Future of CCA/V-ICI
2009-2013
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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 2009
From the Future Plan and the SWOT analyses of the individual programs, specific focus and
actions for 2008 can be identified:
1. Imaging Facilities (including Trainings Centre)
2. Central Clinical Trial Support (Office) and good interaction with the department for
Clinical Epidemiology and Biostatistics
3. Fase I/II unit for clinical trials
4. Biobanking infrastructure
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Program 1: Oncogenesis
Program leaders:
- Prof. R.H. Brakenhoff, PhD (Otolaryngology/Head-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 subthemes:
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
This subtheme 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
Aimed at testing progression models for several human cancers, such as head and neck,
lung, gastrointestinal, cervical and ovarian cancers, this subtheme uses wellcharacterized cohorts of patients and state-of-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
In this subtheme understanding the molecular mechanisms of genome destabilization,
as related to the occurrence of cancer, both familial and sporadic is studied. 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
oral 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).
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Research highlights Program 1 within period 2004-2008
1. Establishment that implementation of HPV testing in regular cervical screening leads to
earlier detection of cervical (pre)cancerous lesions, permitting extension of the
screening interval.
2. Demonstration that offering self-sampling of cervico-vaginal specimens for HPV testing to
non-attendees of regular cervical screening is an effective instrument to increase the
coverage of the screening program.
3. Collection of evidence that high-grade cervical premalignant lesions can be subdivided
into potentially early and advanced lesions on the basis of their chromosomal profiles
and that HPV positive women with clinically relevant cervical lesions can be recognised
by hypermethylation of certain tumor suppressor genes.
4. Development of a novel test algorithm for archival formalin fixed paraffin-embedded
specimens to assess HPV involvement and establishment of the role of HPV in penile
and head and neck cancer, the latter both in sporadic patient groups as in genetically
predisposed Fanconi anemia patients.
5. Development of a non-invasive high-througput molecular screening test for oral
precancer.
6. Classification of head and neck cancers into in least three prognostically relevant
groups: those with transcriptionally active HPV, those with many genetic changes, and
those without apparent changes and a normal DNA index.
7. Generation of a unique in vitro model for head and neck cancer using conditionally
immortalized oral keratinocytes that will pay off the coming years.
8. Identification of five novel Fanconi anemia genes: FANCB (responsible for an X-linked
form of FA), BRIP1/FANCJ (encoding a BRCA1-interacting helicase), FANCM/Hef
(encoding a DNA gyrase), PALB2/FANCN (a stabilizer of BRCA2), and FANCI (encoding a
binding partner of FANCD2).
9. Identification of ESCO2 as the gene defective in Roberts syndrome, a neighboring
syndrome characterized by a specific type of chromosomal instability. The latter two
discoveries have yielded valuable pieces to the puzzle of the FA/BRCA pathway of
genomic maintenance.
10. Identification of biomarkers for stool based and serum based colorectal cancer
screening
The activities of program 1 can further be inferred from the extra impuls by a large Center
for Translational Molecular Medicine grant with the acronym DECODE to the research line
on early detection of colorectal cancer, coordinated by VUmc (prof GA Meijer). A main
focus of this 18.5 million euro program will be large scale validation of molecular markers
for early detection of colorectal cancer.
In addition, within this program large, unique biobanks have been established. These
include 200,000 cervical scrape samples from regular screening and triage cohorts, 15,000
brush samples of the oral cavity of various controls groups, Fanconi anemia patients,
leukoplakia patients and treated oral cancer patients. We also have collected clinical
information as well as tumor biopsies, mucosa biopsies, serum and plasma of over 350 head
and neck and 200 lung cancer patients. In addition, 1,000 AFB-guided bronchial biopties of
patients at risk of lung cancer, 600 sputum samples of lung cancer and COPD patients as
well as 750 faeces samples of colorectal cancer cases and controls have been collected and
stored.
The total number of genetic subtypes in Fanconi anemia has now grown to 13. However, a
unique collection of cell lines and materials from Fanconi anemia families has been
accumulated containing a sizable number of unclassifiable cell lines that still wait for their
gene defects to be identified. This includes patients with ‘overlapping’ syndromes such as
Seckel syndrome.
Perspectives
Within the next five years several research aims are defined. These include the
establishment of a novel, cost-effective algorithm for primary HPV testing in cervical
screening with additional biomarkers added for optimal triage of HPV positive women. 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
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several existing candidate-cancer genes in head and neck, gastrointestinal, lung and
cervical cancer will have been elucidated and their impact on human cancer will have been
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 candidate-cancer 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 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.
Together, it will be clear that the knowledge of the molecular alterations leading to
cancer, as to be gained from this CCA/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 cancer genes 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 and colorectal cancer, both in in vitro models, and in the cancer
patient. This includes the recognition of the cancer genes and miRNAs 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 major departments that participate: Pathology,
Otolaryngology/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, and this has led to a number of important papers.
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 Familial Cancer Clinic with a separate Laboratory for Clinical
Oncogenetics, will stimulate further collaboration within the program. Collaboration has
been established with many outstanding groups, including those of the Netherlands Cancer
Institute (Prof. R. Bernards, Prof. D. Peeper, Dr. R. Agami, Prof. S. Horenblas, Prof. A.
Berns and Prof. H. Te Riele) and the Hubrecht laboratory is expected to pay off in the years
to come. Both Profs. Peeper and Te Riele have been appointed to VUmc, and are active
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participants within CCA/V-ICI. There are also intensive contacts with HPV, EBV and Fanconi
anemia support groups all over the worlds.
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. Mouse models are
accessible through Prof Te Riele.
SWOT analysis Program 1
Strength:
- Intense and successful collaboration both in research and education between the
participants
- 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
- 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
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 is likely to be strengthened by appointment of strategic professorships.
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
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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.
1. Homeostasis control and Inflammation.
Main topics are: understanding the homeostatic control of the immune system and its
dysregulation in inflammatory conditions. The ontogeny of lymph node structures and
the central role 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 immune cell subsets
and post-translational modifications, in particular glycosylation are major components
of study in cellular communication of immune cells, such as DC neutrophil interaction,
migration of DC. In relation to the induction of inflammatory processes (bacterial,
tumor related, colitis related, arthritis related, or neurology related, wound related, or
allergic contact dermatitis related) we 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 neutrophils, 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 is studied.
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. Key innate signalling routes
are investigated in DC upon pathogen contact. 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, helminths and various viruses focuses, on understanding the immuno
suppression they establish. Mycobacterial protein secretion, virulence and factors
involved in granuloma formation are studied using a zebrafish infection model.
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 tumor antigens. Also epigenetic
processes that account for silencing of antigen presentation functions of tumor cells
will be studied. For pre-clinical immune therapy, our main line of research for the next
7
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 of skin resident APC. By in-vivo modulation of DC by local cytokine
administration, or the use of small molecule inhibitors, tumor-induced
immunosuppressive conditions are enhanced in vivo in order to optimize DC and antitumor 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
transfer of tumor reacting T cells, as anti-tumor therapy.
The major goals of Program 2 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. These insights
should enable the identification of immunological parameters crucial for 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 (MF), i.e. how they are suppressed by the tumor microenvironment
(e.g.stromal 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 posttranslational modifications of tumors and pathogens form major focus elements employing
proteomics and glycomics. To come towards pre-clinical immune strategies in-vitro and invivo targeting of tumor antigens to DC and MF is fully explored as well as adoptive transfer
of tumor-specific T cells. Both innate and adaptive components of the immune system in
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 chronic inflammation, tumor development and invading pathogens.
These immune regulatory parameters may lie in the field of inflammatory or tumor microenvironment, altered glycosylation, altered DC/MF 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 pre-clinical
strategies to come to a better treatment of chronic inflammation, cancer and infectious
diseases.
The following keys were identified in program 2:
1. Strong DC and stromal cell 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. Certified laboratory available for developing immune diagnostic and monitoring
strategies (Medical Immunology)
5. Unique human skin model systems for pathogen infection, DC targeting and skin
inflammation and wound healing
6. Presence of unique murine tumor-models, tolerance induction models, as well as
models of auto-immunity leading to chronic inflammation
7. Strong expertise in lymph node development
8. Well developed adoptive transfer technology and tetramer technology
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9. Unique setting of various pathogen related research and technology
10. 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-glycantargeting) with a special focus on improving treatment of colon carcinoma, breast
cancer, melanoma and virally induced malignancies. Focus will lie in targeting DC invivo 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. In the field of inflammation, we will focus on mechanisms of allergic contact dermatis
and skin wound healing in order to develop novel preventative as well as diagnostic
strategies in order to prevent and treat skin related inflammation.
4. 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. Because of this lack of natural
encounter for all CCA/V-ICI program 2 participants monthly seminars are organised in which
projectleaders as well as scientist present their current research and future directions to
stimulate collaboration. 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. The leaders of program 2 will regularly invite all projectleaders to attend to
discus CCA/V-ICI 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 to visit senior scientists
within program 2 to discuss their work. This will give the scientists 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. Furthermore, for the PhD students a masterclass with the invited speakers
will allow them to learn more about the research area that the seminar speaker is an
expert on. We think this will be an excellent opportunity and learning process for the junior
and senior scientists.
SWOT analysis Program 2
Strength:
- High impact of scientific output.
- Many projects are financed by prestigious innovative grants from NWO/ZONMW such as
VENI, VIDI, VICI.
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Very strong expertise on APC on different levels is present (mice-human-molecularcellular-organism-basic and pre-clinical setting).
Unique in house development of in vitro skin models (animal alternatives for vaccine
development, immuno-toxicology studies and custom designed skin constructs for
wound healing
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, Asthma Foundation, Burns
Foundation etc.
Availability of an excellent platform for communication between clinicians and
immunologists
Opportunity of new biotech initiatives such as DC-PRIME, DC4U, Immunafect and A-SKIN
Strong potency to attract SenterNovem funded grants for translational research and
valorisation
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 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 at the analytical level.
Opportunities:
- 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) will 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 model systems, T cell lines, mouse-model
systems.
- A more integrated pathogen related research can lead to new discoveries to be applied
for cancer and inflammotory mediated diseases.
- Optimize connection to large consortia financed by FES, focussing on valorisation of
basic research discoveries
Threats:
- The program may stand on its own in splendid isolation, as excellent research program,
without any connections with other V-ICI programs.
- Increasing educational obligations for program leaders as well as researchers.
- Increasing difficulties hiring skilled personnel.
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Future of CCA/V-ICI 2009-2013 (16 April 2009)
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, Medical Oncology)
- Prof. C.L. Verweij, PhD (Pathology)
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 diagnostics- molecular targeted therapy
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, non-invasively, 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 subcellular fractionation protocols have been set up for the analysis of proteins in plasma
membrane-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 abundancy. 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, posttranslational 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.
Research highlights Program 3 within period 2004-2008
1. Identification of peripheral blood biomarkers to predict responsiveness to TNF-blockade in
rheumatoid arthritis
2. Identification of peripheral blood biomarkers to predict responsiveness to IFN-beta therapy in
multiple sclerosis
3. Gene signatures implicated with a 4-fold increased risk to develop arthritis in autoantibody
positive arthralgia patients
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Future of CCA/V-ICI 2009-2013 (16 April 2009)
4. Identification DNA copy number profiles associated with response to drug therapy in advanced
colorectal cancer
5. Development of immuno-PET with long-lived positron emitters 124I and 89Zr for navigation of
antibody development and clinical applications: European distribution of technology.
6. Development of nanobody technology for targeting critical growth factors and their receptors:
perspectives for imaging and therapy
7. Identification of novel protein biomarkers for non-invasive early detection of colorectal cancer
8. Implementation and standardization of PET: clinical practice and trials
9. Monitoring response using FDG, H2O PET scanning and DCE-MRI during treatment with EGFR and
VEGF inhibitors in NSCLC
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.
The novel molecular imaging techniques have promise to step beyond the classical TNM-paradigm.
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 feces.
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.
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Future of CCA/V-ICI 2009-2013 (16 April 2009)
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
disease-related proteins and to establish values for sensitivity and specificity.
Collaboration
In and outside 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.
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.
SWOT analysis Program 3
Strength:
- Strong clinical and fundamental research units in one institute with excellent translational
research lines, which are perfectly well fitting with recent national (eg. CTMM) and
international (eg. EU) initiatives on translational research,
- Strong profile on research on prediction of response to therapy, and early (preclinical)
diagnosis.
- Well-focused theme, favorably 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)
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Future of CCA/V-ICI 2009-2013 (16 April 2009)
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 patient cohorts that allow profiling at several levels.
- Limited equipment budget.
- Molecular imaging is just nuclear imaging. Dept of Radiology is quite passive. Optical techniques
have no prominent place.
- More active role of Surgery and Medical Oncology departments 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.
- Integration of immunological and cancer research to develop new immunotherapeutical
approaches
- 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 centralising of key
activities.
- Creation of a multidisciplinary team of experts focused on biomarker discovery, development
and implementation
- Societal and economical value creation through the implementation of clinical relevant
biomarker profiles in clinical practice
- Program 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 centers in the Netherlands
- 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 existing facilities is difficult. Tight links with departments are important.
- 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 2009-2013 (16 April 2009)
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
immune-mediated, non-oncological diseases. The program has been organized along five research
lines:
1. Chemotherapy
2. Immunotherapy
3. Radiotherapy and surgery
4. Gene therapy
5. 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.
1. 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.
2. The research line Immunotherapy investigates new immunotherapeutic approaches for the
treatment of rheumatoid arthritis and other immunological disorders. In addition, immunotherapy 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.
3. 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.
4. 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.
5. 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 anti-inflammatory 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 facilitate these aims. Furthermore, effective
dendritic cell vaccines will be developed and evaluated in clinical studies of various malignancies.
By exploiting the existing expertise within CCA/V-ICI in immune effector-targeted approaches in
cancer therapies, novel immune-therapies will also be explored in treating auto-immune disorders.
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Future of CCA/V-ICI 2009-2013 (16 April 2009)
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 as follows:
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 CCA/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 program 4
Strength
- Research lines that focus on new targeted therapies, with good access to new drugs and
monoclonals
- Combined immuno-oncological research is well represented
- Significant number of ongoing phase I-III studies in the different departments
- QOL research well embedded
- Overall high impact of publications
- Numerous ongoing national and international collaborations
- Staff members are well represented in many editorial boards
Weakness
- Current studies are spread over a large number of tumor types
- A significant proportion of research is still industry-driven
- Lack of VICI-based clinical trials unit to support investigators
Opportunities
- The large number of clinical trials offer opportunities for more translational research,
particularly in the development and testing of new drugs and monoclonals
- Develop further the concept of the malignant stem cell for key tumor sites
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Future of CCA/V-ICI 2009-2013 (16 April 2009)
Threats
- Increasing educational obligations in a setting without protected research time
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