Future of CCA/V-ICI 2008-2012 (24 April 2008)
Future of CCA/V-ICI
2008-2012
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
Introduction
CCA/V-ICI aims to take and hold a leading position in fundamental and patient related research in cancer and
immunology, to improve curative and palliative patient care and to be an attractive partner for external
collaboration.
The projects in CCA/V-ICI are grouped in 4 research programs:
1. Oncogenesis
2. Immunopathogenesis
3. Disease profiling
4. Therapy
The research programs centre around themes, and together they form a continuum from bench to bedside. The
focus is on specified types of oncological and immunological malignancies for which bench to bedside expertise
is present in a substantial group of fundamental and clinical researchers.
Tumortypes:
- Lung cancer
- Colorectal cancer
- Breast/ovarian cancer
- Head and neck cancer
- Leukemia/lymphoma
- Prostate cancer
- Cervical cancer
- Brain tumor
Immunological diseases:
- Rheumatoid arthritis
- Inflammatory Bowel Disease
- Coeliac Disease
These 4 programs each have defined their themes and perspectives in this overview.
Specific Actions for 2008
From the Future Plan and the SWOT analyses of the individual programs, specific focus and actions for 2008
can be identified:
1.
2.
3.
4.
Imaging Facilities (including Trainings Centre)
Central Clinical Trial Support (Office) and good interaction with the department for Clinical Epidemiology
and Biostatistics
Fase I/II unit for clinical trials
Biobanking infrastructure
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
CCA/V-ICI program 1: Oncogenesis
Program leaders:
Prof. R.H. Brakenhoff, PhD (Otolaryngology/Head and Neck surgery)
Prof. H. Joenje, PhD (Clinical Genetics)
Prof. P.J.F. Snijders, PhD (Pathology)
Program 1 covers both basic and translational research and is divided into three sub-themes:
1. Viral oncogenesis
2. Cancer genomics
3. Genetic predisposition
A major common objective of the research brought together in this program is to identify and characterize viral
and non-viral cancer genes as well as genes responsible for inherited cancer predisposition. Their roles in
oncogenic pathways are evaluated in models and clinical material. In addition, molecular markers are sought
that may be utilized for a) screening for cancer and precancerous lesions, b) risk assessment of precancerous
lesions, and c) cancer prevention. To this end an integrated bench to bedside approach is followed
encompassing: 1) marker identification and clinical validation, 2) test development, validation and up-scaling by
robotics, 3) risk group identification, 4) cost-effectiveness modelling, and 5) public acceptance studies.
Screening studies are running for oral precancer, colorectal cancer and cervical cancer, in various risk groups,
and often in the context of population-based screening trials.
1. Viral oncogenesis focuses on the role of human papillomaviruses (HPVs) and Epstein Barr virus (EBV) in
the development of human cancers, such as anogenital cancers, head and neck cancers, and lymphomas.
Virus-induced oncogenic progression is investigated using both in vitro models and clinically well-defined
patient material, and the genes involved in this process are identified and characterized. Viral and host
markers are already being tested in screening and clinical trials for their capability to assess the risk of
premalignant disease with an increased sensitivity and specificity compared to currently existing methods,
and newly identified markers will be investigated likewise.
2. Cancer genomics aims at testing progression models for several human cancers, such as head and neck,
lung, gastrointestinal, cervical and ovarian cancers, using well-characterized cohorts of patients and stateof-the art high-throughput methods for genetic, epigenetic, transcriptome and proteome analyses. Candidate
cancer genes are identified, placed in their respective cancer pathways, and tested for their oncogenic
capacity with the aid of in vitro models. Promising progression markers are evaluated in clinical studies.
3. Genetic predisposition aims at understanding the molecular mechanisms of genome destabilization, as
related to the occurrence of cancer, both familial and sporadic. Attention is currently focusing on Fanconi
anemia (FA), for which the pathway is being unravelled (13 FA genes known to date) and mouse models
are being developed. It is recognized that a subset of sporadic cancers may possess a cellular FA phenotype,
which might be exploited through targeted therapeutic intervention. The possibility to sensitize (resistant)
tumor cells by inhibition of the FA/BRCA pathway will also be explored. Recently the genetic
predisposition to breast/ovarian and colorectal cancer has come into focus and will be developed during the
years to come.
A strong aspect of the research brought together in this program is that patient-oriented research is
complemented by unique model systems allowing to dissect the carcinogenic process in the laboratory. These
model systems include: HPV-transformed cultured keratinocytes mimicking cervical carcinogenesis (Pathology),
conditionally immortalized mucosal keratinocytes allowing unraveling of the carcinogenic cascade mimicking
head and neck carcinogenesis (ORL/HNS), and transgenic animals to study the role of genomic instability in the
origin of cancer (Clinical Genetics).
Perspectives
Within the next five years, we foresee to have established a novel, more cost-effective algorithm for cervical
screening that incorporates HPV testing, and to add additional biomarkers to improve the specificity of the
screenings algorithm. We will also have developed (epi)genetic screening assays for colorectal and oral cancer
and precancer detection, and gained insight in the cost–effectiveness of population-based screening programs in
the various risk groups. In addition, we expect that the function of several existing candidate-cancer genes of
head and neck cancer, gastrointestinal cancer, lung cancer and cervical cancer will have been elucidated and
their impact on human cancer evaluated. We further expect to have detailed progression models worked out for
head and neck cancer, cervical cancer as well as gastrointestinal cancers, and to have identified novel candidatecancer genes that play a role in the development of these tumors using a combined approach of functional
genetic screens, validation of putative targets by genetic analysis of tumor DNA and testing in models.. Novel
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
genes involved in the FA pathway and other chromosome fragility syndromes will have been mapped and/or
identified. Mouse models for genome destabilization syndromes will have been generated and the role of FA
genes in sporadic human cancers ascertained. Finally, we will have established whether loss of the FA pathway
makes cells hypersensitive to inhibition of other biochemical pathways in so called synthetic lethality screens.
This information may be applicable to develop new non-genotoxic therapies for sporadic cancers with the FA
phenotype. In addition, targeted interference with the FA/BRCA pathway will be explored as a means to
sensitize (resistant) tumor cells for chemotherapy.
In general terms: knowledge of the molecular alterations leading to cancer, as to be gained from this V-ICI
program, will be of vital importance for the development of new measures to successfully prevent and/or treat
cancer in the human population.
Summary of the research aims for the coming 5 years:
1. Elucidation of specific genomic stabilisation mechanisms and the role of deficiencies in these mechanisms
in the occurrence of cancer, both familial and sporadic. Interference with recognized targets will be
explored as a means to sensitize tumor cells. This approach includes in vitro model systems as well as
animal models.
2. Determination of the role of specific signal transduction cascades in the origin of sporadic tumors.
3. Establishing the exact role of oncogenic viruses in the origin of cancer, in particular HPV and EBV. This
includes the identification of viral cancer genes and additional genetic and epigenetic alterations essential
for the tumors they induce. The roles of these genetic alterations in oncogenesis will be assessed, both in in
vitro models and in the cancer patient.
4. Unraveling the carcinogenic process in squamous cell carcinoma of the upper aerodigestive tract, both in in
vitro models, and in the cancer patient. This includes the recognition of the signaling pathways that are
most relevant in these tumors, and can be exploited for development of treatment strategies.
5. Detection of new markers to monitor progressive precursor lesions of the cervix, head and neck, colon, lung
and ovarium that may develop into carcinoma. .
6. Development and improvement of high-throughput molecular diagnostic methods for secondary prevention
of cervical (i.e. scrapings), head and neck (i.e. scrapings), colorectal (i.e. faeces), and lung (i.e. sputum)
cancer.
Collaboration
This program is build around the three mainly participating departments: Pathology, Otorhinolaryngology/Head
& Neck Surgery, and Clinical Genetics. The collaboration not only involves common research interests, but also
extends to the organization of the annual master course Oncogenesis. The program leaders meet at least monthly,
to make optimal use of opportunities for collaboration. The recent development of an institution for early
diagnosis and prevention of cancer (Cancer Center Amsterdam, in collaboration with V-ICI) has added new
perspectives on a fruitful collaboration within and amongst the various programs. Especially the establishment of
a “Polikliniek Familiaire Tumoren”, with a separate Laboratory for Clinical Oncogenetics, will stimulate further
collaboration within the program. Collaboration with the groups of Prof. R. Bernards, Dr. D. Peeper, Dr. R.
Agami, Prof. S. Horenblas, and Prof. H. Te Riele (all from the Netherlands Cancer Institute) has been established
and is expected to pay off in the years to come.
Means
Modern technology such as proteomics technology, microarray platforms and functional genetic screens are
needed to identify new biomarkers and candidate-cancer genes that may be exploited as reliable risk-predictors
for the progression of premalignant lesions, especially in cervix, colon, the head & neck region, and the lung. In
addition, biostatistical support is warranted, as well as investment in high-throughput robotics.
SWOT analysis
Strength:
- Intense and successful collaboration both in research and education between the participants, all from only 3
departments
- High impact output
- High citation scores
- Bench to bedside research including basic research in models, descriptive research in tissue material, and
implementation research in screenings trials
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
-
Presence of core facilities allowing proteomics, microarray technology and functional genetic screens
Weakness:
- Small groups, especially in permanent scientific staff
- Few FTE for technical staff.
- No basic research on signal transduction.
- No fysical proximity in the housing of all three major participating labs.
Opportunities:
- Dept Opthalmology is referral center for retinoblastoma. Research in this field at VUMC in collaboration
with Clinical Genetics and Hematology/Pediatrics might not only support this field, but also the other
themes in oncogenesis as the Rb pathway is key player in many solid cancers.
- Existing close collaborations between outstanding research groups at VUMC and Dutch Cancer Institute
might be strengthened by appointment of strategic professorships.
- Securing Oncogenetics section of Dept. of Clinical Genetics section by structural professorship
Threats:
- Increasing educational obligations for researchers
- Increasing bureaucracy at all levels (IRB, animal work, laws on population-based screening, GMO work)
- Increasing difficulties hiring skilled personnel
- Unclear housing Oncogenetics section
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
CCA/V-ICI program 2: Immunopathogenesis
Program leaders:
Prof. R.H.J. Beelen, PhD (Molecular Cell Biology and Immunology)
E. Hooijberg, PhD (Pathology)
Prof. Y. van Kooyk, PhD (Molecular Cell Biology and Immunology)
Prof. R. Mebius, PhD (Molecular Cell Biology and Immunology)
The CCA/V-ICI program 2 covers both fundamental and pre-clinical research in which immunological processes
underlying homeostasis control, in relation with inflammatory diseases and cancer form major topics of research.
Program 2 is subdivided into three research lines:
1. Homeostasis control and Inflammation
2. Host-pathogen interaction
3. Tumor immunology and pre-clinical immune therapy
Program 2 studies the immune system both during its natural homeostatic control as well as its response towards
micro-organisms and tumors. We have identified the following key elements of which regard as the major
themes within the next five years and we like to focus and strengthen our program into that direction.
Ad 1. Homeostasis control and Inflammation. Main topics are: understanding the function of stroma cells in
dictating the micro-environment during lymph node development, as well as in established lymphoid organs for
the induction of regulatory T cells and the induction of homing receptors on T cells, Study of cell subsets and
post-translational modifications, in particular glycosylation are major components of study in these processes.
Also in relation to the induction of inflammatory processes (bacterial, tumor related, colitis related, rheuma
related, or neuro related) we will study dendritic cell and macrophage activation, receptor function and their
heterogeneity, as well as interaction with matrix and endothelial cells, as well as human skin tissue models. We
aim to define at the molecular level anti-inflammatory and protective actions of both macrophages and dendritic
cells that interfere with their function.
Also genetic and epigenetic processes that play a critical role in the regulation of the immune response in health
and disease with a specific focus on antigen presentation, T cell activation and differentiation into functional will
be studied.
.
Ad 2. Host-pathogen interaction. Main topic is to understand immune modulatory processes of pathogens and to
make a link with immune modulation in cancer. Central theme is the immune modulation of antigen presenting
cells (APC), such as dendritic cells (DC) and Langerhans cells. Research will focus on how pathogens interact
with different DC subsets such as myeloid DC and Langerhans cells, and how these interactions modulate DC
signaling pathways resulting in immune activation or immune escape. Identification of molecular mechanisms
governing these processes will help developing novel strategies to combat not only infectious diseases but also
immunological diseases and can help developing better cancer therapies. As pathogens we will study viruses
(HIV-EBV, HSV, measles, HPV), bacteria’s (Mycobacterium), and helminths (schistosomes). Research on
mycobacterial virulence focusses on immunosupression by mycobacterial pathogens; mycobacterial protein
secretion and virulence and factors involved in granuloma formation. These issues will be studied using
a zebrafish infection model.
Ad 3.Tumor immunology and pre-clinical immune therapy. Central aim is to understand micro-environmental
induced modulation of the immune system (function of APC) by tumors through modifications of molecular and
posttranslational signatures of stromal cells and or tumorantigens. Also epigenetic processes that account for
silencing of antigen presentation functions of tumor cells will be studies. For pre-clinical immune therapy,our
main line of research for the next years will remain the in vivo modulation of DC phenotype and function for
tumor immunotherapeutic purposes, through adenovirus-mediated genetic targeting and or liposomal technology.
By in-vivo modulation of DC by local cytokine administration, or the use of small molecule inhibitors, tumorinduced immunosuppressive conditions are enhanced in vivo in order to optimize DC and anti-tumor T cell
activation. Aim is to develop widely applicable “off-the-shelf” therapeutics to boost anti-tumor immunity in
adjuvant settings, combined with other treatment modalities.
As separate strategies we are evaluating the potency of adoptive tranfer of tumor reacting T cells, as anti-tumor
therapy.
Major goals are to progressively acquire knowledge of the normal control mechanisms of the immune system
and subsequently of the subversion and modifications in pathological situations that can be accomplished by
tumor development and invading pathogens or inflammatory processes such as colitis or rheumatoid arthritis.
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
These insights should enable the identification of immunological parameters, being crucial to disease
development and severity. The main objective is to lay the grounds for translational research programs into
therapy of chronic inflammatory diseases, infections and cancer. This program combines the study of infectious
diseases as well as cancers, as common denominators in the immune system that may be altered or suppressed.
Importantly, several cancers are due to viral infections such as EBV and HPV, linking pathogens to cancer
development. The program aims to molecularly define how pathogens as well as developing tumors mitigate the
immune system for their own benefit. We aim to develop strategies to overcome immune suppression and design
vaccination to strengthen immune responses to eliminate tumor development and infectious diseases. Strong
focus within the 3 research lines is on the study of antigen presenting cells such as dendritic cells (DC) and
macrophages (MQ), i.e. how they are suppressed by the tumor microenvironment (e.g.stomal cells, chemokines,
secretion of inhibitory factors, genetic factors) and pathogens, to silence their immune stimulating immune
responses, and induce regulatory T cells. Tumor antigens, such as CEA, MUC1 and virally derived antigens, as
well as post-translational modifications of tumors and pathogens form major focus elements employing
proteomics and glycomics. To come towards pre-clinical immune strategies studies on in-vitro and in-vivo
targeting of tumor antigens to DC and MQ is fully explored as well as adoptive transfer of tumor-specific T
cells. Both innate and adaptive components of the immune system in the relation with their microenvironment
such as stromal cells, that may steer immune responses during infectious diseases as well as tumor development,
are therefore studied.
Perspectives
For the next five years we aim to identify immunological parameters on molecular and cellular basis that have
immune suppressive activity due to modifications in pathological situations, such as tumor development and
invading pathogens. These immune regulatory parameters may lie in the field of tumor micro-environment,
altered glycosylation, altered DC/MQ function, understanding the induction of regulatory T cells preceding and
during tumor development and infectious diseases. We envisage that a good combination with basic research that
forms the basis of understanding escape mechanisms for immune activation will help to create innovative preclinical strategies to come to a better treatment of cancer and infectious diseases.
The following keys were identified in program 2:
1. Strong DC biology and preclinical knowledge and experimental setting
2. Strong expertise in glycobiology and related tools for research
3. Excellent setting for performing human immunology based research
4. Unique human skin model systems for pathogen infection, DC targeting and skin inflammation
5. Presence of unique murine tumor-models as well as tolerance induction models
6. Strong expertise in lymph node development
7. Well developed adoptive transfer technology and tetramer technology
8. Unique setting of various pathogen related research and technology
9. Very strong expertise for developing pre-clinical DC related therapies
Summary of the research aims for the coming 5 years:
1. Within the next five years we envisage setting out strategic ways to target DC in-vivo with tumor antigens
(receptor-targeting, adeno-viral targeting, altered-glycan-targeting) with a special focus on improving
treatment of colon carcinoma, breast cancer,
melanoma and virally induced malignancies. Focus will lay
in targeting DC in-vivo in such a way that both tumor specific CTL and T-helper cells are induced. For
adoptive transfer purposes, we aim at generating and redirecting high avidity cytotoxic and helper T cells
against virally induced malignancies such as ano-genital cancers, head and neck cancers and lymphomas, as
well as against non-virally induced malignancies.
2. In the field of infection/inflammation due to invading pathogens we will especially focus on the role of
stroma cells in regulating the defence mechanisms by innate cells and how this influx may be suppressed .
3. Detailed determination of molecular and genetic regulators that play a key role in tumor suppression and
pathogen evasion. Knowledge on these regulatory pathways may be further developed and incorporated into
clinical applications, in particular into combination with current treatments for cancer, inflammatory and
infectious diseases
Collaboration
In VUMC:
Projectleaders with projects in program 2 are based at the departments of Molecular Cell Biology and
Immunology (MCBI), Medical Microbiology and Infection (MMI), Dermatology (Derma), Hematology
(HEMA), Medical Oncology (Onco) and Pathology (PA) and are therefore hosted at various locations at the
VUmc/CCA. Therefore a natural encounter does not frequently occur. To facilitate a fluent discussion between
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
all VICI-program-2 participants by the organisation of a monthly seminars in which projectleaders as well as
scientist present their their current research and future directions. This will make projectleaders and their
members more aware of the importance of conducting research within one of the CCA/V-ICI programs, and
facilitate collaborations to further define and strengthen the different sub-themes within our program. On a
regular base leaders of program 2 will invite all projectleaders to attend to discus VICI related matters and
ongoing research and project calls. We aim at achieving synergy by combining know-how and technical skills.
This might lead to better projects that can be financed externally by for instance KWF, NWO, the EU or other
sources.
Outside VUMC:
We have set up monthly immunology seminars in which we invite top-researchers within the field of
immunology and tumor immunology to give a seminar, and visit senior scientists within program 2 to discuss
their work. This will give the scientist within program 2 an opportunity to present their work to leaders in the
field which may improve their quality as well as their international exposure. We aim at promoting the PhD
students to actively participate in the (after-) seminar discussions, in order to improve their skills in questioning
and answering. We think this will be an excellent opportunity and learning proces for the junior and senior
scientists.
SWOT analysis
Strength:
- High impact of scientific output.
- Many projects are financed by prestigeous innovative grants from NWO/ZONMW such as VENI, VIDI,
VICI.
- Very strong expertise on APC on different levels is present (mice-human-molecular-cellular-organism-basic
and pre-clinical setting).
- Strong expertise on innate immunity.
- Very strong expertise on the role of stromal cells in development, inflammation, and establishment of
micro-environments.
- Strong expertise on the level of immunomodulatory processes in infectious diseases.
- Good combination of infectious diseases and cancer related research to define common regulatory
mechanisms in the immune system.
- Innovative directions of research that are focused on exploring new directions in the field of immunology:
ie. Glycosylation, microenvironment, effect of trauma.
- Strong network of projects funded by the Kidney Foundation, Astma Foundation, Burns Foundation etc.
Weakness:
- Lack of good tools to detect a large variety of MHC class I and II alleles involved in tumor antigen
presentation.
- Lack of good source of anti-tumor specific T cells for analysis of DC induced anti-tumor responses.
- Use of various of tumor antigen (CEA,MUC, GP100, HPV) models (colon, breast, melanoma) due to
restriction of immunological tools.
- Inflammatory responses need to be better implemented within the program (IBD and MS).
- Difficulty to get funding from NKB for basic or preclinal cancer related work.
- Necessity of more glycobiology expertise on the analytical level.
- A professional and larger animal facility.
- A microarray facility that works as a service facility.
Opportunities:
- Basic research in this program should connect better to clinical and preclinical enterprises. The topics of this
program will yield basic discoveries that can be implemented into infectious diseases, inflammatory diseases
and cancer. A good, wel- integrated collaboration between basic research on DC (MCBI) and preclinical
evaluation (Medical Oncology, Hematology, Pathology) can lead to further improvement and applications to
clinical evaluation of new therapies. Better exchange of tools generated between the participants of program
2, human tissue modelsystems, T cell lines, mouse-model systems.
- A more integrated pathogen related reseach can lead to new discoveries to be applied for cancer and
inflammotory mediated diseases.
Threats:
- The program may stand on its own in splendid isolation, as excellent research program, without any
connections with other VICI programs.
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
-
To focus basic research only on cancer related topics.
Increasing educational obligations for programleaders as well as researchers.
Increasing difficulties hiring skilled personnel.
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
CCA/V-ICI program 3: Disease profiling
Program leaders:
Prof. G.A.M.S. van Dongen, PhD (Otolaryngology/Head and Neck Surgery + Nuclear Medicine & PET
research)
Prof. O.S. Hoekstra, MD, PhD (Nuclear Medicine & PET research)
C.R. Jimenez, PhD (OncoProteomics Laboratory, Cancer Center Amsterdam)
Prof. G.A. Meijer, MD, PhD (Pathology)
Prof. C.L. Verweij, PhD (Molecular Cell Biology)
The CCA/V-ICI program 3 covers fundamental and translational research to identify new determinants for
diagnosis, prognosis and tailored treatment for immunological and oncological diseases. Program 3 is subdivided
in three disease oriented research lines:
1. Solid tumors
2. Hematological malignancies
3. Chronic inflammatory diseases
The emerging and rapidly growing fields of molecular imaging and genomics provide new opportunities to
unravel the unique biology of a specific disease in a specific patient. Integrating imaging and global molecular
information with clinical data will allow for a model that may yield tremendously valuable indicators for the
individual patient to personalize diagnosis and predictions. This program is a key connection in the line: target
discovery - ligand development - molecular imaging – molecular targeted therapy
Ad 1-3.Solid tumors, hematological malignancies and chromic inflammatory diseases
- In all 3 research lines, modern state-of-art CT and MRI-machines enable imaging of anatomical details with
high precision. In addition, imaging techniques like SPECT, PET, PET-CT and MRI provide, noninvasively, unique molecular and biological in vivo information at the tissue level (“molecular imaging”).
For this purpose novel reporter probes will be developed and evaluated in (pre)clinical studies making use of
the unique facilities (cyclotrons, GMP facilities, animal and clinical PET- and MRI-machines) and expertise
available at the campus.
- Genomics and proteomics have emerged as global tools to measure genetic variation and gene expression at
several levels ie., from a gene‘s primary structure to its protein products and their role in the biology of the
organism. The VUMC Microarray-facility offers high resolution oligonucleotide arrays and CGH arrays for
human and mouse studies. These arrays are increasingly being applied in studies to improve criteria for
disease classification, such as for colorectal, lung and head and neck cancer, lymphoma and other
malignancies, and in chronic inflammatory diseases such as rheumatoid arthritis.
- The OncoProteomics Laboratory provides expertise in biomarker discovery in body fluids and tissue
samples along with state-of-the art facilities for liquid chromatography and tandem mass spectrometry on
two complementary platforms. High throughput methods have been developed for pattern-based approaches
in body fluids like serum and CSF. For tissue samples, robust sub-cellular fractionation protocols have been
set up for the analysis of proteins in plasmamembrane-enriched fractions, sub-nuclear domains and secreted
proteins. These in-depth analyses typically yield datasets of > 1000 proteins per sample along with
quantitative information on relative abundance. The glycoimmunology group at the Dept. of MCBI provides
expertise in glycan profiling (glycomics) using mass spectrometry.
- It is the promise of high-throughput analyses that patterns of transcripts, proteins, post-translational
modifications and/or metabolites can be used to define “molecular signatures” of different forms of the
disease, as well as different stages in the clinical progression. The patterns that are generated with this
integral approach, termed systems biology, provide insight into the processes that take place in a cell.
Perspectives
Within the next five years we foresee the discovery of targets for, and development and (pre)clinical evaluation
of several new SPECT and PET tracers for diagnosis, staging, treatment planning and response evaluation as
well as the exploitation of PET, PET-CT and MRI imaging in the development of novel therapeutics. The
innovative technologies described above should contribute to further individualization of treatment, e.g. by more
accurate staging, prognostication and therapy response monitoring. In recent years, we and others have
introduced and validated the sentinel node biopsy (a combined procedure of imaging, taking biopsies and
morphological evaluation) which proved to be an important improvement within TNM staging. The
multidisciplinary infrastructure developed for breast cancer and melanoma has now been extended to head and
neck cancer, gastrointestinal and gynecological tumors, using the local expertise in ultrasound guided aspiration
cytology and laparoscopic surgery.
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
The novel molecular imaging techniques have promise to step beyond the classical TNM-paradigma. To this
end, we aim to optimize the use of genomics and proteomics technology to reach a molecular signature of
disease subtypes e.g. in colon, head and neck and lung cancer, lymphoma, and other malignancies, and in
chronic inflammatory disease such as rheumatoid arthritis. In addition, we aim to translate protein candidate
biomarkers into non-invasive routine antibody-based assays. The available expertise will allow for integrated
application and assessment of imaging, sampling and profiling. Promising applications will be evaluated with
respect to their clinical relevance and (cost) effectiveness. Efforts will be put on forming a link between
molecular profiling and molecular imaging. Molecular profiling by genomics and proteomics will contribute to
identification of relevant disease markers and targets. These targets can be exploited in the development of
disease specific contrast agents (e.g. using monoclonal antibodies, peptides or small molecules) for imaging as
well as for therapy. Combined molecular profiling – molecular imaging approaches will be applied in several
tumor types, e.g. colorectal, head and neck, lung, lymphoma and other malignancies, and in chronic
inflammatory disease.
Imaging will contribute to increased insight in tumor biology and pathophysiology, e.g. by pharmacokinetic and
dynamic PET analysis. Also molecular interactions can be confirmed and elucidated, which might be of
particular value in the development of new cutting-edge therapeutic agents like monoclonal antibodies, peptides
and small molecules that target the root courses of the disease. Emerging imaging innovations that are candidates
for large-scale clinical application will be further evaluated with respect to their (cost) effectiveness in clinical
practice, as is presently done with several PET applications.
Summary of the research aims for the coming 5 years:
Information on disease biology must be enhanced to facilitate the development of disease specific diagnostic and
therapeutic approaches. Opportunities can be found (but are not restricted) in the following areas:
1. Development of methods to reproducibly measure DNA (e.g. maCGH) and expression profiles (e.g.
expression arrays and proteomics) in pathological and healthy tissue, or surrogate tissues like blood, urine
and faeces. This approach aims to identify disease signatures, markers and targets. These markers and
targets will be exploited for the development of tracers for imaging. Alternatively the cell type can be
identified.
2. For the aforementioned aim, SOPs have to be developed for banking of tissues, blood, saliva, and faeces.
3. Characterization of molecular signatures of tumors (precurser lesions, established tumors, metastases) or
immunological diseases, which are of value for selection of the proper therapeutic intervention.
4. Definition and integration of molecular profiles at various stages of development and progression, to
provide a comprehensive view of the pathways involved in pathogenesis.
5. Definition of tumor/pathogen and host interaction.
6. Validation of the predictive value of various biomarkers using either tissues (see above), body fluids or
images of well defined patient groups who had well-defined therapy with accurate follow-up.
7. Development of novel in vivo imaging tools enabling non-invasive biological and molecular disease
characterization for individual patients. For example for early response monitoring or for prediction of poor
response upon therapy (e.g. hypoxia and angiogenesis in case of cancer therapy) or for evaluation of the
specificity of targeted drugs. Disease-specific contrast agents and software tools for quantification will be
developed.
8. Initiation of clinical studies with molecular targeting agents to validate molecular targets, by taking tissue
samples and or imaging, and to predict the efficacy of a given therapy.
9. Initiation of clinical studies with antibodies to assess the biomarker potential in body fluids of diseaserelated proteins and to establish values for sensitivity and specificity.
Collaboration
In VUMC:
Projectleaders with projects in program 3 are based at several departments in the VUMC: Pathology,
Otolaryngology/Head & Neck Surgery, Nuclear Medicine & PET Research, Molecular Cell Biology,
Rheumatology, Hematology, Medical Oncology, Pulmonology, Gastroenterology, Radiology, Gynecology.
Bilateral collaborations with leading national and international research groups have been established in the
fields of genomics, proteomics, and molecular imaging. In these fields VUmc also participates in many strategic
consortia (STW, TIPharma, CTMM, EU and NCI programs). In addition, many collaborations exist with
innovative industries in the fields of molecular diagnosis, molecular imaging, and molecular targeted therapy.
Industrial collaboration with Invitrogen (Dr. D. Gillooly, Invitrogen, Finland)
Title project: Development of a reproducible method for serum peptide capture using novel C18 Dynabeads.
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
This collaboration has been presented by Dynal and myself at several conferences and resulted in a publication
(Jimenez et al., Prot. Clin. Applic. 2007) and a joint review for the Invitrogen Quest magazine (sept 07 issue).
Currently the article is used in a promotional email campaign targeted at Nature Methods readers.
Industrial collaboration with ThermoFisher (Dr. Maija Partanen)
Title project: Automation of magnetic bead-assisted serum peptide capture on the KingFisher96 platform
The KingFisher was given to Jimenez during one year for free to evaluate the instrument and to develop an
automated protocol in exchange. This work has been published by Jimenez et al. (Prot. Clin. Applic. 2007).
Industrial collaboration with Sciex (Dr. Lyle Burton, Sciex, Toronto, Canada)
-tester for the software tool MarkerView that aids in preprocessing and label-free quantitation of
MALDI-TOF-MS spectra and LC-MS data
This collaboration has given us early access to nice software. An application note is in preparation for
promotional purposes.
Industrial collaboration with Applied Biosystems (Dr. Christie Hunter, Applied Biosystems, Framingem, USA)
Title project: Proof-of-principle study: Targeted detection of 7 genomics candidates in parallel by multiple
reaction monitoring on a novel hybrid tandem mass spectrometer (Qtrap)
Scientific collaboration with Dr. Matthew Fitzgibbon, Fred Hutchinson Cancer Research Center, Seattle, USA
Title collaboration: Tool development for label-free quantitation using LC-MS datasets
Scientific collaboration with Dr. Bogdan Budnik, Proteomics Unit, Childrens Hospital, Harvard, Boston, USA
Title collaboration: Exchange of information on the optimal use of the LTQ-FTMS for biomarker discovery
Scientific collaboration with Dr. R. Bjerkvig and Dr. Simone Niclou, NorLux NeuroOncology group, Bergen
Norway and Luxembourg.
Title collaboration: Sub-cellular brain proteomics: application of membrane proteomics in a xenograft rat model
of glioblastoma
Means
Research within CCA/V-ICI program 3 requires availability of various technology platforms, i.e. presence of
state-of-the-art facilities and know-how. The following technology platforms are available, or planned to be
available and in active operation within the coming year:
1. Microarray-facility
2. OncoProteomics Laboratory
3. (molecular)Imaging facilities
4. Tissue microarray facility
5. Human monoclonal antibody phage display facility
6. Bio-informatics support
The technology platforms are organized as user-groups. For each facility a business plan has been made. For
optimal use of capacity, an inventory is made of projects planned for each facility. Program 3 of CCA/V-ICI
takes care for optimal use of these facilities, and if required the particular user-group will be contacted. In
addition, projects making use of the facilities will be reviewed at a regular basis.
To achieve the abovementioned goals, the following comments can be made: (confidential)
1. Microarray: the microarray group (head core facility: B. Ylstra, PhD) and the user-group microarray are
functioning well. In the beginning, development of technology was a central issue while more recently the
established techniques are used for challenging clinical questions. While at the moment most of the
activities within the field of microarray are performed in house, it is well possible that in the near future
parts will be contracted out. Efficiency and costs will be important aspects of this discussion. Continuation
of the facility has been guaranteed for the coming years.
2. Proteomics: the OncoProteomics Laboratory (head core facility: CR. Jimenez, PhD) has been established
beginning in May 2006. The OPL was created to provide a state-of-the-art proteomics infrastructure and
knowledge center for CCA/V-ICI researchers. A major focus is on targeted MS-based proteomics for
biomarker discovery in tumor tissue and biofluids. The samples are profiled using two complementary
platforms: 1. Biofluid profiling in the peptide range (< 10 kD) using an automated magnetic bead-based
peptide capture method coupled to high-throughput MALDI-TOF-MS and 2. Large scale protein
identification and quantitation using nano-liquid chromatography coupled to LTQFTMS of fractionated
12
Future of CCA/V-ICI 2008-2012 (24 April 2008)
3.
4.
5.
6.
samples. Cancer-related proteins may provide novel drug targets and candidate biomarkers for development
into non-invasive (multiplex) antibody-based assays. Most projects are shaped in close interaction with the
collaborators and can be broadly subdivided into 3 categories: 1. collaborative, 2. OPL core research
(typically initiated by the OPL) and 3. service projects (work on a fee-per-sample basis). Most projects all in
categories 1 and 2. In the past year, several proof-of-principle studies in human samples (serum and tumor
tissue), animal models of cancer and cell lines have been successfully completed.
(Molecular) imaging facilities: Technical facilities for molecular imaging research are mainly located at the
departments of Nuclear Medicine & PET Research (NG&PR), Radiology and Radiotherapy. In addition, for
development of radiopharmaca Cyclotron BV at the VU/VUMC campus is important. The past years there
has been a further integration of radiochemistry research, clinical PET research and other nuclear medical
research. National and international positioning of PET research has been improved. In 2007, a PET-CT
camera has been installed, while a second has been planned for 2008. This will need fine tuning between
aforementioned departments. With respect to this, a working group has been installed to evaluate the
possibilities for centralizing imaging activities in a physical “Center for Molecular Imaging”. Important will
be the integration of molecular profiling (microarray and proteomics) and molecular imaging: identification
of new disease-selective markers/targets will enable the development of disease-selective contrast agents.
For evaluation of marker/target potential, a tissue microarray (TMA) facility has been installed, while
antibody phage display technology has been established. Strategic collaborations are considered to assure
also the availability of small molecule libraries.
Tissue Micro Array (TMA) facility: A TMA facility has been started at the department of pathology. Array
development is ongoing, while for optimal use of the arrays a slide scanner has been installed. This scanner
can be used for a) TMA archiving, analysis and quantification, b) rare event detection (minimal residual
disease), c) immuno-quantification, d) off line DNA cytometry. The TMA facility is indispensable for
“disease profiling” and “target discovery/validation”.
Antibody phage display technology: Genomics, transcriptomics, glycomics and proteomics will provide
insight in the molecules involved in critical oncological and immunological processes. To enable in vitro
and in vivo characterization of these molecules for exploitation in disease profiling, the availability of
selectively binding contrast agents would be of help. Monoclonal antibodies can be very useful reagents for
this purpose. For this purpose, human antibody phage display technology has been established within
CCA/V-ICI.
Bioinformatics: Microarray as well as proteomics facilities require support by bioinformatics. In addition,
bioinformatics is needed for combined use of clinical, tissue micro array, imaging, microarray, and
proteomics datasets, to enable integrated multiparameter testing. A task force will be started to establish
bioinformatics support.
SWOT analysis
Strength:
- Strong clinical and fundamental research units in one institute with excellent translational research lines,
which are perfectly well fitting with recent national and international initiatives on translational research.
- Well-focused theme, favourably placed in relation to other themes. This allows fruitful and innovative
interactions
- Excellent facilities
- CCA and CCA building
- Excellent national and international collaboration with top institutes in the field
- Strong position in national PET field in context of multicenter trials (leading in PET standardization and
centralized PET data-analysis and archiving to link with biobanks)
Weakness:
- Dispersion within program: microbiology, immunology, oncology. Focusing has been started.
- Some diseases with CCA/V-ICI focus are hardly represented within theme 3 (e.g. prostate and brain
tumors), while some diseases out of CCA/V-ICI focus are represented (e.g. cervical cancer, MS,
microbiology). Profiling of some other tumor types like lymphoma is also part of theme 4.
- Just a few departments are actively participating.
- Just a few patient cohorts that allow profiling at several levels.
- Limited equipment budget.
- No concerted action in large funding programs: EC. At national level improvements occurred.
- Molecular imaging is just nuclear imaging. Dept of Radiology is quite passive. Optical techniques have no
prominent place.
- Difficulty in internal communication: no internal scientific meetings
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
-
More active role of depts Surgery and Medical Oncology needed to allow molecular profiling and imaging
in large patients groups.
Lack of data management
Opportunities:
- Development of more bench to bedside research links
- Better focused research program will provide new opportunities. This is particularly true for lung and
prostate cancer. Why focus on brain tumors is not clear.
- Integration of immunological and cancer research to develop new immunotherapeutical approaches
- New facilities from 2006 on, in which units will integrate more intensively
- Cooperation with other research institutes in Amsterdam and the Western Holland
- New initiatives for abdominal surgery possible (Ozon-area)
- Because of restructuring of VUmc/Vu campus, new possibilities arise for centralisation of key activities.
- Programme 3 activities have the possibility to set national/internatioal standards, or perform the role of
reference center, at several levels: PET tracer development, PET data analysis and training, (in)directly
promoting role of other Vumc depts in multicenter trials
Threats:
- Financial situation of university medical center in the Netherlands
- Not all disease profiling research sits within theme 3, e.g. MRD research, mutation analysis.
- Increased focusing of VUMC towards patient care because of financial reasons
- Most facilities are just at starting phase. Maintenance phase will be challenging. In case of success, like in
the development and GMP production of PET tracers, expansion and upgrading of excisting facilities is
difficult. Tight links with departments are important.
- Competition
- Not enough grants in competition (e.g. KWF)
- Limited career prospects for excellent researchers (call for tenure track, ruling by research institutes &
departments, not divisions)
- Limited clinical capacity within Vumc (strategic alliances with large peripheral hospitals, preferably
incorporating in conglomerates, led by Vumc, are required but not established as yet)
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
CCA/V-ICI program 4: Therapy
Program leaders:
Prof. B.A.C. Dijkmans, MD, PhD (Rheumatology)
Prof. G.J. Ossenkoppele, MD, PhD (Hematology)
Prof. G.J. Peters, PhD (Medical Oncology)
Prof. S. Senan, MB, BS, PhD (Radiotherapy)
Prof. H.M.W. Verheul, MD, PhD (Oncology)
The CCA/V-ICI program 4 encompasses translational research within the field of oncological and immunemediated, non-oncological diseases. The program has been organized along five research lines:
- Chemotherapy
- Immunotherapy
- Radiotherapy and surgery
- Gene therapy
- Quality of life
The common feature of the first four research lines is the focus on innovative and targeted therapy using the
corresponding modality. A major aim of the program is to explore potential synergies when new therapies are
introduced for both oncological and immunological diseases.
The research line Chemotherapy includes pre-clinical evaluation and clinical application of the new generation
of the so-called molecular targeted therapies against novel cellular targets, anti-angiogenesis agents and the
pharmacological optimalization of conventional cytotoxic and antirheumatic drugs. Important aspects are target
discovery and in house drug discovery for which (pharmaco)genomics and proteomics as well as profound
knowledge of drug resistance are important tools. In case of development and application of this kind of drugs in
cancer further application in immune-mediated diseases can be considered.
The research line Immunotherapy investigates new immunotherapeutic approaches for the treatment of
rheumatoid arthritis and other immunological disorders. In addition, immuno-therapy of malignant disorders is
evaluating the role of vaccination in the adjuvant and primary settings. Improved survival rates are now
achievable for a number of common malignancies by using combined modalities.
The focus of the research line Radiotherapy and surgery is directed towards clinical implementation and
optimisation of 4-dimensional image-guided approaches that aim to improve local control and reduce normal
tissue toxicity. Preclinical and early studies currently focus on the combination of radiotherapy with
radiosensitizing molecular targeted therapies, with the aim of developing experimental arms for future clinical
trials. Much of these efforts coincide with protocols that involve pre-operative induction therapies.
In the research line Gene therapy, clinical trials evaluating gene therapy in various malignancies are underway,
with the current focus on optimal targeting of tumors and improving viral vector efficacy.
In the research line Quality of life , a key focus is the impact of therapeutic interventions upon the quality of life
of patients with head and neck cancer, neurological and paediatric tumors. The late effects of childhood cancer
with special focus on psychosexual/social functioning as well as physiological changes underlying brain
functioning are the subject of ongoing studies. Furthermore, studies on end of life care and decision making are
part of this research line.
Perspectives
In the next five years, specific patient-tailored therapies will be developed in a range of oncological and
immunological diseases. These therapies will be directed to defined cellular- and tumor environment targets and
characterization of genetic polymorphisms in order to prevent toxicity and increase anti-tumor or antiinflammatory activity. The new techniques will be used in concert with image-guided controlled radiotherapy
and surgery to further refine the concept of personalized tailored therapy. The existing expertise of both the
VUMC micro-array facility and the VUMC OncoProteomics Laboratory will form a solid basis to faciclitate
these aims. Furthermore, effective dendritic vaccines will be developed and evaluated in clinical studies of
various malignancies. By exploiting the existing expertise within the V-ICI in immune effector-targeted
approaches in cancer therapies, novel immune-therapies willl also be explored in treating auto-immune
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
disorders. Last, but not least, improvements in long-term follow-up strategies and better care for patients in the
terminal phase of life will be developed together with scientific tools to evaluate these strategies and care.
Research aims for the coming 5 years:
The focus in the five research lines specified above will be characterised the following:
1. Translational research with a focus on the early clinical application of relevant discoveries. The process of
clinical evaluation can range from early studies of feasibility and toxicity to the validation of efficacy of
new techniques, drugs or vaccines.
2. Targeted therapy in all its forms, including pharmaceuticals, radiation, immunotherapy and surgery, directed
towards the deregulated cell (arising from either malignant or immunological dysfunction) so as to improve
efficacy and minimise collateral damage to normal tissues.
3. Exploit the existing expertise in both immunology, oncology and imaging in order to develop novel
therapeutic approaches in both areas.
Highlights of our priorities in the coming 5 years are as follows:
1. Early clinical trials of chemo-radiotherapy and/or molecular targeted agents incorporating imaging and
translational research..
2. 4-dimensional, image-guided adaptive radiotherapy
3. Selection of patients for tailored therapy using gene expression or gene profiling, and evaluating suitable
markers of early treatment response
4. Development of vaccines against cancer
5. Oncolytic viral therapy
Collaboration
In VUMC
A large number of departments are involved in program 4 (see above). Translational researchers in program 4
are working in close contact with more fundamental/pre-clinical researchers from program 1-3 in order to allow
the transition of bench-to-bedside research.
Information about the research meetings of all the departments in program 4 have been assembled, this will be
made public on the V-ICI website to stimulate cooperation among the different departments. It is anticipated that
this will increase the merging of oncological and immunological research.
Outside VUMC
Researchers in program 4 have partnerships with industry and with other academic centers in and outside the
Netherlands. This will be further exploited in the coming years.
SWOT analysis
Strength
- Large number of fase I, II and III studies in different departments
- Peer review publications > 60% in upper 25%
- A great deal of research projects involves targeted therapy
- QOL research well embedded
- Immuno-oncological approaches well represented
- Well developed pipelines of new drugs and monoclonals
- Many (inter)national collaborations
- Staf members are well represented in many editorial boards
- CCA building
- Possibility of financing novel projects from own resources(department level)
Weakness
- Too large a heterogeneity of tumortypes studies
- Many staff members with only limited time available for research
- Little interactions with other programs
- Industry driven research prevails
Opportunities
- Side studies to clinical studies
- Focus on tumortypes
- Great interest, expertise and possibilities to develop and test new drugs and monoclonals
- Developing the concept of the malignant stemcell
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
Threats
- See weakness
- Increasing educational obligations
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
Translational Management & Care Workgroup
Workgroup leader:
Prof. W.R. Gerritsen, MD, PhD (Medical Oncology)
This workgroup covers the clinical implementation of research activities within CCA/V-ICI. Research within
programs 1-4 have their focus on laboratory research and/or take place mainly within one department. Largescale research projects, involving more than one department will be covered by this workgroup. This workgroup
aims to improve the communication between clinical care and fundamental research and to facilitate translational
research.
The aim is to identify research initiatives along the care “tracks” linking the VUmc to the slogan: ”better
diagnostics, better care will improve top research”. An example is colorectal cancer: the care “track” colorectal
cancer assumes faster and new diagnostics in order to obtain a better cure. Research on new medicins aims to
develop new diagnostics that might determine which patients will benefit from the new therapies. For the
development of new therapies collaboration between oncologist, radiotherapist and surgeon (e.g. rectal
carcinoma) is more and more common. Both treatment and research involve several clinical departments and
several laboratories.
Based on the above the following conclusion can be drawn: one should look in 2 different ways at the current
situation and the future: from the perspective of clustering certain clinical functions and from the perspective of
tumor types.
Within this program four clusters can be identified:
1. Early diagnostics and hereditary predisposition
2. Imaging
3. New drug development/treatment
4. Psychosocial care, palliative care and supportive care
1. Early diagnostics and hereditary predisposition
Programs 1 and 3 cover the large early diagnostic projects of the following tumors:
 Head and neck cancer
 Lung cancer
 Colon cancer
 Cervical cancer
Strong and successful collaboration and exchange of knowledge between the different research groups: most
research is done within the department of Pathology. Research on head/neck cancer takes place in the
Otolaryngology/Head and Neck Surgery department with a strong collaboration with the departments Pathology
and Nuclear Medicine & PET research. Research on cervical cancer at the department Pathology is topresearch.
Colorectal cancer research has a very strong reputation at a national and international level.A secure, robust
infrastructure for the collection of data and material is required. The outcome of clinical studies requires a lot of
investments for many years and long term visions (5-10 years) are mandatory for these lines of research.
Plans are made within the out-patient clinic ‘Hereditary tumors’ for the following projects:
 Colorectal cancer
 Breast cancer
 Prostate cancer
Breast cancer research is well embedded in the department Clinical Genetics in close collaboration with the
group of Prof. Joenje. The role of the faconi anemia genes and hereditary breast cancer will be further explored.
Ten percent of the prostate cancers has a familial occurrence: in the Netherlands little research is done on risk
factors. This line of research will be further explored in the departments of clinical genetics and urology.
Special attention is given to 2 rare cancer predisposition syndromes:
 retinoblastoma (national clinical function)
 Fanconi anemia (european diagnostic centre)
Strength: Fanconi anemia research is excellent. Fundamental research is focussing on more common (sporadic)
tumors and translational research. A good collaboration exists between the VUmc and the Netherlands Cancer
Institute. Extension to breast cancer (in preparation) is strategic important.
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
The VUmc is referral hospital for all young retinoblastoma patients: diagnosis, treatment and follow up has been
done for several years, resulting in an extensive database that holds clinical data and material.
Strength:
- Strong and successful cooperation and exchange of knowledge between the different research groups: most
of the research is done by Pathology.
- Research on head/neck cancer takes place at Otolaryngology/Head and Neck Surgery with a strong
communication between Pathology and Nuclear Medicine & PET research.
- Research on cervical cancer at the department Pathology has a high-quality level and an international
reputation.
- Colorectal cancer research has a very strong reputation at a national level.
Weakness:
- A secure, robust infrastructure for the collection of data and material. Making strategic choices is essential
because it takes years to publish top publications.
Plans are made within the out-patient clinic ‘Hereditary tumors’ for the following projects:
- Colorectal cancer
- Breast cancer
- Prostate cancer
Strength:
- Breast cancer research is well embedded in the department Clinical Genetics in close collaboration with the
group of Prof. Joenje.
- Ten percent of the prostate cancers has a familial occurrence: in the Netherlands no research is done on this
risk factor.
- There is a relation between the occurrence of prostate cancer and breast cancer within families
Weakness:
- Starting research within VUMC.
- Good clinical care is given at the outpatient clinic ‘Hereditary tumors’ but choices are to be made which
care “tracks” have potential to result in top level research.
Special attention is given to 2 rare cancer predisposition syndromes:
- Retinoblastoma (national clinical function)
- Fanconi anemia (european diagnostic centre)
Strength:
- Fanconi anemia research is excellent.
- Fundamental research is focussing on more common (sporadic) tumors and translational research.
- A good collaboration exists between the VUMC and the Netherlands Cancer Institute.
- Extension to breast cancer (in preparation) is strategic important.
- The VUMC is referral hospital for all young retinoblastoma patients: diagnosis, treatment and follow up has
been done for several years, resulting in an extensive database that holds clinical data and material.
Weakness:
- Strong emphasis on the activities in the clinic but less investment in fundamental retinoblastoma research.
2. Imaging
The imaging activities take place at the following departments: Radiology, Nuclear Medicine & PET research
which harbors the Radionuclide Center, and Radiotherapy. The department of Nuclear Medicine & PET research
has a very good reputation on PET-imaging and quantification of PET-signals. The Radionuclide Center has a
national function on the production of tracers for imaging of key tumor/immunological characteristics like
metabolism, proliferation, hypoxia, vascularisation, apoptosis, metastasis, and for labelling of monoclonal
antibodies and cytostatic drugs. The department radiotherapy has a strong research team aimed at treatment
planning using new imaging techniques, like PET-CT scan and soon 2 cone beam CT-scans. The radiology
department has particular attention for head/neck, lung tumors and brain tumors.
VUmc has an excellent research group focussing on the quantification of PET-signals. The goal is to develop a
high level institute for imaging together with industrial partners.
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
A masterplan molecular imaging is needed to integrate and reinforce the efforts of the different departments. The
aim is to create a molecular imaging institute with a new building in 2014. In addition, a smooth transitional
stage is needed to translate the activities at early diagnostics to the development of new medicines.
Strength:
- Excellent communication between several clinical depts and nucl med & PET research
- Existing links with industrial partners (radiochemistry, pharma) and expected ones with complementary
academic ones (Oxford).
- The communication with the departments radiotherapy and radiology is good.
- VUMC has world-wide leading position in PET kinetic modelling and - data-analysis
- The goal is to develop a high level institute for imaging together with industrial partners.
Weakness:
- A masterplan imaging is needed to integrate and reinforce the efforts of the different departments.
- In addition, a smooth transitional stage is needed to translate the activities at early diagnostics to the
development of new medicines.
3. New drug development/treatment
Many departments within the VUmc are involved in the development and implementation of new treatments.
New treatment techniques: in particular the surgery departments, department gastro/intenstinal/liver diseases and
the department radiotherapy are focussed on the acquisition of new equipment and the implementation of this
equipment in patient care.
The impact on the quality of care is easy to explain: examples are robotic surgery for prostate cancer and cervical
cancer, IMRT, new scope techniques (lung, colon) and sentinel node biopsy. The challenge is that introduction
of these new techniques will also have an impact on research programs. An example of a successful project is the
sentinel node project (breast cancer).
Strength:
- The impact on the quality of care is easy to explain: examples are robot-surgeon, IMRT, new scope
techniques (lung, colon) and sentinel node biopsy.
- The challenge is that the new uses of these techniques will also impact the research programs. An example
of a successful project is the sentinel node project (breast cancer).
Weakness:
- In general there is too much focus on new techniques and less focus on research.
New drug development: the departments medical oncology, hematology and lung diseases are regularly involved
in clinical research of new drugs. The emphasis for the department medical oncology is phase I/II trials and for
the other 2 departments phase II/III trials are more common. VUmc specialists are often the principle
investigators for the trials. Approximately 90 % of the trials is executed in collaboration/sponsored by the
pharmaceutical industry. Attempts are made by all departments to perform translational research in addition to
clinical research.
All 3 strong departments have a very good reputation on clinical research. Connection on laboratory research is
very good. Currently 4 themes, can be identified, in which we distinguish ourselves;
 signal transduction (EGFR pathway)
 immunotherapy
 tumorstroma, including angiogenesis
 tumor profiling and response on therapy
Each department has their own network/organisation of doing clinical research. Communication between the
departments can improve. A central office that supports submission of protocols, takes care of quality-control,
and supports shipment of materials, is not yet set up. There is no infrastructure for biobanking and electronic
patient files. The focus of the industry has changed: the importance of executing trials is less important because
of the move of clinical trials to Eastern Europe and Asia, but the industry is looking for partnerships to develop
new diagnostics (like her2/neu determination for herceptin). New drug development program is benefiting from
other strong research programs such as disease profiling and imaging.
New drug development: the departments medical oncology, hematology and lung diseases are regularly involved
in clinical research of new drugs. The emphasis for the department medical oncology is phase I/II trials and for
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
the other 2 departments phase II/III trials are more common. VUMC specialists are often the principle
investigators for the trials. Approximately 90 % of the trials is executed in collaboration/sponsored by the
pharmaceutical industry. Attempts are made by all departments to perform translational research in addition to
clinical research.
Strength:
- 3 strong departments with a very good reputation on clinical research.
- Connection on laboratory research is very good.
- Currently 4 themes, can be identified, in which we distinguish ourselves;
- signal transduction (EGFR pathway)
- immunotherapy
- tumorstroma, including angiogenesis
- tumor profiling and response to therapy
Weakness:
- Each department has their own network/organisation of doing clinical research. Communication between the
departments can improve.
- A central office, that supports submission of protocols, takes care of quality-control, and supports shipment
of materials , is not yet set up.
- There is no infrastructure for biobanking and electronic patient files.
- The focus of the industry has changed: the importance of executing trials is less important because of the
move of clinical trials to Eastern Europe and Asia, but the industry is looking for partnerships to develop
new diagnostics (like her2/neu determination for herceptin).
- A better collaboration between the following departments pathology, clinical chemistry, medical oncology
and nuclear medicine & PET research is aimed in order to develop new diagnostics.
4. Psychosocial care, palliative care and supportive care
Psychosocial care: attention is given to psychosocial care by the following departments KNO, pediatric
oncology and medical oncology. Research is covering mainly the area of brain tumors.
Palliative care: from 2006 onwards a palliative expertise centre is initiated, coordinating research and education.
The research is well embedded in the department social medicine and the pain team.
The research group of social medicine is strong, they have a good clinical group and a strong relation with
hospice Kuria. More and more the 3 research programs can be identified: the development of measurements
within palliative care, alleviation of pain and cachexia.
Strength:
- The interest for psychosocial research in combination with palliative care is increasing.
Weakness:
- Few publications
Palliative care: from 2006 onwards a palliative expertise centre is started, coordinating research and education.
The research is well embedded in the department social medicine and the pain team.
Strength:
- The research group of social medicine is strong, they have a good clinical group and a strong relation with
hospice Kuria.
- More and more the 3 research programs can be identified: the development of measurements, alleviation of
pain and cachexia.
Weakness:
- Most publications are published in their own field literature and a few are published in top oncology papers.
Matrix analysis of clinical clusters versus tumor types
The ‘care tracks’ within the hospital (organized by tumor types) and translational research lines should be
complementary. Tumor working groups should take care of a better integration of care and research. The
Chairmen of the working teams consist of the program leaders and report to the Directorate.
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
Overview:
Early diagnostics
Imaging
New therapies
Immunology
Head/neck
++
+++
+/++
+
Lung
+
+++
++++
Colon
+++
++
+++
Cervical
++++
+
+
Lymphoma/leukaemia
++
++++
++
Breast cancer
+++
+
++
Brain
+++
++
+
+
+
+++
Prostate
++
+++
General focus points:
- Program 1: Oncogenesis (Early diagnostics): one of the 3 programleaders should become chairman of the
tumor working group and responsible for the coordination of early diagnostics (a pathologist)
- Program 2: Immunopathogenesis
- Program 3: Disease profiling (diagnosis / imaging): within the department of radiology the focus should be
more on oncology, should provide a program leader of molecular imaging. One of the program managers
could become chairman of a tumor working group and be responsible for the coordination imaging.
- Program 4: Therapy (new drugs/new therapies):
- A central unit for phase I/II studies
- Set up a good corporation with the pharmacy Slotervaart
- Establish a taskforce Diagnostics, including micro-array and proteomics
- Develop a future plan for immunomonitoring
Focus per tumor type:
1. Head and Neck tumors: the collaborations between E.N.T. specialists, oncologists, radiotherapists and
researcher is very good.
- Early diagnostics: in the coming years the value of early diagnostics should be seen as innovative, high-risk
research.
- Imaging: This research field will become more important by the close collaboration between the
Radiopharmaca center and the Dept Nuclear Medicine.
- Therapy: this department has a high international reputation on surgery. Research on new drugs is limited so
far to phase III trials. One should develop a more own identity by the initiation of own (phase II) trials.
Radiosensitisation will become one of the main new research programs, as presented by the CTMM project.
For publication the focus should be on quality rather than quantity.
2. Lung tumors: in all fields excellent care/diagnostics is being given. The coming years the emphasis should be
on the cohesion between care and research. Laboratory research is done by pathology (Snijders/Thunnissen) and
medical oncology (Kruijt, Rodriguez, Giaccone). As a result of the leave of Giaccone and Rodriguez, clinical
research on lung tumors might diminish. Investments will be made to collaborate with Giaccone at NCI.
-
Early diagnostics: the pathology research should fit into imaging by scopy. One of the questions is whether
the emphasis should be on imaging via fluorescence or on radiological imaging.
Imaging: see above. In addition an important attribution is given by Suresh Senan on imaging and treatment
planning. Two cone beam CT-scans are operational and are offering new possibilities.
Therapy: surgery has a good reputation . Radiotherapeutics has a strong reputation. Research on new drugs
can continue under the supervision of Smit.
The following strong lines / teams can develop :
- Early diagnostics (Snijders, Sutedja, Paul)
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
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Imaging/radiotherapy (Senan, van Dongen, Boellaard)
New drugs/Imaging (Smit, Hoekstra, Buter, Jimenez/Kruyt/Thunnissen)
3. Colon tumors: an excellent program on early diagnostics with a strong connection to imaging. The coming
years joint efforts should result in definite projects. The surgical group has recently invested by appointing new
surgeons specialized in gastric/colon surgery. A team is being formed to investigate/treat rectum carcinoma. In
addition a working group livertumors is in development. It is important is to obtain cohesion for the different
activities. Strong fields could become:
- Early diagnostics, including familiair tumors (Meijer, Craanen/Mulder, Jimenez)
- Radiosensitization rectumcarcinoma (van Triest, Kuenen, van Beusechem, Meijerink)
- New drug and resistance development (anti-stromal therapy) (Kuenen, van Hinsbergh, Peters, Meijer)
- Livermetastasis
- Tumor profiling for predicting response to therapy (Meijer, Meijerink, Peters, Ylstra)
4. Cervical cancer: excellent research on early diagnostics should be continued.
Prophylactic vaccination is now on its way.. Therefore more attention will be paid to future prevention
algorithms in which both primary HPV screening and prophylactic vaccination are incorporated. Also an
immuno-genetics approach will be initiated in the light of prevention of cervical cancer by identification of
women who might/might not benefit from catch-up vaccination.
5. Lymphoma/leukemia:
- Early diagnostics: not clinical relevant
- Imaging: good collaborations in the field of PET-scanning
- Therapy: Leukemia research is excellent with joint efforts of childrenoncology and hematology. The
question is if in future the main point will be immunotherapy or identification of stemcells. VUMC has an
extensive transplantation centre: focus the research on this area?
6. Breast cancer: breast cancer is not one of the focus areas, a decision taken recently by different departments.
However, in 2006 main progresses are made in the area of hereditary breast cancer by Prof. Meijers and the
growing interest of Prof Joenje for breast cancer. It is expected that breast cancer will become a strong research
line.
- Early diagnostics: within familiar tumors focus on clinical genetics and fundamental research
- Imaging: exploration of molecular imaging using MRI is desirable. Discussion is needed to determine which
facilities are desirable for a faster diagnosis.
- Therapy: there is a good participation in research on new drugs. The difficulty is to develop an own identity
because of the competition in this tumor type.
7. Brain tumors: TBD
8. Prostate cancer: a new focus program within CCA/V-ICI that is on new surgery techniques and
immunotherapy.
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Early diagnostics: a man-outpatient clinic is giving the opportunity to early diagnose prostate cancer.
However Rotterdam has a strong focus on screening research activities. Exploration of familiar prostate
cancer might give a possibility in particular when this is fitting in the breast cancer plans.
Imaging: interest of urology (van Moorselaar) and radiotherapy for imaging of therapy in case of locally
advanced prostate cancer
Therapy: development of 3 research lines:
- radio sensitisation of prostate cancer (van Triest, van Beusechem, Geldof)
- immunotherapy of prostate cancer (van den Eertwegh, Gerritsen, de Gruijl, Schepers, Kruisbeek)
- robot surgery
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Future of CCA/V-ICI 2008-2012 (24 April 2008)
Committee for Education & Training
Education Committee:
Prof. C.R Leemans (chair), PhD (Otolaryngology/Head and Neck surgery)
Prof. R.H.J. Beelen, PhD (Molecular Cell Biology and Immunology)
Prof. dr. G.A. Meijer, MD, PhD (Pathology)
R.A. Puraz, PhD
E.M. Ruhé-Hoogervorst (secretary), PhD
Goal
To ensure highly qualified clinicians and researchers within CCA/V-ICI, it is essential to train and pass on
knowledge in a long-life learning program. Education is organized in the Committee for Education & Training of
CCA/V-ICI.
The goal of CCA/V-ICI this committee is to stimulate and facilitate education in the field of oncology and
immunology at various levels, starting already with undergraduate (bio)medical students, through Masterstudents, PhD-students, postgraduate (specialist) training and beyond to education of (care) professionals.
This educational path includes lectures, workshops, tutorials, practical training and clinical demonstrations.
Perspective
At present, CCA/V-ICI is already highly involved in Training and Education at various levels, including:
- Compulsory semester courses during Bachelor and Master phase of (bio)medicine study.
- Optional course Immunology and Oncology during Bachelor phase of (bio)medicine students
- Scientific traineeship during Master phase of medicine study
- TopMaster oncology for biomedicine students
- Oncology graduate school Amsterdam for PhD students (3-day retreat, lectures, meet the professors,
workshops) in collaboration with NKI and UvA/AMC
- Development of a post-graduate centre
- Organization Keynote lectures, workshops (meet the professor) and Symposia
To guarantee high quality training programs, in which numerous CCA/V-ICI members are involved, the main
perspective of program 6 is to survey and coordinate these, and initiate new training activities (within the scope
of development of a graduate school).
Collaboration
This committee stimulates international collaborations and exchanges with top-leading scientist all over the
world.
For the PhD students in the oncology field CCA/V-ICI participates in the Oncology Graduate School
Amsterdam (OOA). The OOA is a joint venture of the Netherlands Cancer Institute (NKI), the VU University
Amsterdam/ VU University Medical Center (VU/VUMC) and the University of Amsterdam/ Amsterdam
Medical Center (UvA/AMC) in the field of oncology training to scientists of different disciplines. The three
organizations strive for excellence in their research and education in basic and clinical oncology.
The mission of the OOA is to offer education in oncology research in the widest sense, and ensure proper
supervision to graduate students in the Amsterdam region.
For the education of PhD students specifically in the immunology field, there is a collaboration with the
University of Leiden, Sanquin Amsterdam, SMBWO (Foundation for the Training of Biomedical Scientists),
NVVI (Dutch Society for Immunology)
and the Amsterdam Medical Center (ALIFI) that provides special courses for the students.
For graduate and postgraduate training cooperation with the VUmc Education Institute (Instituut voor Onderwijs
en Opleiding) exists.
In addition, regular keynote lectures, symposia and workshops with renowned international speakers are
organized.
SWOT analysis
Strength:
 Collaborations with international centres of excellence.
 High number of students interested in oncology and immunology both in the medical field as well as
medical biology field.
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Future of CCA/V-ICI 2008-2012 (24 April 2008)



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

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High number of qualified scientists.
A well respected Top Master in Oncology accreditation as well a well respected differentiation immunology
within the Master Program Biomedical Sciences (FALW).
Education based on good fundamental and clinical embedded research.
Able to provide an educational path to participants from 18-65 year (from student to professional).
Recently (2005) renewed and respected medical curriculum (VUmc-COMPAS).
Large patient group to support clinical training purposes.
Postgraduate Centers, such as the development of PET-CT knowledge Center.
Weakness:
 Full overview of all oncological and immunological training activities given at the VUmc to be completed.
 Suboptimal visibility of immunological education at the VUmc (since it is incorporated presently for
medical biology students in a FALW master) and supoptimal connection with patient groups.
Opportunities:
 Full coverage of training programs ranging from BSc level to post-academic training for professionals in the
field of oncology as well as the field in immunology.
 The new medical curriculum as a platform to expose Oncology and Immunology research.
 Strong and well defined contact with Faculty of Earth and Life Sciences.
 Development of graduate schools. An Oncology graduate school combining the Master Oncology and the
OOA PhD activities.
 An Immunology Graduate School, optionally combined with the oncology graduate school.
Threats:
 A general graduate school for VUmc and FALW absorbing oncology and immunology.
 Limited resources in terms of financial means and staff for establishing new training programs.
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