u Federation belge contre le cancer
u FNRS
43
Partnership
Key Words for R&D
Cancer treatment
Cancer vaccines
Cancerology
Cytolytic T lymphocytes
Immunology
Immunotherapy
Tumor antigens
Tumor resistance
Melanoma
Academic collaborations
u UCL,
Centre du Cancer, Brussels (J.P. Machiels)
Brussels (D. Lienard)
u VUB, Brussels (B. Neyns)
u kul, Leuven (M. Stas)
u CHU de Nantes (B. Dreno)
u University Erlangen (G. Schuler)
u ULB,
Senior Scientists
Industrial collaborations
Nicolas VAN BAREN
[email protected]
Tél. : 32(0)2 764 75 33
u GLAXOSMITHKLINE
u PROSPECT
BIOLOGICALS, Rixensart, Belgium
THERAPEUTICS, USA
Jean-François BAURAIN
[email protected]
Tél. : 32(0)2 764 54 71
International networks
u EORTC:
Melanoma Cooperative Group
(EU-FP6 PROJECT)
u THERAVAC (EU-FP6 PROJECT)
Thierry BOON
[email protected]
Tél. : 32(0)2 764 75 80
u Cancerimmunotherapy
Web site
Main Equipment
http://www.licr.ucl.ac.be/brussels/research/tvep/
tvep.htm
Zeiss Mirax Midi digital microscopy platform
44
D 3
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Mechanisms of tumor resistance to the immune system
and development of a mouse model of inducible melanoma
Senior Scientists :
u Benoît VAN DEN EYNDE
u Catherine UYTTENHOVE
u Didier COLAU
u Vincent STROOBANT
Research Field and Subjects
Representative References
Crucial to the success of cancer immunotherapy is a precise
understanding of the interplay between growing tumors and
the anti-tumor immune response. For example, tumors may
develop a variety of mechanisms to escape immune attack. In
that context, we have observed that a majority of tumor cells
express an enzyme called indoleamine 2,3-dioxygenase (IDO),
which rapidly degrades tryptophan, an essential amino acid
whose supply is mandatory for the activity of T lymphocytes.
Thus, by locally degrading tryptophan, tumor cells completely
inactivate T lymphocytes and thereby blunt the anti-tumor
immune response. We have also shown that this resistance
mechanism can be blocked by treating animals with 1-methyltryptophan, an inhibitor of IDO. These results suggest that
the efficacy of cancer immunotherapy could be improved by
combining immunization strategies with a treatment aimed at
inhibiting IDO. We are trying to develop novel inhibitors of IDO
for that purpose. We are also studying other mechanisms of
tumoral immune resistance.
In order to obtain meaningful information from mouse studies
with melanoma, we have also developed a new model of mice
that develop melanomas upon local application of tamoxifen.
The induction of melanomas is based on Cre-lox recombination and involves conditional activation of oncogene Ras and
inactivation tumor-suppressor gene INK4A. Tumors developing
slowly within a normal tissue are likely to represent the status
of human cancers much more closely than the transplanted
tumors currently used. Such a model will be particularly useful to optimize strategies of cancer immunotherapy, but will
undoubtedly be also of great interest in other contexts, such
as the molecular definition of the successive steps involved in
carcinogenesis, local invasiveness and metastasis.
u C.
Uyttenhove, L. Pilotte, I. Theate, V. Stroobant, D. Colau, N. ParT. Boon and B.J. Van Den Eynde. Evidence for a tumoral
immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Medicine 9, 12691274, 2003.
u I.J. Huijbers, P. Krimpenfort, P. Chomez, M.A. Van Der Valk,
J.Y. Song, E.M. Inderberg-Suso, A.-M. Schmitt-Verhulst, A. Berns
and B.J. Van Den Eynde. An inducible mouse model of melanoma
expressing a defined tumor antigen. Cancer Research 66, 32783286, 2006.
mentier,
Patents
A large portfolio of about 80 issued patents and patent applications on tumor antigens and their use for cancer therapy.
Awards
u 1998 : Prize of the « Fondation Clément Perdieus et Cécile
Petit »
u 1998 : Annual Prize of the « Fondation Maggy et Robert de
Hovre »
u 1998 : Prize of the « Fondation Alexandre et Gaston Tytgat »
u 2001 : Prize of the 165th anniversary of the « Académie
Royale de Médecine de Belgique »
u 2005 : Francqui Chair at the Université Libre de Bruxelles
u 2007 : GlaxoSmithKline Prize
45
Funding
Key Words for R&D
Biochemistry
Cancer vaccines
Cancerology
IDO inhibitors
Immune escape
Immunology
Immunotherapy
Inducible melanoma model
Tumor antigens
u Ludwig
Institute for Cancer Research Ltd
u Commission Européenne (FP6)
u Région Wallonne (Programme d’Excellence “Marshall”, “Pôle
de compétitivité “Sciences du Vivant”)
u Fonds National de la Recherche Scientifique
u Fondation contre le Cancer, Brussels
u UCL, Mandats FSR
Senior Scientists
Partnership
Benoît VAN DEN EYNDE
[email protected]
Tél. : 32(0)2 764 75 72
u Macromol Biologique, Centre d’Ingénierie des Protéines, Université de Liège
u Laboratoire de Chimie Biologique Structurale, Faculté Universitaires Notre-Dame de la Paix, Namur
u Laboratoire de Physiologie Animale, Institut de Biologie et de
Médecine Moléculaires (IBMM), ULB
u Centre d’Immunologie INSERM-CNRS de Marseille-Luminy,
Marseille France
u DKFZ - Deutsches Krebsforschungszentrum (German Cancer
Research Center), Heidelberg, Germany
u Ludwig Institute for Cancer Research Ltd, Lausanne branch,
Switzerland
Catherine UYTTENHOVE
[email protected]
Tél. : 32(0)2 764 74 18
Vincent STROOBANT
[email protected]
Tél. : 32(0)2 764 74 69
Didier COLAU
[email protected]
Tél. : 32(0)2 764 74 21
Web Site
Main Equipment
http://www.licr.ucl.ac.be/brussels/research/tiap/
tiap.html
Laser-assisted microdissection and laser pressure catapulting
(P.A.L.M.®, Microlaser Technologies AG, Benried, Germany)
Products and Services
u Screening
u New
assay for the development of new IDO inhibitors
mouse model of inducible melanomas
46
D 4
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Intracellular processing of tumor antigens recognized
by cytolytic T lymphocytes : role of the proteasome
and other cytosolic proteases
Senior Scientists :
u Benoît VAN DEN EYNDE
u Vincent STROOBANT
Research Field and Subjects
teasome results in differential antigen presentation. Journal of
Immunology, 2006.
u L. Chapatte, M. Ayyoub, S. Morel, A.L. Peitrequin, N. Levy,
C. Servis, B.J. Van Den Eynde, D. Valmori and F. Levy. Processing
of tumor-associated antigen by the proteasomes of dendritic
cells controls in vivo T-cell responses. Cancer Research 66, 54615468, 2006.
u E. H. Warren, N.J. Vigneron, M.A. Gavin, P.G. Coulie, V. Stroobant, A. Dalet, S.S. Tykodi, S.M. Xuereb, J.K. Mito, S.R. Riddell and
B.J. Van Den Eynde. An antigen produced by splicing of noncontiguous peptides in the reverse order. Science 313, 1444-1447,
2006.
Tumor antigens recognized by Cytolytic T Lymphocytes (CTL)
consist of peptides that are presented by MHC molecules at
the cell surface and derive from intracellular proteins that are
degraded by the proteasome. The intracellular pathway leading from the protein to the peptide/MHC complex is known as
“antigen processing”. Our group focuses on the proteasome
and recently described a new mode of production of antigenic
peptides by the proteasome, based on cutting and pasting peptide fragments to form a new spliced peptide. The first example
was a peptide derived from human melanocyte protein gp100.
This antigenic peptide is nine-amino acid long and is produced
by the splicing of two fragments that were initially non-contiguous in the parental protein. The splicing is made by the proteasome, is tightly coupled to the proteolytic reaction, and appears
to occur by transpeptidation involving an acyl-enzyme intermediate. We further described a second example of spliced peptide, where the two fragments are rearranged before splicing.
Patents
A large portfolio of about 80 issued patents and patent applications on tumor antigens.
Awards
We also study the processing differences between the standard
proteasome, which is present in most cells, and the immunoproteasome which is found in dendritic cells and in cells exposed
to interferon-gamma. Several tumor antigens were found to
be processed differently by the two proteasome types, usually
because of a preferential cleavage made by one or the other
proteasome within the antigenic peptide itself. We are currently
working on the characterization of proteasome types that are
intermediate between the standard proteasome and the immunoproteasome.
u 1998 : Prize of the « Fondation Clément Perdieus et Cécile
Petit »
u 1998 : Annual Prize of the « Fondation Maggy et Robert de
Hovre »
u 1998 : Prize of the « Fondation Alexandre et Gaston Tytgat »
u 2001 : Prize of the 165th anniversary of the « Académie
Royale de Médecine de Belgique »
u 2005 : Francqui Chair at the Université Libre de Bruxelles
u 2007 : GlaxoSmithKline Prize
Representative References
Funding
u N.J.
Vigneron, V. Stroobant, J. Chapiro, A. Ooms, G. Degiovanni,
S. Morel, P. Van Der Bruggen, T. Boon and B.J. Van Den Eynde. An
antigenic peptide produced by peptide splicing in the proteasome. Science 304, 587-590, 2004.
u J. Chapiro, S. Claverol, F. Piette, W. Ma, V. Stroobant, B. Guillaume, J.E. Gairin, S. Morel, O. Burlet-Schiltz, B. Monsarrat, T. Boon
and B.J. Van Den Eynde. Destructive cleavage of antigenic peptides either by the immunoproteasome or by the standard pro-
u Ludwig
Institute for Cancer Research Ltd
Européenne (FP6)
u Région Wallonne (Programme d’Excellence “Marshall”, “Pôle
de compétitivité Sciences du Vivant”)
u Fonds National de la Recherche Scientifique,
u Fondation contre le Cancer, Brussels
u UCL, Mandats FSR
u Commission
47
Partnership
Key Words for R&D
Antigen processing
Biochemistry
Cancer vaccines
Immunology
Immunotherapy
Proteasome
Tumor antigens
u Fred
Hutchinson Cancer Institute, Seattle, WA, USA
u Surgery Branch, National Cancer Institute, National Institutes
of Health, Bethesda, MD, USA
u Department of Immunobiology, Yale University, School of
Medicine, New Haven, LT, USA
Senior Scientists
Main Equipment
Benoît VAN DEN EYNDE
[email protected]
Tél. : 32(0)2 764 75 72
Mass spectrometry
Vincent STROOBANT
[email protected]
Tél. : 32(0)2 764 74 69
Products and Services
u Mass
spectrometry
purification
u Proteasome
Web Site
http://www.licr.ucl.ac.be/brussels/research/tiap/
tiap.html
48
D 5
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Regulation of T lymphocyte function in tumors
Senior Scientists :
u Pierre VAN DER BRUGGEN
u Didier COLAU
u Nathalie DEMOTTE
u Danièle GODELAINE
Research Field and Subjects
non-responding patients is not the intensity of their direct T cell
response to the vaccine but the intensity of the immunosuppression inside the tumor. It is therefore important to know which
immunosuppressive mechanisms operate in human tumors.
We have recently discovered a new type of anergy of human
CD8 T cells, which is observed on tumor-infiltrating lymphocytes.
We are analyzing the mechanism of this type of anergy and we
study agents that reverse this anergy. The analysis of the T cell
responses of melanoma patients vaccinated against tumor antigens has led us to consider the possibility that the limiting factor
for therapeutic success is not the intensity of the anti-vaccine
response but the degree of anergy presented by intratumoral
lymphocytes. We therefore intend to pursue clinical trials involving the use of these agents in combination with anti-tumoral
vaccination.
A new mechanism causing anergy of human tumor-infiltrating lymphocytes
We observed that, a few days after antigen stimulation, CTL
clones lose the capacity to secrete cytokines and in some case
the cytolytic activity. These functions are recovered gradually
and are usually completely restored after two weeks. TCRs and
CD8 co-receptors were co-localized at the cell surface of functional CTL but, on the contrary, distant at the cell surface of
non-functional CTL.
A scenario to explain the low level of clinical responses in
vaccinated patients
u Human CD8 tumor-infiltrating T lymphocytes were isolated
from tumor ascites or solid tumors and compared with T lymphocytes from blood donors. TCR were observed to be distant
from CD8 on the cell surface of tumor-infiltrating lymphocytes,
whereas TCR and CD8 co-localized on blood T lymphocytes.
The tumor-infiltrating lymphocytes were anergic, being unable
to secrete INF-g or other cytokines after non-specific stimulation
with anti-CD3 and anti-CD28 antibodies.
The identification of specific tumor antigens recognized by T
lymphocytes on human cancer cells has elicited numerous clinical trials involving vaccination of tumor-bearing cancer patients
with defined tumor antigens. These treatments have shown
a low clinical efficacy. Among metastatic melanoma patients,
about 5% show a complete or partial clinical response following vaccination, whereas an additional 10% show some evidence of tumor regression without clear clinical benefit.
Glycoprotein-galectin lattices restrain mobility of TCR
u Recent
analyses of the T cell responses of melanoma patients
has led us to consider the following scenario. Most melanoma
patients produce a spontaneous T cell response against melanoma tumor antigens at a relatively early stage of the disease
(primary tumor or early metastatic tumor). These T cells can eliminate some tumors at an early stage, but often they do not succeed in eliminating the tumor and they become anergic. Thus,
the tumors of the patients about to receive the vaccine, already
contain anergic T cells directed against tumor antigens. Presumably this anergy is maintained by immunosuppressive factors
present in the tumor. A few patients show tumor regression following vaccination because some T cells generated by the vaccine
penetrate inside the tumor, attack some tumor cells and succeed
in reversing the local immunosuppression, possibly by releasing
cytokines or chemokines. Accordingly, our working hypothesis
is that the crucial difference between the responding and the
On the basis of the work of other groups, we hypothesized that
the absence of TCR-CD8 co-localization at the cell surface of
anergic T cells is due to the loss of mobility of the TCR, which is
trapped in a lattice of galectin-3. The presence of galectin-3 in
ascites and solid tumors has been shown in many studies. To test
this hypothesis, tumor-infiltrating lymphocytes were incubated
with N-acetyllactosamine, a disaccharide ligand of galectin-3.
This treatment restored the TCR-CD8 co-localization and the
capacity to secrete IFN- g and other cytokines after stimulation.
Towards a clinical trial combining vaccination and galectin-binding polysaccharides
These observations indicate that ex vivo human tumor-infiltrating
lymphocytes can recover their effector functions with galectin lig-
49
Partnership
ands and suggest that treatment of cancer patients with galectin
ligands could correct the anergy of tumor-infiltrating lymphocytes.
It is possible that peptide vaccination combined with local injection of a galectin ligand will be more effective at producing tumor
regression than vaccination alone. We have recently identified a
polysaccharide already approved for clinical use that was more
efficient than N-acetyllactosamine to correct the anergy of CTL
clones and human tumor-infiltrating lymphocytes. We therefore
intend to launch a clinical trial combining peptide vaccination
and injections of galectin-binding polysaccharides in melanoma
tumor-bearing metastatic patients.
u UCL,
Brussels, Belgium (P.J. Courtoy)
Brussels, Belgium (K. Thielemans)
u Cliniques Universitaires Saint-Luc, Brussels, Belgium (B. Weynand, E. Marbaix, J.-L. Squifflet, J. Donnez, J.-F. Baurain, J.-P. Machiels)
u Hôpital Cochin, Paris, France (A. Trautman)
u Prospect Therapeutics, Woburn, MA, USA (F. Tao)
u VUB,
Products and Services
Construction of fluorescent MHC-peptide tetramers
Representative References
Key Words for R&D
u T.
Boon, P.G. Coulie, B. Van Den Eynde and P. Van Der Bruggen.
Human T cell responses against melanoma. Annu. Rev. Immunol. 24, 175-208, 2006.
u N. Demotte, V. Stroobant, P.J. Courtoy, P. Van Der Smissen, D. Colau,
I.F. Luescher, C. Hivroz, J. Nicaise, J.-L. Squifflet, M. Mourad, D. Godelaine, T. Boon and P. Van Der bruggen. Restoring the association of
the T cell receptor with CD8 reverses anergy in human tumorinfiltrating lymphocytes. Immunity 28, 414-424, 2008.
Tumor
Immunology
Vaccine
Anergy
Glycobiology
Galectin-3
CTL
Lymphocyte
Melanoma
Ovarian carcinoma
Patents
Senior Scientists
Pierre VAN DER BRUGGEN
[email protected]
Tél. : 32(0)2 764 74 31
About 70 patents.
Didier COLAU
[email protected]
Tél. : 32(0)2 764 74 21
Awards
u Prix
Maggy et Robert de Hovre, October 1995
Alexandre et Gaston Tytgat, 1998
u Prix Allard-Janssen, 2009
u Prix
Nathalie DEMOTTE
[email protected]
Tél. : 32(0)2 764 74 34
Funding
Danièle GODELAINE
[email protected]
Tél. : 32(0)2 764 74 82
u Ludwig
Institute for Cancer Research
contre le cancer
u F.R.S.-FNRS
u European Grants (COCHISE, CANCERIMMUNOTHERAPY)
u Fondation
Web Site
www.bru.licr.org/brussels/research/rtlf/rtlf.html
50
E 1
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Gene profiling, prognosis and diagnosis
Senior Scientist :
u Pierre
Research Field and Subjects
DUPONT
A genetic signature for a given pathology, or a biological condition, is a set of genes on which a model can be built. A genetic
signature can be associated with a diagnosis model, when the
objective is to assess whether such a genetic profile is typical of a
certain cancer type or stage. Alternatively, a gene signature can
be predictive of the positive reaction of a patient to a treatment.
1. Gene Profiling for Prognosis or Prediction in Clinical
Studies
In the context of clinical studies, gene profiling aims at identifying gene signatures on which patients can be classified. Based
on such genetic biomarkers, prognosis models aim at predicting
the future status of a patient while predictive models aim at
predicting the outcome of a treatment.
The large difference between the number of genes measured
and the number of available samples with high throughput
technologies makes analysis prone to a lack of robustness. Our
research focus on advanced statistical analysis and mathematical optimization techniques to address those issues.
Gene profiling is, from a computational viewpoint, a feature
selection problem. We develop novel machine learning techniques to tackle this problem. Our methods include multivariate statistical analysis to monitor the joined influence of several
genes rather than looking at them individually. A multivariate
selection is more complex to implement but also more relevant
from a biological viewpoint.
With our partners, we pay special attention to the biological
interpretation of the extracted signature. If a signature is robust
and has a high predictive power, it can be considered as probably highly informative about the evaluated conditions and the
underlying processes. Such robust signatures then form strong
clues to guide further research on cancer mechanisms.
Applying prognosis models from gene profiles is part of an effort
towards a personalized medicine, to better assess the best treatment for each patient. It can also reduces the associated costs
and time of large clinical studies. Counseling our partners in
the biological and pharmaceutical fields about sound statistical
evaluation protocols and predictive quality metrics is also part of
our expertise. The type of data on which such profiling can be
performed include microarray data, Single Nucleotide Polymorphism data, Copy Number Variation data, etc. Our work also
covers the rigorous assessment of several signatures, proposed
by external partners, both in terms of predictive power and
robustness with respect to the set of patients used as reference.
We also develop dedicated machine learning techniques to
make use of prior biological knowledge in the form of candidate genetic biomarkers. Those candidate markers guide the
final gene signature identification. Such techniques offer an
independent validation methodology to confront predicted
markers with actual expression data.
Representative References
u T. Helleputte, P. Dupont. A Comparative Study of Normalization
and Feature Selection Techniques for Breast Cancer Prognosis
from Gene Expression. In: Benelux Bioinformatics Conference
(BBC), KUL, Leuven, Belgium, November 12-13, 2007.
u J. Louahed, S. Gaulis, T. Helleputte, P. Dupont, O. Gruselle, A. Spatz,
W. Kruit, B. Dreno, F. Lehmann, V. Brichard, Clinical response to the
MAGE-3 immunotherapeutic in metastatic melanoma patients
is associated with a specific gene profile present prior to treatment. In: 33th European Society for Medical Oncology (ESMO)
Congress, Stockholm, Sweden, September 12-16, 2008.
u T. Helleputte, P. Dupont. Feature Selection by Transfer Learning with Linear Regularized Models. European Conference on
2. Robust Gene Signature Identification for Cancer Modeling
Understanding mechanisms regulating cancer generally implies
the analysis of genomic processes such as gene-gene, gene-protein or protein-protein interactions. High throughput technologies such as microarray data, Single Nucleotide Polymorphism
data or Copy Number Variation data allow the measurement of
tens of thousand genes in a single experiment. Such wide spectrum technologies are efficient but they also raise the difficulty
of identifying only a few genes which are really implied in the
process under study. The cost of those experiments also limits
their reproducibility.
51
Machine Learning (ECML), Bled, Slovenia, September 7-11,
2009.
u T. Helleputte, P. Dupont. Partially Supervised Feature Selection
with Regularized Linear Models. 26th International Conference
on Machine Learning (ICML), Montreal, Canada, June 14-18,
2009.
Products and Services
Patents
Key Words for R&D
u Genomic
Data Analysis
Profiling/Biomarker Identification
u Experimental Protocol Assessment
u Pro/Diagnosis Models Estimation & Evaluation
u Gene
Gene Profiling
Biomarkers
Prognosis
Diagnosis
Microarray Data
Feature Selection
High Throughput Technologies
Clinical Studies
UK and US Patents Pending
Funding
u Walloon
Region (Biowin)
pour la formation à la Recherche dans l’Industrie et
dans l’Agriculture (FRIA)
u GSK Biologicals
u Fonds
Senior Scientist
Pierre DUPONT
[email protected]
Tél. : 32(0)10 47 91 14
Partnership
Web Sites
u Christian
de Duve Institute for Cellular Pathology (ICP)
- Département de gynécologie, d’ob­sté­
trique et de pédiatrie
u UCL Laboratory for Applied Molecular Technologies (LTMA)
u UCL MD/MED/MINT/RUMA - Unité de rhumatologie et de
métabolisme phosphocalcique
u Bioinformatics group of the Department of Plant Systems Biology, Ghent University
u GlaxoSmithKline Biologicals
http://www.info.ucl.ac.be/~pdupont/
http://www.ucl.ac.be/mlg/
u UCL/MD/MED/GYPE
Main Equipment
Center for Intensive Computing and Mass Storage (CISM) Computing Grids
52
E 2
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Study of the seric and serological proteomes of cancer
patients to identify and validate predictive / prognostic /
monitoring biomarkers
Senior Scientists :
u Olivier FERON
u Florence DEFRESNE
Research Field and Subjects
kills hypoxic tumor cells in mice. J Clin Invest.118(12):3930-42,
2008.
u F. Defresne, C. Bouzin, C. Guilbaud, M. Dieu, E. Delaive, C. Michiels,
M. Raes, O. Feron. Identification by multiplex serological proteome analysis of GRP78 auto-antibody as biomarker of tumor
progression and response to treatment. Proteomics, 2009.
The goal of the cancer biomarker field is to develop simple,
non-invasive tests that indicate cancer risk, allow early cancer
detection, classify tumors so that the patient can receive the
most appropriate therapy and monitor diseases progression,
regression and recurrence. In addition, biomarkers can be used
to assess response to therapy.
The ease with which the blood can be sampled makes it a logical choice for biomarker applications. Among the blood components that provide an indication of cancer status or response
to anticancer treatments, we focus our attention on serum
auto-antibodies (directed against tumor-associated antigens),
peptides associated with plasma macro-proteins and circulating
tumor/progenitor cells. We use a variety of techniques including 2D-DIGE and SERPA (serological proteome analysis) to identify and validate biomarkers from plasma and serum of cancer
patients or mice bearing human tumor xenografts. Correlations with circulating or micro-dialysed end-products of tumor
metabolism (including nitrites and lactate) are also evaluated.
Current studies are dedicated to colon, liver, breast and bladder
carcinoma.
Awards
u Prize
Belgian Soc Pharm Sci (1997)
u Prize Galien (1999)
u Prize Eugène De Somer (2008)
Funding
u FNRS,
FRSM, TELEVIE
u Fondations Maisin & St luc
u Fondation belge contre le cancer
u Communauté française : ARC
u Private companies
Representative References
Partnership
u E.
u Cliniques
Sbaa, J. Dewever, P. Martinive, C. Bouzin, F. Frérart, J.L. BalligC. Dessy, O. Feron. Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1-driven
postischemic vasculogenesis. Circ Res.98(9):1219-27, 2006.
u C. Bouzin, O. Feron. Targeting tumor stroma and exploiting
mature tumor vasculature to improve anti-cancer drug delivery.
Drug Resist Updat.10(3):109-20, 2007.
u F. Frérart, P. Sonveaux, G. Rath, A. Smoos, A. Meqor, N. Charlier,
B.F. Jordan, J. Saliez, A. Noël, C. Dessy, B. Gallez, O. Feron. The
acidic tumor microenvironment promotes the reconversion of
nitrite into nitric oxide: towards a new and safe radiosensitizing
strategy. Clin Cancer Res.14(9):2768-74, 2008.
u P. Sonveaux, F. Végran, T. Schroeder, M.C. Wergin, J. Verrax,
Z.N. Rabbani, C.J. De Saedeleer, K.M. Kennedy, C. Diepart, B.F. Jordan, M.J. Kelley, B. Gallez, M.L. Wahl, M.W. Dewhirs*, O. Feron*
(*co-last author). Targeting lactate-fueled respiration selectively
Saint-Luc (Drs C. Chantrain, J-P. Machiels, V. Grégoire,
Y. Horsmans)
u AZ VUB (Drs M De Ridder, S Sermeus)
u Prof. Martine Raes, URBC, FUNDP, Namur
and,
Main Equipment
u Ettan
IpgPhor III (GE) [1st dim-electroph]
DALT6 (GE) [2nd dim-electroph]
u TE77 transfer units GE)
u Ettan DIGE Imager (GE)
u Decyder analysis software (GE)
u SE600 large gels electrophoresis unit (GE)
u SG100 gradient maker (GE)
u Ettan Spot Picker (GE)
u Ettan
53
Key Words for R&D
u Home-made
ELISA kit development
reader & injectors (Victor 5, PE)
u Microscale liquid chromatography
u Access to Mass Spectrometry for protein identification
u The above proteomic platform is completed with various preclinical imaging technologies (in vivo bioluminescence detection,
laser Doppler, intravital microscopy set-up) and high-standard
molecular biology/biochemistry and cell biology equipments.
Proteomic
2D-DIGE
Auto-antibody
Tumor-associated antigens
Biomarker
Prognostic
Predictive
Treatment monitoring
u Microplate
Senior Scientists
Products and Services
Olivier FERON
[email protected]
Tél. : 32(0)2 764 52 64 (dir)
Tél. : 32(0)2 764 52 60 (secr)
u Biomarker detection and validation from plasma and serum of
cancer patients and mice bearing human tumor xenografts
u Original auto-antibodies as prognostic, predictive or monitoring cancer biomarkers
u 2D-DIGE experiments to identify differential expression of
proteins, post-translational modifications (PTM) or protein-protein interactions
Florence DEFRESNE
[email protected]
Tél. : 32(0)2 764 52 60 (secr)
Web Sites
http://www.fath.ucl.ac.be
http://www.fath.ucl.ac.be/ACRG.htm
54
F 1
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
New treatments of cancer :
Immunotherapy and targeted therapies
Senior Scientists :
u Jean-François BAURAIN
u Jean-Pascal MACHIELS
Research Field and Subjects
therapy in patients with rectal cancer. Ann Oncol. 18, 738-44,
2007.
u J.F. Baurain, P. Van Der Bruggen, B.J. Van Den Eynde, P.G. Coulie,
N. Van Baren. General principles and first clinical trials of therapeutic vaccines against cancer. Bull Cancer. 95, 327-335, 2008.
u J.P. Machiels, F. Mazzeo, M. Clausse, B. Filleul, L. Marcelis, B. Honhon, L. D’Hondt, C. Dopchie, V. Verschaeve, L. Duck,
D. Verhoeven, P. Jousten, M.A. Bonny, A.M. Moxhon, B. Tombal,
J. Kerger. Prospective randomized study comparing docetaxel,
estramustine, and prednisone with docetaxel and prednisone in
metastatic hormone-refractory prostate cancer. Clin Oncol. 26,
5261-8, 2008.
u A. Debucquoy, K. Haustermans, A. Daemen, S. Aydin, L. Libbrecht, O. Gevaert, B. De Moor, S. Tejpar, W.H. Mcbride, F. Penninckx,
P. Scalliet, C. Stroch, S. Vlassak., C. Sempoux, J.P. Machiels. Molecular Response to Cetuximab and Efficacy of Preoperative Cetuximab-Based Chemoradiation in Rectal Cancer. J Clin Oncol,
2009.
u J.F. Baurain, M. Stas, F. Hammouch, A. Gillain, A. Feyens, N. Van
Baren, I. Tromme, R. Van Wijck, M. Garmyn, P.G. Coulie. Association
of primary melanoma ulceration and clinical benefit of adjuvant
vaccination with tumor-specific antigenic peptides. Proceedings
of the American Association of Clinical Oncology. abstr. 3022,
2009.
Cancer is characterized by an inappropriate activation of molecular pathways leading to uncontrolled tumor proliferation. In
addition, the immune system is not able to recognize the tumor
cells and to eliminate them. Therefore, our main interests are
cancer vaccines and molecular targeted therapies.
Our group is conducting academic clinical trials. We are taking care of designing, writing and coordinating these protocols.
These clinical studies are performed in various tumor types such
as melanoma, brain, head and neck, prostate or rectal cancer.
We are currently running these trials in Belgium but also in
France investigating these new approaches. Our aim is also to
perform translational research to better understand the mechanisms of resistance and response to these innovative treatments.
Biological samples (T cells, plasma, tumor biopsies, …) are taken
from our patients during treatment to be analyzed in the lab.
We are also trying to develop pre-clinical mouse models investigating for example the radio-sensitizing properties of molecular
agents.
Representative References
u J.P.
Machiels, L. Duck, B. Honhon, B. Coster, J.C. Coche, P. ScalY. Humblet, S. Aydin, J. Kerger, V. Remouchamps, J.L. Canon,
P. Van Maele, L. Gilbeau, S. Laurent, C. Kirkove, M. Octave-Prignot,
J.F. Baurain, A. Kartheuser, C. Sempoux. Phase II Study of Preoperative Oxaliplatin, Capecitabine, and External Beam Radiotherapy
in Patients with Rectal Cancer: the RadiOxCape Study. Annals of
Oncology. 16, 1898-1905, 2005.
u J.F. Baurain, M. Stas, B. Neyns, G. Schuler, T. Velu, K. Thielmans,
N. Van Baren, T. Dorval, M. Marchand, P.G. Coulie. Comparing
immunogenicities of tumor-specific antigens administered as
therapeutic vaccines in metastatic melanoma patients. Proceedings of the American Association of Clinical Oncology. 25, 118s
abstr. 3003, 2007.
u J.P. Machiels, C. Sempoux, P. Scalliet, C. Coche, Y. Humblet, E. Van
Cutsem, J. Kerger, J.L. Canon, M. Peeters, S. Aydin, S. Laurent,
A. Kartheuser, B. Coster, S. Roels, J.F. Daisne, B. Honhon, L. Duck,
C. Kirkcove, M.A. Bonny, K. Haustermans. Phase I/II study of preoperative cetuximab, capecitabine, and external beam radioliet,
Awards
u J.P.
Machiels. Translational Research Award, first prize at John
Hopkins Oncology cancer center, 2000
u J.P. Machiels. AMGEN award, belgian Society of Medical
Oncology, 2002
u J.F. Baurain. Straetmans prize, Académie Royale Belge de
Médecine, 2002
u J.F. Baurain. Pfizer educational awards, 2003
u J.F. Baurain. AMGEN award, belgian Society of Medical Oncology, 2005
55
Funding
Key Words for R&D
Cancer vaccines
Immunotherapy
Tumor antigens
Molecular targeted therapies
Translational research
Academic clinical trials
u FRSM
& FNRS
u Fondation belge contre le cancer
u Industrie pharmaceutique
u Fondation Maisin
Senior Scientists
Partnership
Jean-François BAURAIN
[email protected]
Tél. : 32(0)2 764 54 71
u Ludwig
Institute for Cancer Research, Brussels Branch
u Katholieke Universiteit Leuven
u Several academic and non academic clinics in Belgium and
France
Jean-Pascal MACHIELS
[email protected]
Tél. : 32(0)2 764 54 57
Main Equipment
Web Site
http://www.centreducancer.be
u Data
managing unit
u Cell culture facilities
u Molecular analysis equipment
Products and Services
u Opportunities
for non-commercial clinical trials
u Facilities for data collection (patients, blood, tumor samples,…)
56
F 2
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Clinical studies in hematology
Senior Scientists :
u Augustin FERRANT
u Laurent KNOOPS
u Lucienne MICHAUX
u Eric VAN DEN NESTE
u Marie-Christiane VEKEMANS
Research Field and Subjects
Hx-CD20-406: Humax CD20 monoclonal humanized antibody
for CLL refractory to fludarabine and Campath.
EFC6663: Flavopiridol for relapsing CLL, previously treated with
alkylating agents, and refractory to fludarabine.
Acadesine: phase I/II, Relapsing or refractory CLL, after alkylating agents or after fludarabine.
AML HOVON Protocols
HOVON 92 : Randomized induction and post induction therapy
in adult patients (<= 60 yrs of age) with acute myelocytic leukemia (AML) or refractory anemia with excess of blasts (RAEB,
RAEB-t) with IPSS score ≥ 1.5.
The aim is to evaluate Laromustine during induction I and II, for
achieving complete and partial remission, and its effect on survival.
HOVON 81 : Randomized induction and post induction therapy
in older patients (>= 61 yrs of age).
The aim is to evaluate the effect of bevacizumab during induction and consolidation on survival without event.
Multiple myeloma
IFM 01-01 : Melphalan-prednisone, with or without thalidomide in patients ≥ 75 years. Objectives: study of the survival
without progression, complete remission rate after 6 months,
toxic death rate.
CC-5013-MM-020 (IFM 2007-01) : Patients who are not candidates for transplantation; 3-arms study: a/ lenalidomide until
progression b/ every 4 weeks, up to a total of 18 courses c/
melphalan/prednisone/thalidomide every 6 weeks, up to a total
of 12 courses.
Objective: to compare the response rate and the survival probability between the 3 therapies.
LNH Protocols
LNH2007-3B : Comparison between 2 chemotherapy regimens,
both with Rituximab, with a PET-scan after 2 courses, in patients
with a large B cell lymphoma.
GEN 415: Ofatumumab in relapsing LNH.
PTLD: Rituximab alone vs Rituximab + chemotherapy in posttransplant lymphoproliferative diseases.
Mantle cell lymphoma < 65y: 6 x R-CHOP + autoPBSCT vs
R-CHOP/R-DHAP + HD-AraC + auto-PBSCT.
ACT-1: peripheral T-cell lymphoma, <65y; Campath-CHOP14 vs
CHOP14, both with autologous PBSCT consolidation.
ACT-2: peripheral T-cell lymphoma, >65y; Campath-CHOP14 vs
CHOP14
CC-5013-TCL-001:Revlimid (lenalinomide) for relapsing or
refractory T-cell lymphoma.
MMVAR : Velcade-thalidomide-dexamethasone vs thalidomidedexamethasone in patients with progressive disease or relapsing
after autologous transplantation.
MMY-3021 : subcutaneous vs intravenous bortezomib.
Hodgkin’s lymphoma
H10 : stage I//II ; treatment adapted according to the results of
a PET-scan after 2 courses of chemotherapy.
Objective: to evaluate the prognostic impact of PET-scanning.
ALL Protocol
EWALL : acute lymphoblastic leukemia, age > 55 y; includes
dasatinib during induction and consolidation chemotherapy.
H 3-4 : Randomized prospective treatment trial in stage III-IV
Hodgkin’s lymphoma: comparative evaluation of the effectiveness and the toxicity of two treatments: ABVD and BEACOPP.
CLL (chronic lymphocytic leukemia) Protocols
HOVON 68: Fludarabine-cyclophosphamide vs fludarabinecyclphosphamide-campath in poor prognosis CLL.
LUCID: fludarabine-cyclophosphamide-Rituximab vs fludarabinecyclophosphamide-Rituximab-Lumiliximab in relapsing CLL.
CAM203: subcutaneous Campath for CLL relapsing after fludarabine based therapy, and in patients previously treated with
alkylating agents.
Representative References
u S.
Choquet, V. Leblond, R. Herbrecht, G. Socie, A.M. Stoppa,
P. Vandenberghe, A. Fischer, F. Morschhauser, G. Salles, W. Feremans, E. Vilmer, M.N. Peraldi, P. Lang, Y. Lebranchu, E. Oksenhendler,
57
Key Words for R&D
J.J. Garnier, T. Lamy, D. Jaccard, A. Ferrant, F. Offner, O. Hermine,
A. Moreau, S. Fafi-kremer, P. Morand, L. Chatenoud, N. BerriotVaroqueaux, L. Bergougnoux, N. Milpied. Efficacy and safety of
rituxiab in B-cell post-transplantation lymphoproliferative
disorders: results of a prospective multicenter phase 2 study.
Blood.,107:3053-3057, 2006.
u J.J Cornelissen, W.L. Van Putten, L. F. Verdonck, M. Theobald,
E. Jacky, S.M.G. Daenen, M. Van Marwijk Kooy, P. Wijermans,
H. Schouten, P.C. Huijgens, H. Van Der Lelie, M. Fey, A. Ferrant,
J. Maertens, A. Gratwohl, B. Lowenberg. Results of a HOVON/
SAKK donor versus no-donor analysis of myeloablative HLAidentical sibling stem cell transplantation in first remission acute
myeloid leukemia in young and middle-aged adults: benefits for
whom? Blood., 109:3658-3666, 2007.
u C. Ferme, H. Eghbali, J.H. Meerwaldt, C. Rieux, J. Bosq, F. Berger, T. Grainsky, P. Brice, B. Van T’veer, J.A. Walewski, P. Lederlin,
U. Tirelli, P. Carde, E. Van Den Neste, E. Gyan, M. Monconduit,
M. Divine, J.M. Raemaekers, G. Salles, E.M. Noordijk, J. Gabarre,
A. Hagenbeek, O. Reman, M. Blanc, J. Thomas, B. Vie, J.C. Kluinnelemans, F. Viseur, J.W. Daams, P.J. Lugtenburg, C. Carrie, E.J. Jaubert, M. Henry-Amar. EORTC-GELA H8 trial. Chemotherapy plus
involved-field radiation in early-stage Hodgkin’s disease. N Engl
J Med., 357 : 1916-27, 2007.
u E. Van Den Nest, V. Robin, J. Francart, A. Hagemeijer, M. Stul,
P. Vandenberghe, A. Delannoy, A. Sonet, V. Deneys, S. Costantini,
A. Ferrant, A. Robert, L. Michaux. Chromosomal translocations
independently predict treatment failure, treatment-free survival
and overall survival in B-cell chronic lymphocytic leukaemia
patients treated with cladribine. Leukemia 21 : 1715-22, 2007.
AML
Clinical medicine
CLL
Lymphoma
Hematology
Hodgkin
Multiple myeloma
Phase I/II
Randomization
Stem cell transplantation
Senior Scientists
Augustin FERRANT
[email protected]
Tél. : 32(0)2 764 18 80
Lucienne MICHAUX
[email protected]
Tél. : 32(0)2 764 18 09
Eric VAN DEN NESTE
[email protected]
Tél. : 32(0)2 764 18 75
Marie-Christiane VEKEMANS
[email protected]
Tél. : 32(0)2 764 18 72
Laurent KNOOPS
[email protected]
Tél. : 32(0)2 764 18 10
Web Site
Funding
http://rch.adre.ucl.ac.be/browse/list_alpha/SANG
In part by Fondation Salus Sanguinis
Partnership
Multicentric, international studies
58
F 3
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Lung cancer - mesothelioma - clinical research in diagnosis active treatment - supportive care
Senior Scientists :
u Daniel RODENSTEIN
u Philippe COLLARD
u Giuseppe LIISTRO
u Thierry PIETERS
Research Field and Subjects
Main Equipment
The pneumology unit participates since many years to randomized phase I, II, III or IV clinical trials in the treatment of lung
cancer or mesothelioma and in the diagnosis of lung cancer.
Most of studies are financially supported and/or conducted by
pharmaceutical companies.
u Modern endoscopic equipment for diagnostic and therapeutical approach of bronchial carcinoma and pleural diseases.
u Modern computed radiological tomographic systems and
nuclear imaging technics (SPEC-PET).
u 22 inpatient beds unit where oncologic patients can be
admitted. Day hospital oncologic facility for ambulatory chemotherapy.
Diagnostics
- Comparison of FDG-PET and transthoracic needle biopsy for
the diagnosis of lung cancer. - The value of FDG-PET and endoscopic ultrasound-guided fine-needle aspiration to detect mediastinal lymph node involvement in lung cancer.
Funding
u External
Treatment
- Several clinical studies of chemotherapy combinations. - Studies with different Tyrosine Kinase Inhibitors (of EGFR and VEGFR).
- combination of an inhibitor of the CDK2/cyclin E complex with
chemotherapy .
u FNRS
funds from pharmaceutical companies
(Fonds National de la Recherche Scientifique)
Partnership
u UCL
multidisciplinary thoracic oncology group.
studies in collaboration with the pharmaceutical
industry.
u Collaboration with the Belgian Society of Pneumology (oncology and interventional endoscopy).
u International interuniversity program in pneumology, including onco-pneumology
u Numerous
In the future, the unit will develop studies in the early diagnosis
(autofluorescence endoscopy) and local tumor therapy (radiofrequence coagulation).
Product and services
u Opportunities for clinical research on about one hundred new
patients each year.
u Facilities for data collection (oncology care coordinator fulltime available).
59
Key Words for R&D
Chemotherapy
Cytology
Diagnosis
Histology
Immunotherapy
Internal medicine
Lung cancer
Molecular biology
Prognostic factor of molecular markers
Pulmonology
Surgical medicine
Treatment
Senior Scientists
Daniel RODENSTEIN
[email protected]
Tél. : 32(0)2 764 28 86
Philippe COLLARD
[email protected]
Tél. : 32(0)2 764 28 30
Giuseppe LIISTRO
[email protected]
Tél. : 32(0)2 764 28 43
Thierry PIETERS
[email protected]
Tél. : 32(0)2 764 28 33
Web Sites
http://rch.adre.ucl.ac.be/browse/list_alpha/PNEU
http://pneu.ucl.ac.be
http://www.saintluc.be/english/index.html
60
G 1
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Mechanisms of ovarian toxicity of chemotherapeutic
agents used in breast cancer
Senior Scientists :
u Martine BERLIERE
u Etienne MARBAIX,
u Christine GALANT
u Jean-Pascal MACHIELS
Research Field and Subjects
Awards
Gonadotoxic effects of chemotherapeutic agents used in breast
cancer patients are frequently described and well documented
in clinical studies but the prevailing mechanisms of this toxicity
are not well understood. Some studies have suggested that chemotherapeutic agents induced apoptotic changes in pregranulosa cells that subsequently develop into follicules but it has not
been confirmed,other studies found abnormalities of ovarian
vascularisation.
We have initiated a mice model with young adult mice (wild
type FVB). They are given intraperitoneal injections of Cyclophosphamide (200mg/kg.) Apoptosis (western blotting-immunohistochemistry) and vascularisation of ovaries are studied.
Intraperitoneal injections of taxanes and adriamycin are planned
and thereafter combined intra peritoneal injections of the three
different agents. This study is associated with a prospective
multicentric clinical study of the incidence of reversible amenorrhea in premenopausal breast cancer patients receiving chemotherapy. We study the ovarian recovery of ovarian function, the
interest of biological data (hormonal values) and the impact of
amenorrhea on the prognosis.
u Grant
Fonds Joseph Maisin 2007
GGOLFB (groupement des gynécologues de langue
française), 2007
u Grant
Funding
Joseph Maisin Fundation
Partnership
u Christian
u Cancer
De Duve, Institut Cancer Center
Center Claudius Regaud (Toulouse)
Main Equipment
Multiphoton Microscope
Representative References
u M.
Berliere, F. Dalenc, N. Malingret, P. Piette, J. Donnez, M. SymJ. Kerge, H. Roche, J.P. Machiels. Incidence of reversible
amenorrhea in women with breast cancer undergoing adjuvant
anthracyclin based chemotherapy with or without docetaxel.
BMC,218:56-, 2008.
u N. Malingret, J.P. Machiels, J.F. Baurain, F. Mazzeo, J. Donnez,
P. Piette, M. Berliere. Etude prospective de l’aménorrhée des
patientes préménopausées atteintes d’un cancer du sein et
recevant une chimiothérapie. Abstract et présentation orale.
Congrés franco-belge du GGOLFB, février 2009.
man,
61
Key Words for R&D
Chemotherapy
Mouse
Ovarian toxicity
Fertility
Apoptosis
Neovascularisation.
Senior Scientists
Martine BERLIERE
[email protected]
Tél. : 32 (0)2 764 10 75
Etienne MARBAIX
[email protected]
Tél. : 32 (0)2 764 67 55
Christine GALANT
[email protected]
Tél. : 32 (0)2 764 67 53
Jean-Pascal MACHIELS
[email protected]
Tél. : 32 (0)2 764 54 57
Web Site
http://www.centreducancer.be
62
G 2
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Nucleoside analogues in leukaemia
Senior Scientists :
u Françoise BONTEMPS
u Eric VAN DEN NESTE
Research Field and Subjects
u C.
Smal, D. Vertommen, L. Bertrand, S. Ntamashimikiro, M.H. Rider,
E. Van Den Neste and F. Bontemps. Identification of in vivo phosphorylation sites on human deoxycytidine kinase. Role of Ser-74
in the control of enzyme activity. J. Biol. Chem., 281, 48874893, 2006.
u C. Smal, E. Van Den Neste, M. Maerevoet, X. Poire, I. Theate and
F. Bontemps. Positive regulation of deoxycytidine kinase activity
by phosphorylation of Ser-74 in B-cell chronic lymphocytic leukaemia lymphocytes. Cancer Lett., 253, 68-73, 2007.
u L. Bastin-Coyette, C. Smal, S. Cardoen, P. Saussoy, E. Van Den
Neste and F. Bontemps. Mechanisms of cell death induced by
2-chloroadenosine in leukemic B-cells. Biochem. Pharmacol.,
75, 1451-1460, 2008.
u E. De Viron, L. Knoops, T. Connerotte, C. Smal, L. Michaux, P. Saussoy, P. Vannuffel, E. Beert, M-C. Vekemans, C. Hermans, F. Bontemps
and E. Van Den Neste. Impaired up-regulation of polo-like kinase
2 in B-cell chronic lymphocytic leukaemia lymphocytes resistant
to fludarabine and 2-chlorodeoxyadenosine: a potential marker
of defective damage response. Br. J. Haematol., 2009 (in press).
The major interests of the group are the pharmacologic and
therapeutic effects of nucleoside analogues in cancer, and particularly in leukaemia.
The current investigations aim at understanding the mechanisms of progressive chemoresistance of lymphoid malignancies to 2-chlorodeoxyadenosine (CdA) and fludarabine and at
finding strategies to improve their therapeutic efficacy in B-cell
chronic lymphocytic leukemia (B-CLL).
Research topics:
1. Study of deoxycytidine kinase, a key enzyme in the conversion of CdA and fludarabine into their active triphosphate form.
2. Mechanisms of action of nucleoside analogues, and in particular study of their interaction with the cell cycle in B-CLL cell
lines.
3. Search for markers of defective damage response in B-CLL
lymphocytes.
Main Equipment
Representative References
u Cell
culture facilities
equipment for biochemical and molecular biology
u General
u S.
Cardoen, E. Van Den Neste, C. Smal, J-F. Rosier, A. Delacauw,
A. Ferrant, G. Van Den Berghe and F. Bontemps. Resistance to
chloro-2’-deoxyadenosine of the human B-leukemia cell line
EHEB. Clin. Cancer Res., 7, 3559-3566, 2001.
u E. Van Den Neste, S. Cardoen, B. Husson, J-F. Rosier, A. Delacauw,
A. Ferrant, G. Van Den Berghe and F. Bontemps. 2-Chloro-2’-deoxyadenosine inhibits DNA repair synthesis and potentiates UVC
cytotoxicity in chronic lymphocytic leukemia B-lymphocytes.
Leukemia, 16, 36-43, 2002.
u E. Van Den Neste, C. Smal, S. Cardoen, A. Delacauw, J. Frankard,
A. Ferrant, G van den Berghe. and f. Bontemps. Activation of deoxycytidine kinase by UV-C irradiation in chronic lymphocytic leukemia B-lymphocytes. Biochem. Pharmacol., 65, 573-580, 2003.
u E. Van Den Neste, S. Cardoen, F. Offner and F. Bontemps. Old and
new insights into the mechanisms of action of two nucleoside analogs active in lymphoid malignancies: fludarabine and
cladribine (review). Int. J. Oncol., 27, 1113-24, 2005.
assays
u HPLC technology
u Microplate reader
u Liquid scintillation analyzers
Products and Services
u Cell
lines
u Expression
u Enzymatic
vectors
assays
Awards
Pierre and Colette Bauchau Award (2002) :
F. Bontemps and E. Van Den Neste
63
Funding
Key Words for R&D
Cancer
Lymphoid malignancies
B-cell chronic lymphocytic leukemia
Nucleoside analogues
2-chlorodeoxyadenosine (cda)
Fludarabine
Deoxycytidine kinase (dck)
Polo-like kinase 2 (plk2)
Apoptosis
Dna damage response
Protein phosphorylation
u FNRS
u TELEVIE
u Fondation
u Fonds
Salus Sanguinis
Maisin
Partnership
Dr L. Knoops, Hematology and Ludwig Institute for Cancer
Research, Cliniques universitaires St Luc, 1200-Brussels
Senior Scientists
Françoise BONTEMPS
[email protected]
Tél. : 32(0)2 764 75 68
Staff
Total: 7
Eric VAN DEN NESTE
[email protected]
Tél.: 32(0)2 764 75 68
Web Site
www.deduveinstitute.be/nucleoside_analogues_
in_leukaemia.php
64
G 3
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Screening of synthetic and natural compounds
for anti-tumor and anti-angiogenic activity
Senior Scientists :
u Olivier FERON
u Romain BOIDOT
Research Field and Subjects
uC. Bouzin, A. Brouet, J. De Vriese, J. Dewever, O. Feron. Effects
of vascular endothelial growth factor on the lymphocyteendothelium interactions: identification of caveolin-1 and nitric
oxide as control points of endothelial cell anergy. J Immunol.,178(3):1505-11, 2007.
u F. Frérart, P. Sonveaux, G. Rath, A. Smoos, A. Meqor, N. Charlier,
B.F. Jordan, J. Saliez, A. Noël, C. Dessy, B. Gallez, O. Feron. The
acidic tumor microenvironment promotes the reconversion of
nitrite into nitric oxide: towards a new and safe radiosensitizing
strategy. Clin Cancer Res.,14(9):2768-74, 2008.
u P. Sonveaux, F. Végran, T. Schroeder, M.C. Wergin, J. Verrax, Z.N.
Rabbani, C.J. De Saedeleer, K.M. Kennedy, C. Diepart, B.F. Jordan,
M.J. Kelley, B. Gallez, M.L. Wahl, M.W. Dewhirst*, O. Feron*
(*co-last author). Targeting lactate-fueled respiration selectively
kills hypoxic tumor cells in mice. J Clin Invest.,118(12):3930-42,
2008.
New experimental modes of screening and selection of drugs
with a higher selectivity for the tumor vasculature or tumor cells
are avidly needed. Hypoxia is recognized as a hallmark of most
tumor types. Hypoxia triggers angiogenesis and is a source of
resistance to anticancer treatments. We have therefore implemented a technological platform wherein hypoxia is integrated
as a parameter to screen synthetic and natural compounds for
their anti-angiogenic and anti-tumor activity.
In vitro cytoxicity assays and specific tests to evaluate anti-angiogenic activity, both under strictly controlled hypoxia (0.1-1%
O2, cyclic or continuous hypoxia) allow to identify and validate
the therapeutic potential of drugs through the establishment
of dose-response curves. The lab is also equipped to perform
high-standard preclinical evaluation of selected compounds in a
variety of validated mouse tumor and metastases models.
The sources of compounds are issued from chemical libraries (or
de novo synthesis) and from natural extracts of plants.
Patent
u PCT/EP00/07731:
O. Feron & J.L. Balligand. Use of compound
or pharmaceutical composition for the prevention and/or the
treatment of ischemic heart and cerebral diseases, tumor development and for wound healing.
Representative References
Feron. Targeting the tumor vascular compartment to
improve conventional cancer therapy. Trends Pharmacol Sci.,
25(10):536-42, 2005.
u P. Martinive, F. Defresne, C. Bouzin, J. Saliez, F. Lair, V. Grégoire,
C. Michiels, C. Dessy, O. Feron. Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: implications
for anticancer therapies. Cancer Res., 66(24):11736-44, 2006.
u E. Sbaa, J. Dewever, P. Martinive, C. Bouzin, F. Frérart, J.L. Balligand, C. Dessy, O. Feron. Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1-driven
postischemic vasculogenesis. Circ Res.,98(9):1219-27, 2006.
u J. Dewever, F. Frérart, C. Bouzin, C. Baudelet, R. Ansiaux, P. Sonveaux, B. Gallez, C. Dessy, O. Feron. Caveolin-1 is critical for the
maturation of tumor blood vessels through the regulation of
both endothelial tube formation and mural cell recruitment. Am
J Pathol.,171(5):1619-28, 2007.
u C. Bouzin, O. Feron. Targeting tumor stroma and exploiting
mature tumor vasculature to improve anti-cancer drug delivery.
Drug Resist Updat.,10(3):109-20, 2007.
u O.
Awards
u Prize
Belgian Soc Pharm Sci (1997)
Galien (1999)
u Prize Orbita (2001)
u Prize MSD-BLC (2001)
u Prize Eugène De Somer (2008)
u Prize
Funding
u FNRS,
FRSM, TELEVIE
Maisin & St luc
u Région bruxelloise
u Private companies
u Fondations
65
Partnership
Key Words for R&D
Drug discovery
Drug library
Medicinal plant
Natural products
High-throughput screening
Anti-tumor activity
Angiogenesis
Hypoxia
u Prof.
J. Quetin-Leclercq (Pharmacognosy), LDRI, UCL
u Prof. O. Riant and J Marchand (Chemistry), CHOM, UCL
u Prof. R. Kiss (Pharmacognosy), Toxicology, ULB
u Dr Chaltin, CD3 (Centre for Drug Design and Discovery), KUL,
Leuven
Main Equipment
Senior Scientists
Olivier FERON
[email protected]
Tél. : 32(0)2 764 52 64 (dir)
Tél. : 32(0)2 764 52 60 (secr)
u Hypoxia
workstation (Ruskinn, In Vivo500) for cell handling
and cultures
u Microscope Axio-observer (Z1, Zeiss) incl. O2 and CO2 modules and videomicroscopy set-up to track angiogenesis, cell
migration and cell death
u Microplate reader & injectors (Victor 5, PE)
u Automatic liquid handler for sample dilution
u The lab has also high-standard molecular biology, biochemistry and cell biology equipments; imaging technologies are available to evaluate the impact of selected drugs in a variety of
mouse models of human tumor xenografts and metastases:
u In vivo bioluminescence detection (IVIS, Xenogen)
u Intravital microscopy: fluorescence microscopes (Axioskop,
Zeiss) + camera EBCD (Hammamatsu)
u Laser Doppler imager (LDI, Moor)
u Axio-Imager and Apotome pseudo-confocal microscopy
(Zeiss) + AxioCam
u Telemetry (DSI) for hemodynamic measurements
u Local animal facilities for mouse maintenance and breeding
Romain BOIDOT
[email protected]
Tél. : 32(0)2 764 52 60 (secr)
Web Sites
http://www.fath.ucl.ac.be
http://www.fath.ucl.ac.be/ACRG.htm
Products and Services
u Screening of synthetic or natural compounds for anti-tumor
and/or anti-angiogenic activity under hypoxic and/or normoxic
conditions
u Original lead compounds with (hypoxia-selective) anti-tumor
and/or anti-angiogenic activity
66
G 4
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Influence of the tumor microenvironment including tumor
­hypoxia and metabolism on cancer progression and metastases
Senior Scientists :
u Olivier FERON
u Pierre SONVEAUX
Research Field and Subjects
Bouzin, A. Brouet, J. De Vriese, J. Dewever, O. Feron. Effects
of vascular endothelial growth factor on the lymphocyteendothelium interactions: identification of caveolin-1 and nitric
oxide as control points of endothelial cell anergy. J Immunol.,178(3):1505-11, 2007.
u F. Frérart, P. Sonveaux, G. Rath, A. Smoos, A. Meqor, N. Charlier,
B.F. Jordan, J. Saliez, A. Noël, C. Dessy, B. Gallez, O. Feron. The
acidic tumor microenvironment promotes the reconversion of
nitrite into nitric oxide: towards a new and safe radiosensitizing
strategy. Clin Cancer Res.,14(9):2768-74, 2008.
u P. Sonveaux, F. Végran, T. Schroeder, M.C. Wergin, J. Verrax,
Z.N. Rabbani, C.J. De Saedeleer, K.M. Kennedy, C. Diepart, B.F. Jordan,
M.J. Kelley, B. Gallez, M.L. Wahl, M.W. Dewhirst*, O. Feron* (*colast author). Targeting lactate-fueled respiration selectively kills
hypoxic tumor cells in mice. J Clin Invest.,118(12):3930-42, 2008.
u C.
It is known for many years that cellular metabolism within a
solid tumour is markedly different from that of the corresponding normal tissue. One of the most recognized reasons for
altered tumor metabolism is hypoxia and the consecutive induction of the transcription factor HIF1 or hypoxia-inducible factor
1. The net result of HIF1 activation is to shift energy production
by increasing glycolysis and decreasing mitochondrial function.
Interestingly, the exacerbated tumor cell capacity to uptake
glucose -even under aerobic condions (the so-called Warburg
effect)- is associated with a higher invasive potential.
Lactate, the end-product of glycolysis, and more generally
monocarboxylate transporters within tumor cells, are key actors
in the interplay between tumor cell metabolism and local invasion/metastatic progression. Through the use of a variety of in
vitro and in vivo models, we aim to characterize pathways (ie,
therapeutic targets) that regulate lactate homeostasis and to
identify new drugs to interfere with them.
Patents
u PCT/EP00/07731:
O. Feron & J.L. Balligand. Use of compound
or pharmaceutical composition for the prevention and/or the
treatment of ischemic heart and cerebral diseases, tumor development and for wound healing.
u WO 2006113540 and US 7,338,670 B2. M.W. Dewhirst,
J.S. Stamler , T.J. McMahon & P. Sonveaux. Use of an agent that
restores tissue perfusion and oxygenation.
Representative References
Feron. Targeting the tumor vascular compartment to
improve conventional cancer therapy. Trends Pharmacol Sci.,
25(10):536-42, 2004.
u P. Martinive, F. Defresne, C. Bouzin, J. Saliez, F. Lair, V. Grégoire,
C. Michiels, C. Dessy, O. Feron. Preconditioning of the tumor vasculature and tumor cells by intermittent hypoxia: implications
for anticancer therapies. Cancer Res., 66(24):11736-44, 2006.
u E. Sbaa, J. Dewever, P. Martinive, C. Bouzin, F. Frérart, J.L. Balligand, C. Dessy, O. Feron. Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1-driven
postischemic vasculogenesis. Circ Res.,98(9):1219-27, 2006.
u J. Dewever, F. Frérart, C. Bouzin, C. Baudelet, R. Ansiaux, P. Sonveaux, B. Gallez, C. Dessy, O. Feron. Caveolin-1 is critical for the
maturation of tumor blood vessels through the regulation of
both endothelial tube formation and mural cell recruitment. Am
J Pathol.,171(5):1619-28, 2007.
u C. Bouzin, O. Feron. Targeting tumor stroma and exploiting
mature tumor vasculature to improve anti-cancer drug delivery.
Drug Resist Updat.,10(3):109-20, 2007.
u O.
Awards
u Prize
Belgian Soc Pharm Sci (1997 & 2005)
Galien (1999)
u FECS-EJC Award 2007
u VARIAN-Juliana Denekamp Award 2008
u Prize Henri Fauconnier 2008
u Prize Eugène De Somer (2008)
u Prize
Funding
u FNRS,
FRSM, TELEVIE
Maisin & St luc
u Fondations
67
u Fondation
belge contre le cancer
française : ARC
u Région wallonne
u Private companies
u European Research Council
u Axio-observer
(Z1, Zeiss) microscopy incl. O2 and CO2 modules
and Apotome pseudo-confocal microscopy
(Zeiss) + AxioCam Mrc5
The lab has its own peripheral animal facilities for mouse maintenance and breeding
Partnership
Products and Services
u Prof
u Screening of synthetic or natural compounds interfering with
the tumor cell metabolism
u Original lead compounds with inhibitory activity on lactate
transporters (MCT)
u Communauté
u Axio-Imager
MW. Dewhirst (Duke University, USA)
COST TD0901 Hypoxia sensing, signaling and adap-
u Program
tation
Main Equipment
Key Words for R&D
The lab has high-standard molecular biology, biochemistry and
cell biology equipments, including:
u Real-time PCR device (iQ5, Biorad)
u Nanodrop and 96-well PCR devices
u virus and plasmid handling platforms
u 6 electrophoresis and transfer units
u Proteomic platform including DIGE imager, spot picker and
microscale LC
u Micro- and ultracentrifuges
u Chemi- and fluo imager (Geliance, PE)
u 4 laminar fluxes and 6 CO2 incubators
u Cell counter
u MACS and local access to flow cytometer
u Cryostat (MicroM HM560, Prosan)
u Hypoxia workstation (Ruskinn, In Vivo500)
u Microplate reader & injectors (Victor 5, PE)
u Microdialysis analyzer (ISCUS)
The lab is also equipped with imaging technologies to characterize tumor and metastatic progression in a variety of mouse
models of human tumor xenografts and metastases:
u In vivo bioluminescence detection (IVIS, Xenogen)
u Axioskop Intravital microscopy (Zeiss) + camera EBCD (Hammamatsu)
u Axiovert Fluorescence microscopy (Zeiss) + MRC5 camera
(Zeiss)
u Laser Doppler imager (LDI, Moor)
Tumor microenvironment
Tumor hypoxia
HIF
Tumor metabolism
Lactate
Monocarboxylate transporter
Metastases
Senior Scientists
Olivier FERON
[email protected]
Tél. : 32(0)2 764 52 64 (dir)
Tél. : 32(0)2 764 52 60 (secr)
Pierre SONVEAUX
[email protected]
Tél. : 32(0)2 764 52 60 (secr)
Web Sites
http://www.fath.ucl.ac.be
http://www.fath.ucl.ac.be/ACRG.htm
68
G 5
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Prevention and treatment of hepatocellular carcinoma
Senior Scientists :
u Yves HORSMANS
u Peter STÄRKEL
u Ivan BORBATH
Research Field and Subjects
Representative References
The aim of the project is to assess the potential role of drugs in
the chemoprevention of primary liver cancer, namely hepatocellular carcinoma (HCC).
u P.
Stärkel, C. Desaeger, C. Sempoux, E. Legrand, I. Leclercq,
Y. Horsmans. Blunted DNA synthesis and delayed S-phase entry
following inhibition of CDK2 activity in the regenerating rat
liver. Lab Invest; 85:562-71 (IF 2005: 3,859), 2005.
u I. Borbath, I.A. Leclercq, J. Abarca-Quinones, et al. Inhibition of
early preneoplastic events in the rat liver by the somatostatin
analog lanreotide. Cancer Sci; 98(12):1831-1839, 2007.
u I. Borbath, I. Leclercq, P. Moulin, et al. The PPARgamma agonist
pioglitazone inhibits early neoplastic occurrence in the rat liver.
Eur J Cancer; 43(11):1755-1763, 2007.
u A. Da Silva Morais, A. Saliez, I. Leclercq, Y. Horsmans, P. Stärkel.
Inhibition of the RAS oncoprotein reduces proliferation of hepatocytes in vitro and in vivo in rats. Clin Sci (Lond); 114s:73-83 (IF
2007: 3,900), 2008.
u T. Schneider-Merck, I. Borbath, N. Charette, C. De Saeger,
J. Abarca, I. Leclercq, Y. Horsmans, P. Starkel. The Ras inhibitor
farnesylthiosalicyclic acid (FTS) prevents nodule formation and
development of preneoplastic foci of altered hepatocytes in
rats. Eur J Cancer; in press (IF 2007: 4,454), 2009.
The drugs that are studied are lanreotide, a somatostatine analogue, studied in vitro and in vivo, as in human population and
the synthetic Ras inhibitor FTS.
The effects of the two drugs have been assessed in rats having
induced cirrhosis, to look at the preventive effect on neoplastic nodules in an already pre-neoplastic organ, and preliminary
results have already been published.
We have shown that lanreotide was efficient in the reduction of
the size of pre-neoplastic and neoplastic nodules. The mechanisms of its action are not fully understood at the present time,
but preliminary data show differential alteration of proliferation and apoptosis, inhibition of fibrogenesis and angiogenesis.
Further analyses will be performed to determine the effect of
lanreotide on fibrogenesis, of which the main actors are hepatic
stellate cells (HSC). We will isolate HSC from HCC-bearing rats
to analyse changes in their morphotype as well as their sensitivity to Lanreotide.
Main Equipment
The ras oncoprotein plays an important role in the regulation of
normal cellular proliferation and differentiation but may also be
implicated in carcinogenesis. Activation of the ras proto-oncogene seems to be a frequent event in hepatocellular carcinoma.
Our second pole of HCC research focuses on the in vitro and in
vivo evaluation of the inhibitory effect of the synthetic Ras inhibitor FTS on proliferation and apoptosis of human HCC cell lines
as well as on the development and/or regression of chemically
induced hepatic carcinomas in rats. The molecular pathways
that might be implicated in this potential anti-tumour effect are
also studied. Preliminary results confirm an anti-tumor effect
of the compound in vivo by inducing apoptosis in transformed
hepatocytes. Further confirmation that ras and ras-dependent
pathways might be important in liver tumour development and
the possibility of inhibiting them by FTS, could represent a novel
source for developing new therapeutic strategies.
u Western
Blot
u Real-time PCR
u Immunohistochemistry
u Flow Cytometry
u Laboratory animal handling and surgery
69
Key Words for R&D
Chemoprevention
Gastroenterology
Liver
Liver tumors
Senior Scientists
Yves HORSMANS
[email protected]
Tél. : 32(0)2 764 28 22
Peter STARKEL
[email protected]
Tél. : 32(0)2 764 28 22
Ivan BORBATH
[email protected]
Tél. : 32(0)2 764 28 22
70
G 6
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Anti-cancer drug discovery and synthesis
Senior Scientists :
u Bernard MASEREEL
u Johan WOUTERS
Research Field and Subjects
Partnership
This research axis of the laboratory is a drug discovery program aimed at finding new chemical entities presenting anticancer properties by inhibiting the immunosuppression mediated by indoleamine 2,3-dioxygenase (IDO) and/or tryptophane
2,3-dioxygenase (TDO) expression in tumors. Indeed, IDO is an
immunomodulatory enzyme produced by some alternatively
activated macrophages and other immunoregulatory cells (also
used as an immune subversion strategy by many tumors). This
enzyme catalyzes the degradation of the essential amino acid
L-tryptophan to N-formylkynurenine. IDO is the first and rate
limiting enzyme of Tryptophan catabolism through Kynurenine
pathway, thus causing depletion of tryptophan which can cause
halted growth of microbes as well as T cells.
Part of the research also encompasses a phase I/II clinical trial
with a first-generation IDO inhibitor, and a diagnostic application leading to the development of new diagnostic test for
detecting IDO-positive cancers.
A similar approach is used to develop inhibitors of carbonic
anhydrase type IX which is overexpressed in cancer cells.
u University
of Louvain
of Liège
u Euroscreen
u GSK
u Maastro Lab (The Netherlands)
u University of Florence (Italy)
u ICPAL, University of Lille (France)
u University
Main Equipment
u Differential
calorimetric analysis apparatus
diffractometer
u Dipolemeter
u Spectrometric analyses (FPLC, GC, IR, UV…)
u Viscosimeter
u Monocrystal/powder
Funding
u FNRS-FSR
Representative References
u RW
S. Rolin, D. Vullo, A. Frankart, A. Scozzafava,
J.-M. Dogné, J. Wouters, C.T. Supuran, B. Masereel. Indanesulfonamides as carbonic anhydrase inhibitors and anticonvulsant
agents: structure-activity relationship and pharmacological evaluation. Eur. J.Med. Chem., 43, 2853-2860, 2008.
u A. Thiry, A. Delayen, L. Goossens, R. Houssin, M. Ledecq, A. Frankart, J.-M. Dogné, J. Wouters, C.Supuran, J.-P. Henichart, B. Masereel Synthesis and biological evaluation of a new family of antibenzylanilinosulfonamides as CA IX inhibitors. Eur. J. of Med.
Chem., 44, 511-518, 2009.
u A. Thiry, M. Ledecq, A. Cecchi, R. Frédérick, J.-M. Dogné, J. Wouters, B. Masereel, C. Supuran Ligand-based and structure-based
virtual screening to identify carbonic anhydrase IX inhibitors.
Bioorg. Med. Chem., 17: 553-557, 2009.
(Biowin)
u A.Thiry,
Products and Services
Crystallography, organic synthesis, molecular modeling, characterization, drug design, medicinal chemistry
71
Key Words for R&D
IDO
TDO
Immunotherapy
Carbonic anhydrase
Inhibitor
Cancer treatment
Senior Scientists
Bernard MASEREEL
[email protected]
Tél. : 32(0)81 72 43 38
Johan WOUTERS
[email protected]
Tél. : 32(0)81 72 45 50
72
G 7
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Mechanisms involved in cancer cell resistance
to apoptosis and/or autophagy induced
by chemotherapeutic drugs under hypoxia
Senior Scientists :
u Carine MICHIELS
u Thierry ARNOULD
Research Field and Subjects
Representative References
Chemotherapy is an integral component of standard care for
solid tumors. However, recurrence may occur, with a poor clinical outcome. During tumor growth, the central area becomes
hypoxic due to poor access to blood vessels capable of delivering oxygen. Hypoxic regions have been evidenced in a wide
range of cancers. Low tumor oxygenation has been identified
as an independent negative prognostic factor and is associated
with a higher risk of metastatic spread. In addition, hypoxia contributes to resistance to radiation therapy and to chemotherapy.
Hypoxia may lead to treatment resistance by modulating gene
expression resulting in resistance to cell death.
The aim of our work is to better understand the mechanisms by
which hypoxia modulates the sensitivity of cancer cells to chemotherapeutic drugs, both regarding the induction of apoptosis
but also of autophagy.
In previous work, we showed that hypoxia protected HepG2
cells against etoposide-induced apoptosis but other cell lines
and other agents are under investigation. In order to define the
mechanisms initiated by hypoxia which are responsible for its
protective effects, molecular profiles of changes in gene expression and transcription factor activity induced in these conditions are established. mRNA levels of genes encoding proteins
involved in the regulation of apoptosis process are assayed using
DNA microarrays or microfluidic cards. Unbiaised cluster analyses are performed to evidence correlations between expression
profiles,profiles of transcription factor activity and apoptotic
profile. Validation of candidates is then performed using siRNA
silencing.
u J.P. Piret, D. Mottet, M. Raes and C. Michiels. Is HIF-1alpha a
pro- or an anti-apoptotic protein? Biochem Pharmacol 64, 889892, 2002.
u J.P. Piret, E. Minet, J.P. Cosse, N. Ninane, C. Debacq, M. Raes and
C. Michiels. Hypoxia-inducible factor-1-dependent overexpression of myeloid cell factor-1 protects hypoxic cells against tertbutyl hydroperoxide-induced apoptosis. J Biol Chem 280, 93369344, 2005.
u J.P. Piret, J.P. Cosse, N. Ninane, M. Raes and C. Michiels. Hypoxia
protects HepG2 cells against etoposide-induced apoptosis via
a HIF-1-independent pathway. Exp Cell Res 312, 2908-2920,
2006.
u J.P. Cosse, A. Sermeus, K. Vannuvel, N. Ninane, M. Raes and
C. Michiels. Differential effects of hypoxia on etoposide-induced
apoptosis according to the cancer cell lines. Mol Cancer 6, 61,
2007.
u A. Sermeus, J.P. Cosse, M. Crespin, V. Mainfroid, F. De Longueville,
N. Ninane, M. Raes, J. Remacle and C. Michiels. Hypoxia induces
protection against etoposide-induced apoptosis: molecular profiling of changes in gene expression and transcription factor
activity. Mol Cancer 7, 27, 2008.
u J.P. Cosse and C. Michiels. Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer
progression Anticancer Agents. Med Chem 8, 790-797, 2008.
73
Funding
Key Words for R&D
Hypoxia
Chemotherapy
Apoptosis
Autophagy
Resistance
Signal transduction
Gene expression regulation
u TÉLÉVIE
u FNRS/FRIA
Partnership
Biowin : Keymarker project
Senior Scientists
Carine MICHIELS
[email protected]
Tél. : 32(0)81 72 41 31
Main Equipment
u Cell
culture facilities, hypoxic chambers
equipment for biochemical and molecular biology
u General
Thierry ARNOULD
[email protected]
Tél. : 32(0)81 72 41 25
assays
u Absorbance, fluorescence, luminescence microplate readers
u real-time PCR, equipped for microfluidic cards
u Full proteomic plateform with Maldi and MS-MS mass spectrometers
u Confocal microscope
Web Site
http://www.fundp.ac.be/urbc/
Products and Services
u Cellular models for the evaluation of the capacity of drugs to
induce apoptosis and/or autophagy
u Proteomic plateform
74
G 8
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Active and passive targeting of anticancer nanomedicine
Senior Scientists :
u Véronique PREAT
u Olivier FERON
u Jacqueline MARCHAND
Research Field and Subjects
of PCL-PEG for the Covalent Immobilisation of Biomolecules.
Biomacromolecules, doi: 10.1021/bm900027r. 2009.
u F. Danhier, N. Lecouturier, B. Vroman, C. Jerome, J. MarchandBrynaert, O. Feron, V. Préat. Paclitaxel-loaded PEGylated PLGAbased nanoparticles: in vitro and in vivo evaluation. J Control
Release. 133,11-7, 2009.
u F. Danhier, N.Magotteaux, B. Ucakar, N. Lecouturier, M. Brewster, V. Préat. Novel self-assembling PEG-p-(CL-co-TMC) polymeric
micelles as safe and effective delivery system for Paclitaxel, Eur J
Pharm Biopharm, 2009.
u F. Danhier, B. Vroman, N. Lecouturier, N.Crokart, V. Pourcelle,
H. Freichels, C. Jerome, J. Marchand-Brynaert, O. Feron, V. Préat.
Targeting of tumor endothelium by RGD-grafted nanoparticles
loaded with Paclitaxel, J Control Release.
Nanomedicines, in particular polymeric micelles and nanoparticles, loaded with anticancer drugs, siRNA or diagnostic
substances have been developed i) to enhance the solubility
of poorly soluble drugs (e.g., paclitaxel) ii) to protect drugs
from degradation (e.g. si RNA) iii) to passively target anticancer drugs to the tumor by the Enhanced Permeation Retention (EPR) effect through the leaky tumor endothelium iv) to
actively target the anticancer drugs to the tumor endothelium
or to tumor cells by grafting of specific ligands (e.g., RGD) or
by external triggering.
The research focuses at developing new nanosized drug delivery
systems of poorly soluble anticancer drugs or siRNA, comparing
the efficacy of active and passive targeting of those drugs and
developing new ligands of tumor endothelium to be grafted on
the nanoparticles.
Award
u Prize
Galien (OF)
Representative References
Partnership
Feron. Targeting the tumor vascular compartment to
improve conventional cancer therapy. Trends Pharmacol SciOct;25(10):536-542, 2004.
u A. Brouet , J. DeWever, P. Martinive, X. Havaux, C. Bouzin, P. Sonveaux, O.Feron. Antitumor effects of in vivo caveolin gene delivery are associated with the inhibition of the proangiogenic and
vasodilatory effects of nitric oxide. FASEB J. Apr;19(6):602-4,
2005.
u C. Bouzin, O. Feron. Targeting tumor stroma and exploiting
mature tumor vasculature to improve anti-cancer drug delivery.
Drug Resist Updat. Jun;10(3):109-20, 2007.
u V. Pourcelle, S. Devouge, M. Garinot, V. Preat, J. MarchandBrynaert. PCL-PEG-based Nanoparticles Grafted with GRGDS
Peptide: Preparation and Surface Analysis by XPS. Biomacromolecules, 8, 3977-3983, 2007.
u V. Rerat, G. Dive, G.C. Tucker, A. Cordi, R. Bareille, J. Amedee,
L. Bordenave, J. Marchand-brynaert. αvβ3 Integrin-targeting RGDpeptidomimetics containing OEG spacers. J. Med. Chem., submitted, 2009.
u V. Pourcelle, H. Friechels, F. Stoffelbach, R. Auzely-Velty,
C. Jerome, J. Marchand-Brynaert. Light Induced Functionalization
u O.
Different small biotechs and big pharmas
Funding
u TÉLEVIE
u FRSM
u Biowin
u Waleo
« Targetum »
« Targan »
Main Equipment
u Nanosizer
ZS (Malvern)
culture facilities
u HPLC
u In vivo bioluminescence detection (IVIS, Xenogen)
u Intravital microscopy: fluorescence microscopes (Axioskop,
Zeiss) + camera EBCD (Hammamatsu)
u Cell
75
Key Words for R&D
u Microscope Axio-observer (Z1, Zeiss) incl. O2 and CO2 modules and videomicroscopy set-up to track angiogenesis, cell
migration and cell death
u Laser Doppler imager (LDI, Moor)
u Telemetry (DSI) for hemodynamic measurements
u Local animal facilities for mouse maintenance and breeding
u Organic synthesis facilities and structural analysis (MS, NMR
500 MHz, …)
u Access to surface analysis (XPS, SiMS, AFM, …)
Nanoparticles
Polymeric micelles
Tumor targeting
Angiogenesis
Hypoxia
Peptidomimetics
Integrin ligands
Senior Scientists
Véronique PREAT
[email protected]
Tél. : 32(0)2 764 73 20
Products and Services
u Formulation and physicochemical characterisation of drugloaded nanoparticles
u In vitro and in vivo screening of therapeutic nanomedecine for
anti-tumor and/or anti-angiogenic activity
u Synthesis of biologically active molecules and linkers for grafting on materials.
Olivier FERON
[email protected]
Tél. : 32(0)2 764 52 64
Jacqueline MARCHAND-BRYNAERT
[email protected]
Tél. : 32(0)10 47 27 46 (or 40)
Web Sites
http://www.uclouvain.be/farg
http://www.fath.ucl.ac.be/ACRG.htm
http://www.uclouvain.be/en-267015.html
76
G 9
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Isolation and structure determination of cytotoxic,
anticancer or anti-angiogenic compounds from plants
Senior Scientists :
u Joëlle QUETIN-LECLERCQ
u Gabrielle CHATAIGNE
Research Field and Subjects
u H.
Mavar-Manga, D. Chapon, S. Hoet, S. Block, M.C. De PauwGillet, J. Quetin-Leclercq. N1,N2,N3-trisisopentenyl guanidine
and N1,N2-diisopentenyl guanidine, two cytotoxic alkaloids
from Alchornea cordifolia (Schumach.& Thonn.) Mull. Arg.
Euphorbiaceae) root barks. Natural Product Communications
1(12), 1097-1100, 2006.
u J. Lorent, M.P. Mingeot-Leclercq, J. Quetin-Leclercq. Biological actions of alpha hederin on cancer cells. Planta Medica 74
p.1003, 2008.
Plants are a large reservoir of original molecules which may act
on new targets or possess new modes of action and can be
used as prototypes by chemists. The aim of our studies is to
isolate, by different preparative or semi-preparative techniques
(Centrifugal Partition Chromatography (CPC), MPLC, overpressure laminar chromatography (OPLC),…), cytotoxic and antiangiogenic molecules from plants selected on an ethnopharmacological basis. Structures are determined by comparison with
known compounds and spectroscopic methods (UV, IR, HPLCMS, 1 or 2D, NMR).
Several new bioactive terpenic structures have been identified
as well as alkaloids.
The mode of action and cellular targets of the most interesting
compounds are analysed in collaboration with specialized teams
and derivatives are synthetised in collaboration with chemists to
study structure-activity relationships. Methods for quantification
of these bioactive molecules in extracts are also developed.
Funding
Brussels region
Partnership
u Université
u Brussels
libre de Bruxelles (ULB)
Region (Nathypox)
Representative references
Main Equipment
Block, C. Baccelli, B. Tinant, L. Van Meervelt., R. Rozenberg,
J.L. Habib Jiwan, G. Llabrès, M.C; De Pauw-Gillet, J. Quetin-Leclercq. u Preparative MPLC
Diterpenes from the leaves of Croton zambesicus. Phytochemis- u HPLC/UV, HPLC-DAD, HPLC-MS, high resolution HPLC-MSn
try, 65, 1165-1171, 2004.
(Orbitrap)
u S. Hoet, C. Stévigny, S. Block, F. Opperdoes, P. Colson, B. Balu GC-FID, GC-FTIR, GC-MS.
deyrou, A. Lansiaux, C. Bailly, J. Quetin-Leclercq. Alkaloids from
u Overpressure Laminar chromatography (OPLC)
Cassytha filiformis and related aporphines: antitrypanosomal u Microwave extraction
activity, cytotoxicity, and interaction with DNA and topoisomer- u Centrifugal Partition Chromatography (CPC)
ases. Planta Medica, 70, 407-413, 2004.
u C. Stévigny, M.C. Wautier, J.L. Habib Jiwan, P. Chiap, P. Hubert,
J. Quetin-Leclercq. Development and validation of a high-­ Products and Services
performance liquid chromatographic method for quantification
of aporphine alkaloids in different samples of Cassytha filiformis u Analysis and quantification in complex extracts of natural bioL. Planta Medica 70, 764-770, 2004.
active compounds.
u S. B lock, D. B rkic, P. H ubert, J. Q uetin -Leclercq. A validated
u Preparative purification techniques.
method for the quantification of pimarane and trachylobane u Structure analysis
diterpenes in the leaves of Croton zambesicus by capillary
gas chromatography. Phytochemical Analysis, 16, 342-348 ,
2005.
u S.
77
Key Words for R&D
Medicinal plants
Pharmaceutical sciences
Pharmacognosy
Separation techniques
Structural chemistry
Senior Scientists
Joelle QUETIN-LECLERCQ
[email protected]
Tél. : 32(0)2 764 72 54
Gabrielle CHATAIGNÉ
gabrielle.chataigné@uclouvain.be
Tél. : 32(0)2 764 72 34
Web Site
www.cham.ucl.ac.be
78
G 10
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Treatment of skin carcinoma using phototherapy
Senior Scientist :
u Martine
Research Field and Subjects
RAES
u F.
Bougard, C. Giacomelli, L. Mespouille, R. Borsali, P. Dubois and
R. Lazzaroni. Influence of the macromolecular architecture on
the self-assembly of amphiphilic copolymers based on poly(N,Ndimethylamino-2-ethyl methacrylate) and poly(epsilon-caprolactone). Langmuir 24:8272-8279, 2008.
u J.H. Caberg, P.M. Hubert, D.Y. Begon, M.F. Herfs, P.J. Roncardi,
J.J. Boniver and P. Delvenne. Silencing of E7 oncogene restores
functional E-cadherin expression in human papillomavirus
16-transformed keratinocytes. Carcinogenesis 29:1441-7,
2008.
The project aims to develop an original phototherapy to induce
the cell death of cancer cells in the context of skin carcinoma.
This approach is based on metallic complexes able to react with
biological macromolecules such as nucleic acids after illumination. Using this approach we hope to develop a new gene
silencing based therapy using complexed antisense oligonucleotides (ASO), targetting specific RNA messengers. The method
will be first developed and evaluated on immortalized keratinocytes cultured in monolayers or in organotypic culture in
vitro. In a second step, we will use a xenograft model of HPV
positive cells in NOD/SCID mice. The project also aims to screen
the transfection efficiency of cationic polymers, with controlled
architecture to vectorize the complexed ASO as well as to optimize the galenic formulation of the complexed AOS, compatible with their transcutaneous delivery.
Funding
Walloon Region, DGO
Partnership
The interdisciplinary project is based on a consortium of 6 laboratories from 4 universities (see Partnership).
Carcinom Network DGO-Waleo-2 (Walloon Region): Philippe
Dubois (UMH), Andrée Kirsch-De Mesmaeker & Cécile Moucheron
(ULB), Jacques Piette, Philippe Delvenne & Géraldine Piel (ULg)
Representative References
Main Equipment
u S.
Pirotton, C. Muller, N. Pantoustier, F. Botteman, S. ColliC. Grandfils, G. Dandrifosse, P. Degée, P. Dubois and M. Raes.
Enhancement of transfection efficiency through rapid and noncovalent post-PEGylation of poly(dimethylaminoethyl methacrylate)/DNA complexes. Pharm Res., 21:1471-1479, 2004.
u S. Deroo, V. Toncheva, E. Defrancq, C. Moucheron, E. Schacht
and A. Kirsch-De Mesmaeker. Photo-cross-linking between polymers derivatized with photoreactive ruthenium-1,4,5,8-tetraazaphenanthrene complexes and guanine-containing oligonucleotides. Biomacromolecules, 8:3503-3510, 2007.
net,
Imaging technology (confocal Microscopy), Gene expression
tools, Cell culture facility
Products and Services
Imaging technology (confocal Microscopy), Gene expression
tools
79
Key Words for R&D
Cancerology
Keratinocytes
Skin-carcinoma
Phototherapy
Antisense-oligonucleotides
Metallic-complexes
Gene-silencing
Cationic-polymers
Controlled-synthesis
Transfection
Senior Scientist
Martine RAES
Tél. : 32(0)81 72 41 24
[email protected]
Web Site http://www.fundp.ac.be/facultes/sciences/ departements/biologie/recherche/centres/urbc/
80
G 11
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Design, synthesis, and biological evaluation of mixed DNA
methyl transferase and Histone Deacetylase inhibitors as
epigenetic regulators
Senior Scientists :
u Johan
u Didier
Research Field and Subjects
Key Words for R&D
Epigenetic modifications
Cancer treatment
HDAC
DN
Methyl transferase
Histone deacetylase
Drug design
Deregulation of gene expression is a hallmark of cancer. It has
become increasingly recognized that aberrant epigenetic modifications play major roles in the tumorigenic process in addition to
genetic lesions. These modifications are imposed on chromatin,
do not change the nucleotide sequence of DNA, and are manifested by specific patterns of gene expression that are heritable
through many cell divisions. The present research is a drug discovery program aimed at finding, preparing and evaluating mixed
inhibitors of DNA methyltransferases and Histone deacetylase as
potential anticancer drugs. It also encompasses biological evaluation of enzymes, cells, and animals and a Phase I trial.
It gets support from the Télévie (FNRS).
Senior Scientists
Johan WOUTERS
[email protected]
Tél. : 32(0)81 72 45 50
Didier LAMBERT
[email protected]
Tél. : 32(0)2 764 73 47
Partnership
u University
of Louvain
of Liège & Gembloux: Lucas Willems, Philippe Delvenne
u University of Brussels : Carine Van Lint, Jean-Paul Sculier,
François Fuks
u Hôpital Bordet
u University
Main Equipment
u Differential
calorimetric analysis apparatus
/ powder diffractometer
u Dipolemeter
u Spectrometric analyses (FPLC, GC, IR, UV…)
u Viscosimeter
u Monocrystal
Funding
u FNRS-FSR
WOUTERS
LAMBERT
(TELEVIE), FRIA
Products and Services
Molecular modelling, organic synthesis, crystallography, characterization, drug design, medicinal chemistry
81
82
H 1
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Limb salvage in tumor surgery with massive bone
allografts (Bone Bank)
Senior Scientists :
u Christian DELLOYE
u Olivier CORNU
u Xavier BANSE
u Pierre-Louis DOCQUIER
Research Field and Subjects
Another research area is the introduction of computerised navigation for bone tumor resection and cutting of a bone allograft in order to obtain millimetric adjustment between the host
bone and the allograft. It is hypothesized that such adjustment
will give better chance to allograft healing.
- Study of massive allografts complications (fracture, infection,
non-union) ;
- Bone allografts incorporation ;
- Treatment of non union or delayed union by autologous cell
therapy ;
- Computerized selection of bone allografts ;
- Computer-guided navigation of tumor resection and bone
allograft cutting.
Representative References
u O.
Cornu, X. Libouton, B. Naets, B. Godts, J. Van Tomme, C. DelX. Banse. Freeze-dried irradiated bone brittleness improves
compactness in an impaction bone grafting model. Acta Orthop
Scand, 75, 309-314, 2004.
u C. Delloye and G. Bannister. Impaction Bone Grafting in Revision Arthroplasty. 456pp, illustrated, Index. Dekker Inc, NewYork. ISBN:0-8247-4799-2, 2004.
u P. Docquier, C. Delloye. Treatment of aneurysmal bone cysts by
introduction of demineralized bone and autogenous bone marrow. J Bone Joint Surg, 87A, 2253-2258, 2005.
u C. Delloye, X. Banse, B. Brichard, P.L Docquier, O. Cornu. Pelvic
reconstruction with a structural pelvic allograft after resection of a
malignant bone tumor. J Bone Joint Surg (Am) 89A: 579-587, 2007.
u C. Delloye, O. Cornu, V. Druez, O. Barbier. Bone allografts: what
they can offer and they cannot. J Bone Joint Surg (Br), 89B: 574579, 2007.
u L. Paul, P.L. Docquier, O. Cartiaux, O. Cornu, C. Delloye,
X. Banse. Inaccuracy in selection of massive bone allograft using
template comparison method. Cell Tissue Bank, 9: 83-90, 2008.
u O. Cartiaux, P.L. Docquier, B.G. Paul, L. Francq, O. Cornu,
C. Delloye, B. Raucent, B Dehez, X. Banse Surgical inaccuracy of
tumor resection and reconstruction within the pelvis: an experimental study. Acta Orthop. 79:695-702, 2008.
loye,
Bone allografts have a long history as a substitute for limb
reconstruction after tumor resection. They are commonly used
because they provide immediate structural support that can
be associated with a prosthesis or with osteosynthesis. Among
several advantages, their use allows anatomical reconstruction of the skeletal defect, biological union to host bone
through callus formation, soft tissue adherence around the
grafted bone and the possibility of tendon reinsertion on its
counterpart left on the bone graft. Among possible disadvantages, there are the risk, albeit remote, of disease transmission through the implant, and a high rate of non union and
fracture. These complications are related to the non vitality of
the bone graft.
Research projects are conducted to remote disadvantages
of bone allografts. Methods of bacterial screening and graft
decontamination are assessed by in vitro testing. Using the graft
as an antibiotic delivering system is also considered.
As a bone allograft serves primarily as an osseous spacer that
allows osteoconduction of host cells into its mass, biological
answer results in a progressive incorporation of the graft into
the host bone. Incorporation includes a series of events leading to gradual replacement of the grafted bone by host bone
through a mechanism of osteoclastic resorption followed by
new bone deposition. This intricate process however is very
limited in time and space, leaving eventually a mass of dead
bone that has been poorly substituted by new bone. Efforts are
made to overcome this limited substitution though improvement of the revascularisation and revitalisation of the bone.
The research is organised to explore the different avenues
available to achieving a better incorporation and avoiding a
mechanical failure.
Products and Services
The Tissue Bank is able to deliver massive bone allografts to
surgeons for skeletal reconstruction ([email protected]).
Research projects may cover all fields of interests from microbiological studies (in vitro testing of bacterial screening and decontamination) to in vivo model of allografts incorporation (Tibial
critical defect in sheep). Mechanical and morphological assess-
83
Partnership
ment of allograft reconstruction may be performed. Among the
different avenues to improve allograft incorporation and bone
healing, autogenous cell augmentation represents an indirect
approach.
u Royal
Military School - Engineering (Prof Van Thomme), Bruxelles,
Belgium
u University of Toronto – Phospho-calcic metabolism Lab (Prof
Grynpas), Toronto, Canada
u Institut Rizzoli (Prof Donati), Bologne, Italy.
u Azienda Ospedaliera Careggi (Prof Capanna), Florence, Italy
Main Equipment
u Bone
morphological analysis
culture and Cleanroom facilities
u Digitalisation table
u Exact saw
u Fluoroskan Ascent
u Hip walking simulator
u Leitz saw 1600
u Microradiography (Bemtograph)
u Microscopy
u Microtome Leica.
u Multiscan RC200-240C
u p-QCT, model XCT Research SA+® Stratec (RUMA)
u Radiographic digitizer (Widar)
u Tissue Bank
u UTS model 100-1 (ERM)
u Zwick model Z50/TH3A (ERM)
u Cell
Key Words for R&D
Allografts
Anatomopathology
Autologous cell therapy
Bacteriology
Biomechanic
Bone induction
Bone remodeling
Delayed-union
Fracture
Infection
Limb salvage
Orthopaedic
Surgery
Transplantation
Senior Scientists
Christian DELLOYE
[email protected]
Tél. : 32(0)2 764 29 50
Awards
u Dr
D. Dufrane BELACT - 2000
A. Bavadekar EFORT – Rhodos - 2001
u Dr D. Dufrane ESACT – Tylösand - 2001
u Dr P.L. Docquier – SORBCOT– 2004
u Dr
Olivier CORNU
[email protected]
Tél. : 32(0)2 764 53 88
Xavier BANSE
[email protected]
Funding
Pierre-Louis DOCQUIER
[email protected]
u TELEVIE-FNRS
u Salus
Sanguinis fundation.
Web Site
http://rch.adre.ucl.ac.be/browse/list_alpha/ORTO
84
I
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
1
Molecular imaging of cancer and experimental
radiotherapy
Senior scientists :
u Vincent GREGOIRE
u François JAMAR
u Bruno KRUG
u Max LONNEUX
u Stanislas PAUWELS
u Véronique ROELANTS
u Pierre SCALLIET
u Thierry VANDER BORGHT
u Xavier GEETS
u Anne BOL
u Jean-Marc DENIS
u Jean GEORGE
u Hubert MEURISSE
u Stéphane VYNCKIER
u Stéphane WALRAND
u Thomas DOUMONT
u Jacques GILLART
u Daniel LABAR
Research Field and Subjects
ics, biodistribution and metabolism. Eur J Nucl Med Mol Imaging.35(7):1282-9, 2008 Jul. Epub 2008 Mar 4.
u N. Christian, J.A. Lee, A. Bol, M. De Bast, B. Jordan, V. Grégoire. The limitation of PET imaging for biological adaptiveIMRT assessed in animal models. Radiother Oncol. 2009
Apr;91(1):101-6. Epub 2008 Dec 26.
u A. Eisbruch, V. Gregoire. Balancing risk and reward in target
delineation for highly conformal radiotherapy in head and neck
cancer. Semin Radiat Oncol. 19(1):43-52. Review. 2009 Jan.
- Biological targeting in conformal (3D-CRT) and intensity modulated (IMTR) radiation therapy
- Use of functional imaging with PET and MRI for traeatment
planning in conformal radiotherapy of head and neck and brain
tumors.
- Dosimetry studies with Palladium-103
- Dosimetry intercomparisons for hadron beams
- Detection of tumor hypoxia with chemical probes
- Radiosensitization by nucleoside analogues
- Biological effects and radiobiological calibration of non conventional radiation beam.
Patent
J. Marchand, V. Grégoire, O. Josse, D. Labar (1999) European
patent n° 99870172.6 “Methods for preparing parfluorinated
[18F] radiolabelled nitroimidazole derivatives for cellular hypoxia
detection.
Representative References
Grégoire. Teaching Session A: Target Volume Selection and
Delineation in Head and Neck Tumors: Beyond ICRU Definition.
Clin Oncol (R Coll Radiol). Apr;19(3 Suppl):S9-S10, 2007. No
abstract available.
u P. M ahy , M. D e B ast , T. de G root , A. C heguillaume , J. G il lart , K. H austermans , D. L abar , V. G régoire .Comparative pharmacokinetics, biodistribution, metabolism and hypoxiadependent uptake of [18F]-EF3 and [18F]-MISO in rodent
tumor models. Radiother Oncol. 2008 Dec;89(3):353-60.
Epub 2008 Jul 21.
u P. Castadot, J.A. Lee, A. Parraga, X. Geets, B. Macq, V. Grégoire.
Comparison of 12 deformable registration strategies in adaptive
radiation therapy for the treatment of head and neck tumors.
Radiother Oncol. 2008 Oct;89(1):1-12. Epub 2008 May 22.
u J.A. Lee, X. Geets, V. Grégoire, A. Bol. Edge-preserving filtering of images with low photon counts. IEEE Trans Pattern Anal
Mach Intell.;30(6):1014-27, 2008 Jun.
u N. Christian, J.A. Lee, A. Bol, M. De Bast, B. Gallez, V. Grégoire.
Immobilization device for in vivo and in vitro multimodality
image registration of rodent tumors. Radiother Oncol. 2008
Apr;87(1):147-51. Epub 2008 Mar 24.
u P. Mahy, X. Geets, M. Lonneux, P. Levêque, N. Christian, M. De
Bast, J. Gillart, D. Labar, J. Lee, V. Grégoire. Determination of
tumour hypoxia with [18F]EF3 in patients with head and neck
tumours: a phase I study to assess the tracer pharmacokinetu V.
Partnership
u American
Association for Cancer Research (AACR)
Radiation Research Society (RRS)
u American Society for Therapeutic Radiology and Oncology
(ASTRO)
u Belgian Association for Cancer Research (BACR)
u European Laryngological Society (ELS)
u Head and Neck group of the European Organization for
Research and Treatment of Cancer (EORTC)
u Radiotherapy group of the European Organization for
Research and Treatment of Cancer (EORTC)
u European Society for Therapeutic Radiology and Oncology
(ESTRO)
u Société Belge de Radiothérapie Oncologie (ABRO)
u American
Funding
National Collaborations
FNRS – Télévie
Belgian Federation against Cancer
Walloon Region
85
International Collaborations
European Commission
INCa – C. Oscar Lambret
Key Words For R&D
Biological targeting
Radiation therapy
Functional imaging
Head and neck and brain tumors
Dosimetry
Tumor hypoxia
Nucléoside analogues
Main Equipment
radio-HPLC 1 y-spectrophotometer HPGe Canberra
GC 1 y-counter
u 1 radio-TLC (Raytec)1 β-counter A
u Phosphoimager Fuji u PET Siemens HR961 (ded. to research : human, monkey, pig,
dog,…)
u PET Philips Mosaic
u PET Siemens HR+
u SPECT Linoview
u PET-CT Philips
u Cyclotron cyclone 30 (IBA)
u Cyclotron cyclone 18 (IBA)
u Remote systems for radiolabeled molecules production
u 6
u 3
Senior Scientist
Vincent GREGOIRE
[email protected]
Tél. : 32(0)2 764 94 43
Web Site
http://rch.adre.ucl.ac.be/browse/list_alpha/IMRE
Products and Services
u Biological calibration of beams of particles by missions on site
of the team of radiobiology UCL (3-6 weeks)
u Center radiobiological experiments near Cyclotron (CERCYL):
neutron irradiation facilities, making it possible to irradiate and
treat biological samples in the same place.
86
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ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
2
Study of the effects of direct irradiation or using targeted
nanoparticles containing several radioactive atoms on the
interactions between tumor cells and endothelial cells
Senior Scientists :
u Stephane LUCAS
u Carine MICHIELS
u Bernard MASEREEL
Research Field and Subjects
Representative References
We started a close collaboration with several groups in order to
investigate the molecular mechanisms of the cell responses to
radiation with the aim to improve or to design new therapeutic
strategies for cancer patients. Two main projects are developed.
u V.
Bouchat, V.E. Nuttens, S. Lucas, C. Michiels, B. Masereel,
O. Feron, B. Gallez and T. Vander Borght. Radioimmunotherapy
with radioactive nanoparticles: first results of dosimetry for vascularized and necrosed solid tumors; Med Phys 34, 4504-4513,
2007.
u S. Lucas, G. Genard, C. Michiels, B. Masereel, O. Feron, B. Gallez, T. Vander Borght and N. Moreau. Production and preliminary
characterization of CD plasma polymerized allylamine film
(PPAA) by NRA, ERD and XPS Nucl Instr Meth Phys Res B 266,
2494-2497, 2008.
u A.-C. Wera, K. Donato, C. Michiels, Y. Jongen and S. Lucas. Preliminary results of proton beam characterization for a facility of
broad beam in vitro cell irradiation. Nucl Instr Meth Phys Res B
266, 2122-2124, 2008.
The TARGAN project is aimed to develop a nanocluster containing several radioactive atoms, coupled to a monoclonal
antibody targeting a specific marker of the tumoral endothelial
cells. Nanoparticles containing 99mTc or 90Y are functionalized
using plasma deposited polymerized allylamine film. Alternatively, gold or other nanoparticles are coated with polyelectrolytes. The amine functions of this coating are then used to
couple monoclonal antibodies that will target the nanocluster
to the tumor. In vitro and in vivo studies in mice are performed
to characterize the specificity of the targeting. Simultaneously,
modelisation for dosimetry using these radioactive nanoparticles is performed for vascularized and necrosed solid tumors.
These clusters can be used for diagnostic or therapy.
Patent
RADIOACTIVE DEVICE, 2006, EP1838354, WO2006063418.
The Télévie project is aimed to study the cell responses to various radiations. A facility for broad beam in vitro cell irradiation
has been developed in the center of Physics of matter and Radiation (PMR) of the Physics Department, using a particle accelerator (named ALTAIS). The irradiation conditions (dose rate,
energy, pulsed or unpulsed beam) are controlled in real time
and the experimental setup allows to irradiate the cells with
different particles (proton, alpha, lithium or carbon). Radiationresponsive bioassay measurements including survival curves for
tumor cells but also for endothelial cells are then performed.
In addition, changes in gene expression and cytokine secretion
are investigated. The effects of cell irradiation on co-cultures of
tumor and endothelial cells will then be studied
Partnership
u UCL
(Mont Godinne Hospital) : Prof. T. Vander Borght
u UCL (Brussels) : Prof. O. Feron, FATH, Prof. B. Gallez, CMFA
u IBA-Molecular (Fleurus)
u Institut des Radioélements (IRE) (Fleurus)
Funding
u Waleo
project TARGAN
u TÉLÉVIE
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Main Equipment
Key Words For R&D
Radiobiology
Nanoparticles
Gold
Antibody
Apoptosis
Signal transduction
Gene expression regulation
u Tandetron
accelerator and associated irradiation station
u Radioactive nanoparticle synthesis reactor (physical methods)
u All type radiation detection systems
u Nanoparticle measurement techniques (TEM, SEM, BET,…)
u Cell culture facilities
u General equipment for biochemical and molecular biology
assays
u Absorbance, fluorescence, luminescence microplate readers
u Real-time PCR, equipped for microfluidic cards
u Full proteomic plateform with Maldi and MS-MS mass spectrometers
u Confocal microscope
Senior Scientists
Stephane LUCAS
[email protected]
Tél. : 32(0)81 72 54 81
Carine MICHIELS
[email protected]
Tél. : 32(0)81 72 41 31
Products and Services
Bernard MASEREEL
[email protected]
Tél. : 32(0)81 72 43 38
u Complete
hardrontherapy platform for in-vitro cell irradiation
models for the evaluation of radiation effects
u Proteomic plateform
u Cellular
Web Sites
http://www.fundp.ac.be/recherche/projets/page_
view/05272202/
http://www.fundp.ac.be/urbc/
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ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Psycho-oncology
Senior Scientists :
u David OGEZ
u Maud COLMANT
Research Field and Subjects
Key Words for R&D
Psycho-oncology
Psychological support
Coping strategy
Systematic consultations
Psychotherapy
Consultation-liaison psychiatry
Appraisal of a systematic psychological consultation for cancer
patients.
Studies about depression, anxiety and coping strategy in oncology.
Psychotherapy in oncology.
Consultation-liaison psychiatry.
Senior Scientist
David OGEZ
[email protected]
Tél. : 32(0)2 764 21 60
Representative References
u Appraisal of a systematic psychological
follow-up for patients who suffer from cancer. International
psycho-oncology society congress 2009 (poster).
u Appraisal of a systematic psycho-oncologist consultation with
patients who suffer from breast cancer. ECCO15, 2009 (poster).
Web Site
www.centreducancer.be
Partnership
Faculty of Psychology (Pr E. Zech) - Université Catholique de
­Louvain
Main Equipment
Psychological tests, questionnaires
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ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Research institutes of international reputation are present within the Académie Louvain: the St Luc Cancer Center, with its Head
and Neck Oncology Program and the Ludwig Institute for Cancer Research (LICR). Additionally the Académie Louvain laboratories
closely collaborate with a European platform, present at Woluwe and which gathers research teams specialized in oncology clinical
trials, radiotherapy, surgical oncology, and patient advocacy (EORTC, NCI-LO, ESTRO, ESSO, ECCO).
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Cancer Center at UCL and Saint Luc academic hospital
Mission Activities
A reference centre for Europe, the Cliniques Universitaires SaintLuc Cancer Centre is a leader in cancer care in French-speaking
Belgium. The successor to the Cancer Institute, inaugurated in
Louvain in 1927, the Cancer Centre carries on a tradition of
excellence in terms of care, research and teaching.
Over the years, the Cliniques Universitaires Saint-Luc Cancer
Centre has organised itself so as to provide optimum care for
patients. Here are some things that set the centre apart:
Expertise : With its tradition of excellence and innovation, the
Universitaires Saint-Luc Cancer Centre is the leader in cancer
treatment in French-speaking Belgium in terms of numbers of
patients cared for each year. It is the only Belgian centre that
treats all types of cancer in both adults and children. This gives
its specialists a huge wealth of experience in cancer patient care.
Its location within a general teaching hospital guarantees all
patients comprehensive care of excellent quality, with particular
emphasis on the human aspect.
Our main mission is to FIGHT CANCER
By guaranteeing patients comprehensive care of optimum quality.
A global hospital : The Cancer Centre is fully integrated within
Cliniques Universitaires Saint-Luc. This means that every patient
treated in the Cancer Centre has the guarantee of global care,
which takes account of everything to do with his or her state
of health.
For example, cancer patients with diabetes will be given global
care, benefiting from the expertise of different doctors treating the cancer and the diabetes in the same location. Patients
are also guaranteed perfect communication between all carers,
thus guaranteeing each carer full knowledge of what is on the
patient’s medical file.
By developing cutting-edge research in oncology and facilitating
exchanges between clinicians and scientists.
By providing training for tomorrow’s doctors and researchers.
As part of a general hospital, we care for patients, not just
tumours. Patients thus have a guarantee that everything to do
with their health will be taken into account and they will benefit from the expertise of every Cliniques Universitaires SaintLuc specialists. Each patient’s medical file is computerised and
directly and fully accessible to every doctor. This sharing of information, combined with proximity, ensures perfect communication between staff members.
Treating patients as human beings
To guarantee optimum quality of care for all patients, the Cancer
Centre has created a job unique in Belgium, the oncology care
co-ordinator or CSO. The co-ordinator accompanies patients
throughout their treatment, playing a key role in keeping both
patients and relatives informed and supported. The co-ordinator
also ensures perfect co-ordination between the various people
involved.
In the fight against cancer, patients are at the centre of our
team-based care. Teams make their expertise and knowledge
of the various academic domains fully available, always paying
particular attention to the human aspect of patient care.
When cancer strikes, both patients and families can be plunged
into fear and distress. The support of a psychologist will be
offered, and the psychologist may be involved in all stages in
the disease.
In this perspective, we have also created a job unique in
Belgium, the Oncology Care Co-ordinator or CSO. This coordinator ensures that thorough care is provided, accompanies patients throughout their treatment, plays a key role
in keeping patients and their relatives informed and supported and provides perfect co-ordination between everyone involved.
To provide the best care, all specialists involved in diagnosing
and treating the patient must meet together beforehand to discuss the methods of the treatment.
93
Multidisciplinary approach
The Cliniques Universitaires Saint Luc Cancer Centre contains
several multidisciplinary groups, which cover all types of cancer and, as their name suggests, consist of specialists from
different disciplines: oncologists, haematologists, radiotherapists, house doctors, surgeons, radiologists, anatomopathologists and genetic specialists. Each group specialises in one
type of cancer Each patient’s case is discussed individually and
specifically during these multidisciplinary meetings, thus guaranteeing optimum care and personalised treatment, based
on the expertise of the multidisciplinary group, international
literature and the latest scientific progress in diagnostic and
therapeutic tools.
Ludwig Institute, whose laboratories are world-famous for their
cancer research.
Clinical research offers patients opportunities to test new molecules or combinations of molecules before they are marketed.
These are clinical trials offered by pharmaceutical firms and
studies initiated by the Cancer Centre clinicians.
The aim of these trials is twofold: on one hand, to offer patients
the most up-to-date treatment, and on the other hand, to
advance research in the fight against cancer. We therefore offer
patients the opportunity to benefit from the latest updated
treatments.
The forefront of innovation
Multidisciplinary groups :
Adult haematology
Breast tumours - The Breast Clinic
Cancers of the head, neck and upper respiratory system
Chest and lung tumours: Oncology and chest surgery group
Colo-rectal Tumours
Endocrine and thyroid tumours
Eye tumours
Hepato-Bilio-Pancreatic Tumours
Locomotive system or Sarcoma
Oesogastric tumours
Paedratic haematology and oncology
Pelvic Tumours
Tumeurs de la peau - Clinique du mélanome
Tumours in the central nervous system
Urinary system tumors
The teaching aspect
The Cancer Centre is an integral part of Cliniques Universitaires
Saint-Luc, which has a basic threefold teaching mission: to provide top-quality care, develop up-to-date research and offer
excellent teaching facilities.
All these activities are combined on the same site, guaranteeing optimal interaction between actors. This close collaboration
between researchers and clinicians allows us to perfect new
treatments aimed at improving the prevention, treatment and
cure of cancer. Our patients are the first to benefit from proximity and exchanges.
People
Over the years, we have created a network linking numerous
world-famous hospitals and cancer centres.
Many doctors are regularly sent abroad to improve their medical knowledge, learn new surgical techniques, and familiarise
themselves with new technology. All this keeps the Saint-Luc
Cancer Centre at the forefront with the latest innovations.
New technology
We invest continually in new equipment, to offer patients the
best care and also to help research progress.
Among our latest acquisitions is tomotherapy hi-art, a real revolution in radiotherapy, one of the first machines of its kind
installed in Europe and the first to be operational in Frenchspeaking Belgium. It helps us treat even the most inaccessible
tumours effectively.
We also have a latest generation PET-CT, which helps us provide
more efficient examinations when diagnosing certain types of
cancer.
CHIP (intra-peritoneal chemohyperthermia) is a recent technique used on colorectal cancer patients. It involves administering chemotherapy at the end of an operation during which
cancer-affected organs are removed. This technique, involving
some twenty different specialities, has improved the prognosis
for patients with advanced colorectal cancer.
Intensive research activities
The Cancer Centre is actively involved in cancer research,
through laboratories and clinical studies managed by the doctors.
Finally, in the laboratories, each tumour is individually mapped
in order to determine the hereditary risk of certain cancers and
the interest of specific targeted treatments.
A specific feature of teaching centres with a direct link to a
medical faculty, basic research is carried out in the laboratory.
At the Woluwé site of the Catholic University of Louvain (UCL),
a number of laboratories are dedicated exclusively to research
into new cures for cancer.
This is the location of ICP (Christian de Duve Institute of Cellular Pathology), an international biomedical research institute.
Among other organisations, it houses the Brussels branch of the
Methodology
Oncology boards are meant to bring together the various cancer experts in the hospital, around individual patient cases, in
order to discuss the diagnosis, treatment and follow-up strategy
that seems the most appropriate. The ultimate goal is to bring
homogeneity in the quality of care in oncology at the level of
the hospital.
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ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Contact Person
At regular intervals, depending on the type of cancer, the radiation oncologist, medical and surgical oncologist, pathologist,
specialist in imaging, research nurse, psychologist meet to discuss the new cancer cases, diagnosed since the previous board
meeting. For frequent tumours, like lung cancer, weekly meetings are required.
Prof. Marc HAMOIR
Head of cancer centre
[email protected]
Tél.: 32(0)2 764 19 76
Adress
Every individual case is discussed prior to any therapeutic intervention. The board makes proposals and a registry is maintained
for recording the board decisions. Doctors are seating as peers
and the decisions are collegial.
Avenue Hippocrate 10
B-1200 Brussels
Belgium
Web Site
It is the mission of each board to produce documented protocols for diagnosis, treatment and follow-up, the so-called guidelines or SOR (standards, options, and recommendations), and to
enforce them in the routine practice.
http://www.centreducancer.be/fr
The principles of operation are based on the collegial structure
in the decisions, the correct stadification of all the patients and
the recording of all the data in a computerized way. The treatments are applied according to the “guidelines“, strictly and
regularly confronted to the data of the literature; the doctors
of the clinic take part in many clinical studies on the level of
various national and international authorities of cancer research
(EORTC, GORTEC, …).
Structure of operation :
u investigations necessary to allow a therapeutic decision
u standardized staging (TNM).
u protocols of treatment used in routine with their limits (age,
index of performance, etc). They must be based on the evidence
(french SOR, NCI, START. ..).
u research protocols with their eligibility criteria.
u recommendations in terms of monitoring (frequency, standard examinations, patient contact or MT, etc.), including the
decentralized monitoring.
u a multidisciplinary decision-making for each patient, either
before or after surgical operation according to the anatomical
site.
u therapeutic discussion of the attitude at the time of new
events in the oncological history of a patient.
u regular update of the protocols (staging and treatment).
u discussion of research protocols and assessment.
Partnership
u EORTC,
GORTEC, GELA, SIOP
Belge contre le Cancer
u Vivre comme avant
u Cancer et psychologie
u Fondation
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Head and Neck Oncology Program – Cancer Center
Senior scientists :
u Vincent GREGOIRE
u Marc HAMOIR
u Hervé REYCHLER
u Emmanuel COCHE
u Guy COSNARD
u Thierry DUPREZ
u Benoît LENGELE
u Max LONNEUX
u Jean-Pascal MACHIELS
u Etienne MARBAIX
u Birgit WEYNAND
u Jean-Christophe DEGOLS
u Jean-Marc GERARD
u Michèle MAGREMANNE
u Pierre MAHY
u Sandra SCHMITZ
Research Field and Subjects
tion of lymph node levels in head and neck computed tomography images. Radiother Oncol., 87: 281-9, 2008.
u F. Janot, D. de Raucourt, E. Benhamou, C. Ferron, G. Dolivet,
R.J. Bensadoun, M. Hamoir, B. Géry, M. Julieron, M. Castaing,
E. Bardet, V. Grégoire, J. Bourhis. Randomized trial of postoperative reirradiation combined with chemotherapy after salvage
surgery compared with salvage surgery alone in head and neck
carcinoma. J Clin Oncol., Dec 1;26(34):5518-23, 2008.
u M. Magremann, C. Vervaet. Melanoma of the oral mucosa. Rev
Stomatol Chir Maxillofac. Jun;109(3):175-7, 2008.
u P. Mahy, M. De Bast, T. de Groot, A. Cheguillaume, J. Gillart,
K. Haustermans, D. Labar, V. Grégoire. Comparative pharmacokinetics, biodistribution, metabolism and hypoxia-dependent
uptake of [(18)F]-EF3 and [(18)F]-MISO in rodent tumor models.
Radiother Oncol., 89(3):353-60, 2008.
u A. Persu, M. Hamoir, V. Grégoire, P. Garin, E. Duvivier, H. Reychler, G. Chantrain, G. Mortier, M. Mourad, D. Maiter, M. Vikkula.
High prevalence of SDHB mutations in head and neck paraganglioma in Belgium. J Hypertens. Jul; 26(7):1395-401, 2008.
u S. Schmitz, J.P. Machiels, B. Weynand, V. Gregoire, M. Hamoir.
Results of selective neck dissection in the primary management
of head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol. 266(3): 437-43, 2008.
u S. Van der vorst, A.F. Dekairelle , L. Irenge, M. Hamoir, A. Robert,
J.L. Gala. Automated cell disruption is a reliable method of isolating
RNA from fresh snap-frozen normal and malignant oral mucosa
samples. Clin Chem Lab Med. Feb 5, 2009 (Epub ahead of print).
Evidence-based guidelines for the management of patients with
Head & Neck tumors.
First edition, September 2001
Second edition, September 2003
Third edition, May 2006
Fourth edition, June 2009
Clinical trials : see website
http://www.md.ucl.ac.be/ccmf/
http://centreducancer.be
Detection of tumor hypoxia with chemical probes
Radiosensitization by nucleoside analogues
Translational research in immunotherapy with analysis of the
immune response from vaccined patients
Use of functional imaging with PET and MRI for treatment planning in conformal radiotherapy of head & neck and brain tumors
Identification of molecular markers predictive of lymph nodes
metastasis
EGFR blockade in head and neck squamous cell carcinoma
p53 status and radiosensitivity
Partnership
Representative References
u American
u American
u P.
Castadot, J.A. Lee, A. Parraga, X. Geets, B. Macq, V. Grégoire.
Comparison of 12 deformable registration strategies in adaptive
radiation therapy for the treatment of head and neck tumors.
Radiother Oncol., 89: 1-12, 2008.
u N. Christian, J.A. Lee, A. Bol, M. De Bast, B. Gallez, V. Grégoire.
Immobilization device for in vivo and in vitro multimodality
image registration of rodent tumors. Radiother Oncol., 87: 14751, 2008.
u O. Commowick, V. Grégoire, G. Malandain. Atlas-based delinea-
Head and Neck Society: M. Hamoir
Society of Clinical Oncology (ASCO): J.P. Machiels
(Member)
u Belgian Society of Medical Oncology: J.P. Machiels (Vice secretary)
u European Society for Therapeutic Radiology and Oncology
(ESTRO): V. Grégoire (Président)
u Governing counsil of the International Federation of Head and
Neck Oncologic Societies (IFHNOS): M. Hamoir
u Groupe de contact de Pathologie cervico-faciale from FNRS:
V. Grégoire, M. Hamoir, P. Mahy, H. Reychler
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Key Words for R&D
u Groupe
interuniversitaire de chirurgie cervico-faciale: M. Hamoir
d’Oncologie Radiothérapie Tête et Cou (GORTEC):
V. Grégoire, M. Hamoir, J.P. Machiels
u Groupe radiothérapie from EORTC: V. Grégoire (treasurer and
Vice-Chairman)
u Groupe Tête et Cou from EORTC V. Grégoire, M. Hamoir,
J.P. Machiels, B. Weynand
Tumor hypoxia
Radiosensitization
Immunotherapy
Functional imaging Molecular markers
u Groupe
Senior Scientists
Main Equipment
Vincent GREGOIRE
[email protected]
Tél. : 32(0)2 764 94 43
As a multidisciplinary comprehensive center, we can profit from
the equipment of all the partners units and from the cliniques
universitaires Saint Luc.
Marc HAMOIR
[email protected]
Tél. : 32(0)2 764 19 74
Products and Services
Hervé REYCHLER
[email protected]
Tél. : 32(0)2 764 57 12
u Multidisciplinary
u Treatment
concertation
of patient with head and neck tumors
Web Sites
u R&D
u Establishment
http://www.md.ucl.ac.be/ccmf/
http://www.centreducancer.be
of guidelines and update.
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The Brussels Branch of the Ludwig Institute
for Cancer Research
Mission sive. To overcome these obstacles, the Ludwig Institute has
developed a broad-based discovery program that seeks to
understand the full complexity of cancer. Research is organized
according to the four major programmatic themes that define
the Institute : genetics, cell biology, cell signalling and immunology.
The purpose of the Ludwig Institute for Cancer Research is to
conduct long-range research programmes directed to the ultimate goal of eradicating cancer.
The Brussels branch is active in the field of cancer immunology
and cancer genetics. Main orientations of the branch are the
study of tumor rejection antigens and that of cytokines.
Research fields
u Tumor
immunology and antigen processing group :
http://www.licr.ucl.ac.be/brussels/research/tiap/tiap.html
u Genes expressed in cancer and germline cells group :
http://www.licr.ucl.ac.be/brussels/research/gecgc/gecgc.html
u Regulation of T Lymphocyte Function in Tumors group :
http://www.licr.ucl.ac.be/brussels/research/rtlf/rtlf.html
u Immunotherapy Analysis group :
http://www.licr.ucl.ac.be/brussels/research/iman/iman.html
u Therapeutic vaccination and expression profiling group :
http://www.licr.ucl.ac.be/brussels/research/tvep/tvep.html
u Cytokines in immunity and inflammation group :
http://www.licr.ucl.ac.be/brussels/research/cii/cii.html
u Signal transduction group :
http://www.licr.ucl.ac.be/brussels/research/stg/stg.html
Activities
Cancer is a major concern in human health. The prospects for
bringing cancer under control require linked innovative basic
and clinical research. In this view, Daniel K. Ludwig created in
1974 the Ludwig Institute for Cancer Research, an international
organization bringing together scientists and clinicians from
around the world. Ludwig investigators are active in many areas
of science, involving genetics, bioinformatics, immunology,
virology, cell biology and signal transduction.
Faithful to the organizing principles laid down by Mr Ludwig,
the Institute conducts its research through ten Branches, located
in seven countries. The Branch structure allows the Institute to
interact with a number of different research and clinical environments. Each Branch is focused on a research program defined by
the Branch Director in relation with the overall objectives of the
Institute. The Branches are established in association with University Hospitals, to stimulate close collaborations between research
laboratories and the clinic. By organizing and controlling its own
clinical trials programs, the Institute has indeed created a continuum that integrates laboratory and clinical research.
Partnership with UCL
In 1978 the Ludwig Institute for Cancer Research decided to
base its Belgian branch within the walls of UCL, at the de Duve
Institute. A happy collaboration between the two Institutions
has been pursued since that time. Even though the two Institutes are completely independent, the collaborations between
the scientists of ICP and the Ludwig Institute is extremely close
and the sharing of resources is considerable.
Branch staffs vary in size from 30 to over 70, and internationally
the Institute employs some 600 scientists, clinicians and support personnel. The quality of the research is monitored on an
ongoing basis by the Institute’s Scientific Committee and by an
external peer review process.
The Brussels Branch, under the leadership of Thierry Boon, specializes in cancer immunology and cancer genetics. The notion
that the immune system might be enlisted to rid the body of
cancer draws on past work at the Branch which revealed that
most human tumors bear antigens that can be recognized by
cytotoxic T lymphocytes (CTLs). Some of these antigens are
The biological properties of any given cancer cell constantly
change, allowing tumors to spread and become more aggres-
99
highly tumor-specific, others are expressed on certain normal
cells. A number of antigens have been found on many different
types of tumors, suggesting that a therapeutic strategy targeting such antigens could be used to treat a wide range of cancers. The Branch continues the search for tumor antigens, and
evaluates their therapeutic potential in vaccine trials of cancer
patients.
Staff
Total : 67
Contact Persons
Prof. Thierry BOON
Director
[email protected]
Tél.: 32(0)2 764 75 80
The Brussels Branch is also involved in research on the immunological functions of several cytokines, particularly IL-9 and IL-22,
which have been discovered at the branch. Signal transduction
by certain cytokine receptors is also under intense study.
Dario FLOREAN
Administrator
[email protected]
Tél.: 32(0)2 764 73 34
Address
Avenue Hippocrate 74 (Tower 75)
B-1200 Brussels
Belgium
Web Sites
http://www.licr.ucl.ac.be/
http://www.licr.ucl.ac.be/brussels/research/tiap/
tiap.html
http://www.licr.ucl.ac.be/brussels/research/gecgc/
gecgc.html
http://www.licr.ucl.ac.be/brussels/research/rtlf/rtlf.
html
http://www.licr.ucl.ac.be/brussels/research/iman/
iman.html
http://www.licr.ucl.ac.be/brussels/research/tvep/
tvep.html
http://www.licr.ucl.ac.be/brussels/research/cii/cii.
html
http://www.licr.ucl.ac.be/brussels/research/stg/stg.
html
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The European CanCer Organisation – ECCO
Introduction
without whose research there would be no advances in treatment and care.
ECCO – the European CanCer Organisation (formerly FECS –
the Federation of European Cancer Societies) is a Non-Profit
Organisation that serves as an interconnective platform to
respond to all stakeholders in oncology Europe-wide, promote
multidisciplinarity and advance education through the organisation of leading conferences and timely initiatives.
Through its 24 member organisations – each representing the
interests of their respective professions/groups spanning the
entire spectrum from basic, applied and translational research
to practice, treatment, care, prevention and advocacy – ECCO
not only serves over 50,000 professionals but also benefits the
oncology community at large.
ECCO also plays an important role in advancing education
through the implementation and development of initiatives and
programmes such as its eLearning educational opportunities
online for oncologists and researchers, its patient information
section aimed at patient advocates and organisations, as well as
a special Young Professionals zone which is being set up to cater
to the needs of young physicians, practitioners and scientists.
With the goal of ultimately establishing a harmonised CME
system in Europe, ECCO also endorses and actively promotes
the Accreditation Council of Oncology in Europe (ACOE) - the
unique European multidisciplinary accreditation body in oncology through which to endorse the quality, value and recognition
of Continuing Medical Education (CME) across Europe (visit:
www.acoe.be).
Mission
ECCO exists to uphold the right of all European cancer patients
to the best possible treatment and care, and promote interaction between all organisations involved in cancer research, education, treatment and care at the European level.
Activities
Following the philosophy that every cancer patient deserves
the best, ECCO’s core activities focus on creating awareness of
patients’ needs and wishes, encouraging progressive thinking in
cancer policy, training and education, and advancing European
cancer research and its application through the organisation of
international multidisciplinary meetings.
The continued support, willing and collaboration of ECCO’s
member societies and a unified approach aimed at strengthening policy on cancer are central to these efforts. To ensure that
cancer stays at the top of the EU health and research policy
agenda, ECCO, through the expertise of its Policy Committee,
aims to provide the collective voice of European oncology professionals and engage with policymakers to promote the interests of cancer patients, those who care for them, and those
Partnership
The partnership of ECCO with UCL is mainly through the membership of its member societies, some of which are also established on the Woluwe UCL campus including the European
Society for Therapeutic Radiology and Oncology (ESTRO), the
European Society of Surgical Oncology (ESSO), the European
Oncology Nursing Society (EONS), the European Organisation
for Research and Treatment of Cancer (EORTC) and the European Society for Paediatric Oncology (SIOPE).
ECCO’s especially appointed Committees welcome physicians,
researchers and oncology professionals from the UCL to actively
contribute to the implementation of ECCO’s mission and objectives.
In addition, their participation in ECCO’s educational programmes as well as conferences organised by ECCO – in particular the joint biennial ECCO – ESMO Multidisciplinary Congresses
either as faculty members, speakers or participants contribute
to further developing interaction with UCL.
101
Staff
ECCO incorporates a staff of 21 highly dedicated and driven
individuals, who, in embracing ECCO’s mission, have collectively defined their own vision and values of ECCO. To find
out more about who we are and what we do visit the ECCO
website at: www.ecco-org.eu (select ‘Contact’).
Contact Person
Amanda WREN
Communications Manager
[email protected]
Tél. : 32(0)2 775 02 48
Address
ECCO – the European CanCer Organisation
Avenue E. Mounier 83
B-1200 Brussels
Belgium
[email protected]
Tél. : 32(0)2 775 02 01
Fax : 32(0)2 775 02 00
Web Site
ECCO communicates and connect with the European cancer
community through its website where visitors can browse the
latest news, issues and comment, select from a wide variety
of educational resource and tools, and discover the many reasons for attending some of the leading congresses and conferences in oncology across Europe: www.ecco-org.eu
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ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
European Organisation for Research and Treatment
of Cancer-EORTC
Mission
therapeutic benefit for patients.
Establishing new standards of cancer care with high-quality
research
After testing promising agents in the laboratory and on animals,
the next step is testing on humans; these clinical studies will
determine whether or not a new anti-cancer agent will be registered, i.e. approved by health authorities and then marketed.
Activities
The European Organisation for Research and Treatment of Cancer (EORTC) is an international association under Belgian law,
created in 1962 by prominent European cancer specialists.
The aims of the EORTC are to promote, coordinate, analyze and
publish cancer research performed by multi-disciplinary groups
of clinicians and scientists in Europe. These research groups
include surgeons, radiotherapists, chemotherapists, pathologists, immunologists, basic researchers and numerous other
specialists as well as health care professionals. The ultimate goal
of the EORTC is to establish state-of-the-art cancer treatment
to improve survival rate, quality of life and quality of care for all
patients with cancer.
The EORTC is primarily devoted to :
– Translational research and clinical studies, to evaluate new
anti-cancer agents including cytotoxic drugs but also innovative agents as well as modalities such as vaccines, biological
response modifiers and other novel treatments resulting from
breakthrough discoveries in genomics etc...
– High-quality clinical research, to establish optimal therapeutic
strategies via large multi-center clinical studies in a multidisciplinary approach leading to state-of-the-art treatment and quality of cancer care.
The EORTC headquarters
The Headquarters play a coordinating role in all activities and
deal with the scientific, legal and administrative issues related to
the EORTC. The Headquarters also include the Education Office
and the Cancer Communication Office.
Progress in the treatment of cancer requires high quality research
The EORTC is collaborating with the pharmaceutical industry to
decrease the time needed to develop new anti-cancer agents
and to minimize the delay between laboratory discoveries and
The EORTC also promotes and funds translational research on
new compounds/ concepts discovered in universities and private research institutions. In this way, it facilitates the passage of
experimental discoveries into state-of-the-art treatment.
Evaluation of the best therapeutic approaches and development
of new standards of cancer care
EORTC clinical groups, are dealing with a specific type of cancer (breast cancer, lung cancer, gastrointestinal cancer, genitourinary tract cancer, leukemia, soft tissue and bone sarcoma and
others) or therapeutic modality (radiation therapy).
These groups conduct large clinical trials to quickly assess a
sufficient number of patients for the results to be statistically
meaningful, convincing and widely applicable and thereby to
have maximum impact on the quality of cancer care. These
results are analyzed in a scientific, objective and independent
manner at the EORTC Headquarters.
All studies are conducted according to national legal and ethical
requirements as well as to the international Guidelines of Good
Clinical Practice.
All EORTC research projects and clinical studies are peer
reviewed and have to be approved by the relevant committee
including the protocol review committee.
The EORTC Headquarters, a unique center of excellence in Europe
Overall, there are more than 6.500 new patients treated each
year according to EORTC protocols.
All research observations made by EORTC members are forwarded to the EORTC Headquarters which comprises more than
160 staff members (14 nationalities) including medical doctors,
statisticians, quality of life specialists, health economists, lawyers, other scientific and administrative staff, computer specialists, as well as research fellows and health care professionals.
103
The Headquarters’ methodology (working procedures and Standard Operating Procedures) to evaluate new anti-cancer agents
and to conduct clinical studies was filed at the Food and Drug
Administration in 1998. This greatly facilitates the submission of
EORTC clinical data for drug registration in the USA.
The Headquarters computerized clinical trials management system (VISTA) interfaces with the EORTC website. The central registration and randomisation server (ORTA) allows clinicians to
enroll their patients into EORTC clinical studies 24 hours a day.
E-forms is a remote data entry system developed by the EORTC.
A permanent Independent Data Monitoring Committee reviews
the status of clinical trials and makes recommendations on
safety and efficacy leading to trial’s continuation, modification
and/or discontinuation.
Quality control procedures are conducted by the Quality Assurance Unit in collaboration with the Quality Assurance Committee.
The overall functioning of the groups is reviewed by the Scientific
Audit Committee, an advisory committee to the EORTC Board.
The activities of the EORTC Headquarters are evaluated regularly by a committee of experts from the National Cancer Institute (NCI) of the USA. These assessments have always been very
positive and the financial support allocated to the EORTC Headquarters by the NCI has been continuous since 1974.
Other sources of funding for Headquarters are the EORTC Charitable Trust, the Fonds Cancer, corporate sponsorship, private
donations and The National Lottery of Belgium. In addition, support is provided by the pharmaceutical industry (for clinical studies on new anti-cancer agents performed in cooperation with
the EORTC) and occasionally by the European Commission (for
specific research projects).
The EORTC has initiated a European tumour bank project to
improve and harmonise the histological review and the prospective tissue collection to facilitate translational research in
the context of EORTC trials, by providing rapid access to tumour
tissues and to clinical databases.
“Strength through unity”
The EORTC is a unique research network which coordinates the
research of about 2000 European clinicians and scientists and
works in more than 300 university hospitals or affiliated institutions located in 32 countries.
There is a true need to promote participation of all partners in
clinical trials in Europe and worldwide. Therefore the EORTC
is also actively involved in intergroups studies. The Intergroup
office deals with all logistic, legal and methodological issues to
enable inter-group collaboration.
Publication of the results of EORTC research
Every year, the EORTC has hundreds of scientific articles published in prestigious international peer reviewed journals and
over 250 scientific communications are presented at international scientific meetings.
This wide dissemination of EORTC studies plays a crucial role in
assuring optimal treatment of all patients including for those
treated outside research oriented institutions.
Partnership with UCL
In 1972, the National Cancer Institute established his liaison
office adjacent to the EORTC headquarters on the UCL campus,
in Brussels.
Scientific collaborations with St Luc Hospital and Ludwig Institute.
Contact Person
Françoise MEUNIER
Director General
[email protected]
Tél. : 32(0)2 774 16 30
Address Avenue E. Mounier 83 bte 11
B-1200 Brussels - Belgium
Web Site
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www.eortc.be
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ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
European Society Of Surgical Oncology – ESSO
Mission
The European Society of Surgical Oncology (ESSO) was founded
in 1981 to advance the art, science and practice of surgery for
the treatment of cancer.
u ESSO provides surgical expertise and support for ECCO – the
European CanCer Organisation’s Congresses, of which ESSO is
co-organiser
Partnership
ESSO aims to promote the highest standards of surgical care
in the management of patients with solid tumours. By facilitating the dissemination of knowledge and expertise, ESSO strives
to ensure that the highest possible standard of surgical treatment is available to cancer patients throughout Europe. Further,
the society aims to optimise the clinical management of cancer
patients through multidisciplinary collaboration.
ESSO is a member society of ECCO-the European Cancer
Organisation, and has interconnections with the other cancer
societies and organisations also established onsite.
Physicians from the UCL regularly contribute as speakers or
participants to the scientific programme of ESSO biennial congresses or as teachers in courses organised by the society or in
joint co-operation with ECCO, EONS, EORTC, ESTRO or SIOPE,
the other onsite cancer organisations.
Activities
Staff
Leading Education, Exchange and Debate
ESSO is highly committed to promoting education in cancer surgery. By providing the European Surgical Oncology community
with a wide range of educational opportunities and initiatives,
ESSO contributes to the advancement of knowledge and expertise in oncology surgery and the clinical management of cancer
patients:
u ESSO’s Biennial Congresses provide oncology surgeons with
the most expansive and interconnective educational platform in
Europe;
u ESSO’s Training Fellowship Programme offers young surgeons
the opportunity to visit a specialist centre, expand experience,
and acquire new insight;
u ESSO organises multidisciplinary projects and courses in
partnership with other leading organisations such as: quality
assurance project on outcomes of cancer treatment, advanced
course on interdisciplinary treatment of lung cancer, advanced
course in Colorectal Metastases Management, masterclass on
colorectal cancer, etc.
u ESSO offers Travel Fellowships to attend ESSO Congresses
and the ECCO/AACR/ASCO Workshop on Methods in Clinical
Cancer Research
u ESSO furthers education through the European Board of Surgery examination and Core Curriculum in Surgical Oncology
Executive Director : Tatjana ROMANYK
Administrator : Carine LECOQ
Contact Person
Carine LECOQ
ESSO Administrator
[email protected]
Tél. : 32(0)2 537 31 06
Address
Avenue E. Mounier 83
B-1200 Brussels - Belgium
Web Site
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www.esso-surgeonline.org
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ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
European Society for Therapeutic Radiology
and Oncology-ESTRO
Mission
- ESTRO scientific meetings
The European Society for Therapeutic Radiology and Oncology,
ESTRO, was founded in Milano in September 1980 as a Society
of individual members working in the field of radiotherapy and
oncology.
Each year, ESTRO organises several scientific meetings, reviewing
advances in radiotherapy and oncology and encouraging a multidisciplinary approach to the treatment of cancer.
- ESTRO education program
Its principal objectives are to :
u Foster radiation oncology in all its aspects
u Develop benchmarks, tools and methodologies for assuring
the quality of radiation oncology in Europe and stimulate their
implementation in clinical practice
u Improve the standards of cancer treatment by enscribing
radiation oncology as a clinical specialty in the multidisciplinary
approach to cancer treatment
u Promote international exchange of scientific information on
radiotherapy & oncology and related fields of science such as
radiophysics and radiobiology and stimulate research
u Develop guidelines for education and best practice in radiation oncology and associated professions
u Establish relationships and co-operation with international,
regional and national societies and bodies in the field of radiation oncology.
The society’s continuously evolving and expanding offer of
course modules is designed to assist national radiation oncology, medical physics and radiation technologists’ societies in the
provision of adequate teaching for the topics described as mandatory in the European curricula developed by it. Gradually also
the offer in the field of continued professional development is
being built up and broadened.
The ESTRO teaching courses play an important role in the growing cohesiveness of the European radiation oncology community. By adding a European dimension to the education of young
professionals, mobility within Europe is both encouraged and
supported. The ESTRO Board also recognised the importance of
exchange and transfer of expertise by committing resources to
the extremely successful Technology Transfer Grant Programme
for short visits to other departments which, in previous years,
was funded by the European Commission
Activities
ESTRO, coveted and imbedded in its early years in the UZ
KULeuven hospital envi-ronment, moved in 1997 to the UCL
site to join other cancer societies such as EORTC and FECS
already established there.
ESTRO’s core activities are articulated in its mission statement.
Besides activities for the exchange of scientific information and
for the education and training of radiotherapy professionals, as
evidenced below, ESTRO has generated with support from various EU programmes, a broad range of initiatives for the development of guidelines and infrastructures for the surveillance
of the quality in RT, for drafting best practice guidelines and
encouraging research for the optimisation of radiation oncology.
Partnership with UCL
Besides its geographical proximity to the UCL Faculty of Medicine campus as a tenant in an UCL-owned building, ESTRO
became closely associated with its ”landlord” through the
active involvement of department heads and other professionals
of the UCL radiation oncology department in ESTRO structures
and activities.
UCL experts have served or still function as members of ESTRO
scientific, website and education committees, are active as
members of the society’s international teaching faculty, coordinators or co-partners in ESTRO projects, co-editor of its journal
and other publications. Finally they served in the ESTRO Board
as secretary and executive administrator.
107
Staff
International Board : 15
Staff onsite : 12
Contact Person
Alessandro CORTESE
[email protected]
[email protected]
Tél. : 32(0)2 775 93 40
Address
ESTRO
Avenue E. Mounier 83
B-1200 Brussels
Belgium
Web Site
http://www.estro.org
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ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
The U.S. National Cancer Institute Liaison Office - NCI L.O.
Mission
The US National Cancer Institute is the US Federal Government’s principal agency for cancer research and training. It coordinates the National Cancer Program, which conducts and supports research, training, health information dissemination and
other programs with respect to the cause, diagnosis, prevention, and treatment of cancer.
The NCI Liaison Office in Brussels was created in 1972 and was
initially part of NCI’s Division of Cancer Treatment & Diagnosis.
It is now an integral part of the Office of International Affairs.
It facilitates the interchange of information, ideas, experimental drugs, scientific expertise and scientists, and works in collaboration with the EORTC, with Cancer Research United Kingdom (CRUK), as well as with other European cancer research
institutes and pharmaceutical/chemical industries, in areas of
mutual interest in preclinical and clinical cancer research. The
collaboration has been extended to closer interactions with the
International Network for Cancer Research & Treatment, INCTR,
a unique organization dedicated to helping patiens in developing countries, which is also located in Brussels and partially supported by the NCI’s Office of International Affairs.
The Office is the European hub for NCI’s TELESYNERGY® Medical Consultation WorkStation*). This sophisticated videoconference system allows numerous research collaborators at
greatly separated geographic sites to interact as if they were in
the same room, viewing the same medical images. By integrating powerful telecommuniations technology into health care
research and delivery, telemedicine enables clinical researchers
to simultaneously communicate and view and manipulate data
necessary for collaborations, including patient diagnosis and
care, such as x-ray films and pathology samples.
Activities
The Office provides a European contact point for NCI and the
European cancer research community, and assists NCI staff in
matters related to European collaborations and cancer research
programs.
It acts as a link between NCI headquarters in Bethesda and
EORTC, CRUK, and other European cancer research organizations and Institutes (i.e. the Mario Negri Institute in Italy, the
Max-Delbrück Zentrum in Germany) as well as the European
pharmaceutical/chemical industries.
For more than 25 years the Office has assisted with the international exchange of experimental drugs for preclinical and clinical
evaluation. A web-based submission process for new potential
anti-cancer compounds to be tested in NCI’s in-vitro screen has
been made available via the NCI Developmental Therapeutics
Program (DTP) website (http://dtp.nci.nih.gov), and the NCI L.O.
assists European suppliers with inquiries of all kinds related to
the submission and selection of their compounds.
The Office collects, submits and updates European cancer
research protocols for the Office of Communications and Education, International Cancer Research Databank Branch (ICRDB),
NCI, for inclusion in NCI’s clinical database PDQ http://www.
cancer.gov. The office actively seeks new European groups
with an interest to submit their research protocols to the
NCI’s clinical protocols database. It also coordinates the additional review of EORTC PhIII protocol outlines by selected NCI
specialists.
Through the NCI Liaison Office, the NCI is represented on various European committees involved in new drug development,
as well as on the EORTC Board and Council and the CRUK PhI/II
clinical trials committee. The office assists with the organization
of joint NCI-European meetings and symposia, and coordinates
the use of the Telesynergy® Medical Workstation.
*) TELESYNERGY® Medical Workstation
Researchers of the National Cancer Institute and the Center for
Information Technology of the U.S. National Institutes of Health
developed TELESYNERGY®, a telemedicine system with broadcast-quality multi-site teleconferencing capabilities that is also
capable of transmitting most types of diagnostic-quality medical images. By making the knowledge and experience of oncology experts accessible regardless of where in the world those
109
experts are, TELESYNERGY® has the potential to dramatically
accelerate cancer research and improve cancer care by facilitating unique collaborations and connections.
Note : The TELESYNERGY® Workstation is available to outside
collaborators for a very low cost. For further information please
feel free to contact the NCI Liaison Office.
Staff
3
Contact Person Susanne RADTKE
Programs Manager
[email protected]
[email protected]
Tél. : 32(0)2 772 22 17
Partnerships with UCL
Through the collaboration with EORTC (European Organization
for Research and Treatment of Cancer)
Address Avenue E. Mounier 83
B-1200 Brussels
Belgium
Web Sites http://ncilobrussels.cancer.gov
Website for NCI :
http://www.cancer.gov
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ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Key Words Index
2-chlorodeoxyadenosine (cda)
G2
2D-DIGE
E2
ABCG2
B8
Academic clinical trials
F1
Adaptive radiotherapy
C1
Allografts
H1
AML
F2
Anatomopathology
H1
Anergy
D5
Angiogenesis
C2, G3, G8
Antibody
I2
Antigen processing
D4
Antisense-oligonucleotides
G10
Anti-tumor activity
G3
Apoptosis
B1, B2, B6, B7, B9, G1, G2, G7, I2
Applied statistics
A2
Artificial ovary
A1
Atlases
C1
Auto-antibody
E2
Autologous cell therapy
H1
Autophagy
B1, B2, B6, G7
Bacteriology
H1
B-cell chronic lymphocytic leukemia
G2
Bcl-2 family members
B7
Bcr-Abl
B2
Biochemistry
D3, D4
Biocompatibility
C2
Biological targeting
I1
Biomarker
E2, C2, E1
Biomaterials
C2
Biomechanic
H1
Bone induction
H1
Bone remodeling
H1
Breast cancer
B10
Calcium
B9
Cancer stem cell
B8
Cancer treatment
D2, G6, G11
Cancer vaccines
D2, D3, D4, F1
Cancer
B2, C2, G2
Cancer-germline genes
Cancerology
Carbonic anhydrase
Cationic-polymers
CD44
Cell coat
Cell death
Cerebral tumor
Chemoprevention
Chemoresistance
Chemotherapy
Clinical medicine
Clinical Studies
Clinical trials
CLL
Consultation-liaison psychiatry
Controlled-synthesis
Coping strategy
Cryopreservation
CTL
Cytokine
Cytology
Cytolytic T lymphocytes
Delayed-union
Deoxycytidine kinase (dck)
Diagnosis
Diagnostic
DN
Dna damage response
DNA methylation
DNA repair
Dose accumulation
Dosimetry
Drug design
Drug discovery
Drug evaluation
Drug library
Endoplasmic reticulum
Epidemiology
111
B5
B1, D2, D3, G10
G6
G10
B8
B8
B1, B2
C4
G5
B9
B6, C2, F3, G1, G7
F2
E1
A2
F2
J1
G10
J1
A1
D5
B3
F3
D2
H1
G2
E1, F3
C3
G11
G2
B5
B5
C1
I1
G11
G3
A2
G3
B9
A2
Epigenetic modifications
EPR
ER stress
ES cells
Expression profiling
Feature Selection
Fertility preservation
Fertility
Fludarabine
Follicle isolation
Fracture
Free radicals
Functional imaging
Galectin-3
Gastroenterology
Gene expression regulation
Gene expression
Gene Profiling
Gene regulation
Gene-silencing
Genomic stability
Glioblastoma
Glioma
Glycobiology
Glycocalyx
Gold
Growth factor
HDAC
Head and neck and brain tumors
Health- and medical statistics
Hematology
HIF
High Throughput Technologies
High-throughput screening
Histology
Histone deacetylase
Hodgkin
Hox
Hsp90
G11
C2
B2
B4
D1
E1
A1
G1
G2
A1
H1
C2
C2, I1, K2
D5
G5
G7, I2
B5, B6
E1
B10
G10
B5
C4
C4
D5
B8
I2
B3
G11
I1
A2
F2
G4
E1
G3
F3
G11
F2
B10
B2
Hyaluronan
Hyaluronic acid
Hyaluronidase
Hypoxia
IDO inhibitors
IDO
Image registration
Image segmentation
Imaging
Immune escape
Immunology
Immunotherapy
Inducible melanoma model
Infection
Inhibitor
Integrin ligands
Interaction
Interactors
Interleukin
Internal medicine
Intra-operative MRI
JAK
Keratinocytes
Lactate
Leukemia
Limb salvage
Liver tumors
Liver
Lung cancer
Lymphocyte
Lymphoid malignancies
Lymphoma
MAGE gene
Mammography
Medicinal plant
Melanoma
Menadione
Metallic-complexes
Metastases
112
B8
B8
B8
B6, G3, G7, G8
D3
G6
C1
C1
C2
D3
D2, D3, D4, D5
D1, D2, D3, D4, F1, F3, G6, K2
D3
H1
G6
G8
C3
B10
B3
F3
C4
B3
G10
G4
B2
H1
G5
G5
F3
D5
G2
F2
B4
C3
G3, G9
D1, D2, D5
B2
G10
G4
ACADÉMIE UNIVERSITAIRE LOUVAIN - C a n c e r o l o g y
Methyl transferase
Microarray Data
Microarray
Mitochondria
Molecular and cellular biology
Molecular biology
Molecular markers
Molecular targeted therapies
Monocarboxylate transporter
Mouse
MRI 3.0 Tesla
MRI
Multiple myeloma
Myeloma
Nanoparticles
Natural products
Neovascularisation
Neuropathology
Neurosurgery
NMR
Nucleoside analogues
Nucléoside analogues
Occupational medicine
Ontology
Orthopaedic
Ovarian carcinoma
Ovarian tissue
Ovarian toxicity
Oxidative stress
Oxygen
p53
Pbx
Peptidomimetics
Pharmaceutical sciences
Pharmacognosy
Pharmacology
Pharmacotherapy
Phase I/II
Phototherapy
G11
E1
B6
B7, B9
B7
F3
K2
F1
G4
G1
C4
C2
F2
B1
G8, I2
G3
G1
C4
C4
C2
G2
I1
A2
C3
H1
D5
A1
G1
B2
C2
B7
B10
G8
G9
G9
C2
A2
F2
G10
Polo-like kinase 2 (plk2)
Polycythemia vera
Polymeric micelles
Post-chemotherapy
Post-translational modifications
Predictive
Prevention
Preventive medicine
Prognosis
Prognostic factor of molecular markers
Prognostic
Proteasome
Protein phosphorylation
Proteomic
Psychological support
Psycho-oncology
Psychotherapy
Pulmonology
Radiation therapy
Radiobiology
Radiosensitization
Radiotherapy
Randomization
Receptors
Recombinant mice
Resistance
Scaffold
Segmentation
Semantics
Separation techniques
Signal transduction
Skin-carcinoma
Spectroscopy
Spin trapping
STAT
Stem cell transplantation
Stem cells
Structural chemistry
Surgery
113
G2
B3
G8
A1
B7
E2
C3
A2
E1
F3
E2
D4
G2
B1, E2
J1
J1
J1
F3
I1
I2
K2
C2
F2
B3
B10
B6, G7
A1
C3
C3
G9
B1, B3, B6, G7, I2
G10
C2
C2
B3
F2
B5
G9
C4, H1
Surgical medicine
C4, F3
Systematic consultations
J1
TDO
G6
Telomerase and alternative lengthening of telomeres
B5
Telomeres
B5
Testicular tissue
A1
Transcription factors
B10
Transfection
G10
Transgenic mice
B4
Translational research
F1
Transplantation
A1, H1
Treatment monitoring
E2
Treatment
F3
TRP
B9
Tumor antigens
D2, D3, D4, F1
Tumor hypoxia
Tumor metabolism
Tumor microenvironment
Tumor resistance
Tumor suppressor genes
Tumor targeting
Tumor
Tumor-associated antigens
Usability
User-centered design
Vaccination
Vaccine
Visualization
Vitamin C
114
G4, I1, K2
G4
G4
D2
B7
G8
C2, D5
E2
C3
C3
D1
D5
C3
B2
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