Download The Netherlands Cancer Institute Today’s research, for tomorrow’s cure

The Netherlands
Cancer Institute
Today’s research, for tomorrow’s cure
Today’s research,
for tomorrow’s cure
The Netherlands Cancer Institute
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Scientific brochure NKI
Contents
Contents
Contents
07
Foreword
08
Introduction
15
From basic research to clinical application
23
Basic research (research groups)
24
69
Clinical research
70
Medical oncology
74
Surgical oncology
78
Radiotherapy
82
Diagnostic oncology
86
Facilities
92
Career and training
97
Contact
98
Colophon
index research groups
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Scientific brochure NKI
Creating new opportunities for patienttailored cancer treatments through basic,
translational and clinical research
Foreword
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Foreword
With great pleasure and pride I offer you this brochure
The challenge is now clear. We know that research is
on the research performed at The Netherlands Cancer
the only way to improve cure rates and enhance the
Institute-Antoni van Leeuwenhoek Hospital.
quality of life for cancer patients. But we know that
scientific research only will make a difference when the
The Netherlands Cancer Institute (NKI) is an exciting
acquired insights can be applied in a clinical setting.
and rewarding place to work, and has become an
So having the Antoni van Leeuwenhoek Hospital as an
internationally recognized center of scientific excellence
integrated partner is essential.
in many key areas relating to cancer. Recognition of
our status is evident from our publication record, from
As director, I have the privilege of overseeing this
the many invitations that staff receive to organize and
motivated group of investigators as they explore basic
speak at major conferences, from the prestigious prizes
principles of cell and molecular biology and translate
our staff receive, and from our ability to attract funding.
them into clinically useful tools and strategies. I am
fascinated by the variety of approaches that we are
Our success arises largely from two key policies.
advancing, ranging from genetic screening and imaging
First, we only hire ambitious researchers who wish
technologies to new drugs and therapeutic regimens.
to participate in a highly interactive community of
scientists and doctors. Second, the institute has a
A major outcome will be the ability to identify the best
‘flat’, non-hierarchical management style that gives our
method of treating individual patients. My firm belief is
research staff the freedom to explore areas of interest
that in the next decade we will see a move away from
and empowers them to pursue their goals and produce
single forms of treatment for all patients in a broad
results. This makes it easy for group leaders to direct
category of cancer, to a much more patient-centered
their work along exciting paths, with the expectation
therapy where each patient receives treatment tailored
that they will make a valuable contribution to cancer
to have maximum impact on his or her tumors, with the
research.
fewest side-effects.
As a consequence, the NKI contains a wonderfully
This brochure shows many of the people who will make
broad range of interests and experience. While some
this happen, and gives a flavor of how today’s work will
of the work has direct relevance to cancer, other
lead to tomorrow’s cure.
projects are more fundamental in their nature. These
fundamental projects, however, generate a foundation
of knowledge and resources that the applied cancer
Prof. dr. Anton Berns,
research can build on.
Scientific Director.
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Introduction
Improving cancer treatment depends heavily on a better scientific understanding of the function and
development of normal cells and tumor cells. Through fundamental and clinical research we hope to
contribute to better cancer treatment. Discoveries made in the laboratory are rapidly introduced into the
clinic through our translational research program driven by close collaboration between our scientists and
clinicians. The Netherlands Cancer Institute (NKI) aims to be a national and international center of excellence
in cancer research. To reach our goals the NKI has a dedicated staff of internationally recognized scientists,
highly motivated students and state of the art support facilities.
The NKI
cancer center in the Netherlands and maintains an important
The Netherlands Cancer Institute was established on
role as a national and international center of scientific and
October 10, 1916. The founders, Rotgans, professor of
clinical expertise, development and training.
Surgery, the publisher De Bussy, and De Vries, professor
of Pathology, wanted to build a cancer institute ‘where
The three major areas of research are fundamental, clinical
patients suffering from malignant growths could be treated
and translational cancer research. A thorough understanding
adequately and where cancer and related diseases could
of the biological processes of normal cells is the basis for
be studied’. They bought a house on one of the canals in
understanding cancerous cells. The laboratory covers all ma­jor
Amsterdam and named it the ‘Antoni van Leeuwenhoek
areas of cancer research, with special emphasis on cell-based
Huis’, after the famous Dutch microscopist. The clinic
screens, mouse tumor models, cell biology, structural biology
had room for 17 patients, while the laboratory could
and epidemiology. The institute coordinates and participates
accommodate 8 to 10 scientists.
in many clinical trials; most of these are phase 1, 2 or 3
studies of potential new treatments such as combinations
Nowadays, The Netherlands Cancer Institute-Antoni
of chemotherapeutics, radiotherapy and/or surgery. Results
van Leeuwenhoek Hospital (NKI-AVL) accommodates
obtained from fundamental research are translated into clinical
approximately 550 scientists and scientific support personnel,
applications as part of our translation research program.
53 medical specialists, 180 beds, an out-patients clinic that
receives 24,000 new patients each year, five operating
From its first inception the NKI-AVL saw close collaboration
theaters and nine irradiation units. It is the only dedicated
between scientists and clinicians as essential to fighting
Introduction
cancer. Having a laboratory and hospital under one roof
Advisory Board consisting of internationally recognized
in a single independent organization with an open and
scientists. Members of the board are frequently asked
collaborative atmosphere has led to many important
to advise the Director of Research on issues such as the
discoveries and improved therapies.
appointment of faculty members, evaluation of research
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programs and policies. They also discuss the quality,
Organization
significance, and main focus of individual NKI researcher’s
Scientific research groups are organized into divisions: usually
projects.
research groups on one floor form a division. Clinical research
groups are also organized into scientific divisions according
The NKI-AVL Board of Directors consists of three members.
to the clinical departments of the cancer hospital. One of
The Board operates as a collective, although each member is
the group leaders is head of the division. He/she oversees
responsible for his own field of expertise.
the quality of the science within the division, promotes
collaboration between division members, and conducts the
The Board of Governors is composed of knowledgeable and
general management of the division. The divisions and their
respected members of Dutch society. Governors monitor the
group leaders are listed on the next page. For the clinical
Institute’s operations to ensure that the organization not only
research divisions only the head of the division is indicated.
fulfills its scientific and clinical mission but also operates in a
financially responsible manner, and according to the highest
In order to maintain the highest standards of research, the
ethical standards. They advise and control the Board of
NKI has established a national and international Scientific
Directors.
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Division of Cell Biology
Division of Cellular Biochemistry
Division of Molecular Biology
Arnoud Sonnenberg (head)
Wouter Moolenaar (head)
Hein te Riele (head)
John Collard
Nullin Divecha
Piet Borst
Kees Jalink
Huib Ovaa
Jos Jonkers
Ed Roos
Wim van Blitterswijk
Sabine Linn
Fred van Leeuwen
Bas van Steensel
Marcel Verheij
Lodewyk Wessels
René Bernards (head)
Division of Immunology
Division of Tumor Biology
Roderick Beijersbergen
Jannie Borst (head)
Jacques Neefjes (head)
Anastassis Perrakis
John Haanen
Reuven Agami
Titia Sixma
Heinz Jacobs
Maarten Fornerod
Ton Schumacher
Rob Michalides
Division of Molecular
Carcinogenesis
Peter Peters
Division of Molecular Genetics
Division of Psychosocial Research
Division of Diagnostic Oncology
Maarten van Lohuizen (head)
and Epidemiology
Marc van de Vijver (head)
Anton Berns
Neil Aaronson (head)
John Hilkens
Flora van Leeuwen
Daniel Peeper
Division of Radiotherapy
Division of Experimental Therapy
Harry Bartelink (head)
Alfred Schinkel (head)
Adrian Begg
Division of Medical Oncology
Jan Schellens
Sjoerd Rodenhuis (head)
Fiona Stewart
Marc van de Vijver
Division of Surgical Oncology
Laura van ’t Veer
Bin Kroon (head)
Introduction
International Scientific Advisory Board
P. Nurse, Professor of Microbiology,
T. de Lange, Leon Hess Professor, The Rockefeller University,
President of The Rockefeller University, New York, USA
New York, USA
R. Nusse, Professor of Developmental Biology,
R.A. Flavell, Professor of Immunobiology, Yale University School of
Stanford University, Stanford, USA
Medicine, New Haven, USA
H.L. Ploegh, Whitehead Institute for Biomedical Research,
S. Hellman, Pritzker distinguished service professor,
Cambridge, USA
University of Chicago, Chicago, USA
K. Vousden, Director, Beatson Institute for Cancer Research,
W.G.J. Hol, Professor of Biochemistry and Biological Structure,
Glasgow, UK
University of Washington, Seattle, USA
R.A. Weinberg, Professor of Biology, Massachusetts Institute of
J. Mendelsohn, President MD Anderson Cancer Center,
Technology, Whitehead Institute for Biomedical Research,
University of Texas, Houston, USA
Cambridge, USA
National Scientific Advisory Board
Patron
L.A. Aarden, Professor of Molecular Immunology,
Her Majesty Queen Beatrix
University of Amsterdam
S.W.J. Lamberts, Professor of Internal Medicine,
Board of Governors
Erasmus University Rotterdam
W. Kok, president
B. Löwenberg, Professor of Hematology,
H.C.J. van der Wielen, vice-president
Erasmus University Rotterdam
P.J. Kalff, treasurer
C.J.L.M. Meijer, Professor of Pathology,
P.F. van der Heijden
Free University Amsterdam
F.H. Schröder
C.J.M. Melief, Professor of Immunohematology, Leiden University
D. Sinninge Damsté
H.M. Pinedo, Professor of Clinical Oncology,
M.C. Smeets
Free University Amsterdam
J. Van der Meer
F.H. Schröder, Professor of Urology, Erasmus University Rotterdam
P.C. Van der Vliet
G.N.J. Tytgat, Professor of Gastroenterology,
G.P. Vooijs
University of Amsterdam
A.J. van der Eb, Professor of Fundamental Virology,
Board of Directors
Leiden University
A.J.M. Berns, chairman and director of research
P.C. van der Vliet, Professor of Physiological Chemistry,
S. Rodenhuis, director clinical research and development
Utrecht University
W.H. van Harten, director organization and management
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From basic research to clinical application
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From basic research to clinical application
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From basic research
to clinical application
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Understanding cancer:
basic research at the NKI
The basic research at the NKI aims for a more profound understanding of how cancer arises, and strives to
translate this knowledge into new approaches to diagnosing and treating cancer. This encompasses many
scientific themes in tumor-cell biology, notably how genetic mutations arise, in which genes, and with what
consequences; how genes are organized in the nucleus and regulated, and how this regulation may go
wrong in cancer; signaling in normal and cancer cells – at the cell surface and the transmission of signals to
the cell interior; cell fate; cell division; programmed cell death (apoptosis); tumor growth and metastasis;
and resistance to cancer treatment.
Cutting-edge technologies
which could either enhance or reduce a gene’s activity.
Scientists at the NKI are among the world’s most talented
To enhance the activity of a particular gene, for example,
inventors and users of new technologies. This can involve
NKI scientists can use transgenic mouse technology
gadgets and reagents for use at the laboratory bench, the
to introduce molecular machinery to switch a gene on
creation of new animal models, or new high-throughput
and maintain its activity at high levels, even at stages in
devices in centralized facilities. The NKI has particular
development when it is normally switched off. Conversely,
expertise in using and generating new animal models for
NKI scientists use a technique known as RNA interference
cancer. These are helping to provide insights into many
(RNAi) to selectively switch off the activity of a particular
aspects of cancer biology, especially in understanding how
gene, or genes, and examine the consequences for various
the effects of different genetic mutations can combine to
cell processes. This involves introducing small pieces of
promote tumor development. They also serve as tools for
RNA to effectively silence individual genes. The NKI has a
the pre-clinical testing of new therapies and drugs. The
collection of over 30,000 small RNA pieces, which in total
NKI’s animal models are valuable not only to NKI researchers
correspond to all human genes. Besides contributing to
but also to other research institutes and pharmaceutical
understanding gene function, this technique also helps to
companies for the testing of new anticancer drugs.
identify new targets for drug development.
Functional screens
Understanding mutations – the trigger for cancer
NKI scientists use various techniques for altering the action
Genetic mutations lie at the heart of tumor formation.
of individual genes in both laboratory cell cultures and
As mutations accumulate in genes that are critical to cell
in animal models. This enables them to identify a gene’s
growth and signaling, cells stop producing key proteins, or
normal function and to mimic the effects of mutation,
produce abnormal versions, and begin to behave incorrectly.
From basic research to clinical application
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They break free of normal constraints on cell growth and
‘recognize’ tumor cells as abnormal and alert and attract
division and spread to other parts of the body. Mutations
other cells to kill the cancer cells. None of this would
that result in cancer can either be spontaneous, appearing
occur without extensive signals being exchanged between
in a cell for the first time, or can be inherited by children
different cells, through receptors on their surfaces and the
from their parents, which increases the risk of developing a
release of molecules called cytokines. NKI scientists are
particular form of cancer, such as in the breast or colon.
searching for ways to enhance these processes, including
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the design of novel cancer vaccines, which are currently
On a basic level, NKI scientists are investigating the effects
being tested in animals before moving to clinical trials.
of genetic mutations on processes that normally maintain
cells in good health, for example, the repair of damage
Tumor growth and metastasis
or other alterations to DNA. When chemicals or radiation
The ability of tumors to grow and ruthlessly destroy the
damage the nucleotide building blocks of DNA, a complex
body’s vital organs is the key feature that distinguishes them
of proteins normally repairs the damage by replacing
from normal tissues. NKI researchers are investigating how
altered nucleotides with new ones. A similar repair process
normal cells start to ignore the signals that would normally
occurs when enzymes responsible for replicating DNA make
prevent a cell dividing too often. Alongside this, they are
an error and insert the wrong nucleotide into the DNA
studying how cells start to move around the body and grow
sequence, which can occur if mutations arise in one or more
in new tissues, a process known as metastasis. Advances in
of the enzymes. Using in vitro cell culture, functional screens,
understanding these processes may one day lead to new
biochemistry and protein crystallography, NKI scientists
approaches to cancer treatment.
are investigating the processes leading to DNA damage
or replication errors, and the effects of mutations on DNA
repair proteins.
Cell signaling
Cells do not exist in isolation. Rather, they are in continuous
communication with their surroundings, receiving and
responding to signals from hormones, cytokines, and other
cells. NKI scientists are investigating the mechanisms by
which signals are relayed to the cell interior, and how these
can go wrong in cancer cells. Research into abnormalities in
the receptors on the surface of breast cancer cells has led
to the creation of a new screening tool for patients which
can determine how well they may respond to hormone
treatment.
The body’s immune defenses, best known for their role in
fighting infections, are also important in protecting against
cancer. This too depends upon signaling at the surface of
the immune system’s ‘soldiers’, the lymphocytes. These can
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Improving cancer treatment:
clinical research at the NKI
Clinical research aims to introduce new forms of treatment into the clinic and to improve excisting ones.
Highly trained clinical and auxiliary professionals, multidisciplinary patient reviews, specially trained
oncology nurses, and excellent support facilities for clinical trials allow many clinical trials to be performed
at the hospital.
Improving diagnosis and prognosis
ways of identifying the type of tumor a patient has, and the
Through collaboration with surgeons, the NKI-AVL’s
extent to which it has spread beyond its original site.
pathology department has amassed an impressive bank of
tumor tissue from breast cancer patients. This has allowed
Therapies of the future
researchers to develop new tests for predicting metastasis
Cancer treatments of the future are likely to be more finely
using DNA microarray analysis, a method that is now widely
tuned to the needs of the individual patient than at present.
used in the laboratory, but is only just beginning to have an
Most existing anticancer drugs target rapidly dividing cells
impact in the clinic. This works by detecting patterns in
indiscriminately, which is why they can have severe side
gene activity that differ between tumor cells and normal
effects such as nausea, dizziness, loss of taste sensation,
tissues.
fatigue, and hair loss. Radiotherapy too can have long-term
side effects on the tissues surrounding tumors, including
NKI researchers are now also applying microarray
causing secondary cancers and heart disease.
technology to predict the effects of different drugs on a
tumor. These studies would not be possible without the
The NKI therefore places great emphasis on the goal of
institute’s bioinformaticians, who analyze the data and
creating new approaches to cancer therapy that reduce
develop the computer algorithms needed for making
side effects and enhance patient survival. One approach is
confident predictions.
to make existing treatments more effective by combining
two or more different modalities, such as chemotherapy
Meanwhile, NKI researchers are also searching for new
and radiotherapy. This allows smaller doses of either to
diagnostic markers in biological fluids – mainly blood, urine
be given to the patient, and may help to avoid long-term
and cerebrospinal fluid. The aim is to develop non-invasive
side effects.
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Similarly, the use of photodynamic therapy, isolated limb
Protecting against cancer
perfusion, and hyperthermic intra peritoneal chemotherapy
The devastating effect of cancer sometimes leads patients
(HIPEC) enable chemotherapy to be given at high dose in
or their relatives to volunteer as subjects for cancer research.
more localized parts of the body, thus sparing other organs
Following the availability of new genetics tools during the
from exposure.
late 1980s and 1990s, the NKI-AVL set up a Family Cancer
Clinic where family members receive genetic counseling on
These treatments still fail, however, to distinguish between
their own risk of developing cancer. Molecular biologists and
most normal tissues and tumors. NKI scientists are therefore
epidemiologists at the NKI are following families affected
exploring new ideas for targeting therapy specifically at
by cancer in order to identify new mutations associated
cancer cells. These are tested in animal models first, to
with the disease, and to pinpoint how environmental factors
gauge safety and effectiveness, before entering clinical
such as diet, exercise and hormones may raise the risk of
trials. One example is the use of DNA-based vaccines
developing cancer, or serve as protection.
against cervical cancer and melanoma, to trigger the
immune system to target tumors, combined with low
Coping with cancer
doses of radiation to boost the influx of immune cells to
Being diagnosed for cancer changes one’s whole
a tumor site.
perspective on life. Not only the patient, but also relatives,
have to cope with the diagnosis and treatment. Re­search
Overcoming resistance
into coping mechanisms has led to changes in treatment
Scientists at the NKI are working to enhance drug uptake
and care that help patients and their close relatives.
into the body so as to enable patients to take drugs orally
rather than by injection, and to raise the dose and extend
Forging ahead
the time that drugs are active in the body. They are also
The NKI-AVL is proud of its position as one of the
attempting to overcome the problem of drug resistance,
Netherlands’ foremost biomedical research institutions,
which often arises through mutation in a patient’s tumor.
dedicated to improving the treatment and care of
One strategy is to find and design drugs that attack
patients with cancer, and helping healthy individuals to
alternative weak spots in a cancer cell and render the tumor
avoid cancer in future. Its clinical services operate to the
more sensitive to treatment.
highest international standards, and continue to extend
the boundaries of what can be done for cancer patients.
Through imaging technology such as MRI and PET, patients
Its scientific achievements are celebrated internationally
can be monitored to see whether or not the drug is killing
through awards and highly cited publications in peer-
and shrinking a tumor, enabling clinicians to monitor the
reviewed journals. With well-integrated clinical and basic
success of a particular treatment.
research operations, the NKI-AVL aims to have a critical
impact on cancer in the future.
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Basic research
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Basic research
Basic research
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Aaronson, Neil
Psychosocial and behavioral oncology
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Agami, Reuven
RNAi, microRNAs and cancer
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Begg, Adrian
Individualization of radiotherapy
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Beijersbergen, Roderick
The RNAi strategy in cancer research
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Beijnen, Jos
Anticancer drug development
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Bernards, René
Functional cancer genetics
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Berns, Anton
Mouse models for cancer
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Borst, Jannie
Cell survival and death pathways
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Borst, Piet
Drug resistance and DNA base J
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Collard, John Tiam1-Rac signaling and cancer
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Divecha, Nullin
Cancer cells: PIPed at the post
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Fornerod, Maarten
Transactions at the nuclear envelope
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Haanen, John
Attacking cancer with T-lymphocytes
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Hilkens, John
Breast cancer genes
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Jacobs, Heinz
Programmed mutagenesis
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Jalink, Kees
Biophysics of cell signalling
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Jonkers, Jos
Mouse models of breast cancer
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Michalides, Rob
Estrogen receptor and breast cancer
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Moolenaar, Wouter
LPA, a multifunctional growth factor
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Neefjes, Jacques
Improving immune responses to tumors
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Ovaa, Huib
Chemical tools for cancer research
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Peeper, Daniel
Identifying novel cancer genes
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Perrakis, Anastassis
Structural biology
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Peters, Peter
Cryo-electron tomography in the cell
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Roos, Ed
Metastasis: tumor cells on the move
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Schellens, Jan
Pharmacology of anticancer drugs
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Schinkel, Alfred
Improving anticancer drug efficacy
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Schumacher, Ton
Immunotechnology & immunotherapy
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Sixma, Titia
Structural biology
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Sonnenberg, Arnoud
Cell-matrix adhesion
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Stewart, Fiona
Vascular damage after radiotherapy
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Te Riele, Hein
Gene modification: subtle is the oligo
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Van Blitterswijk, Wim
Membrane rafts as gateways for drug
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Van de Vijver, Marc
Genetic alterations in breast cancer
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Van Leeuwen, Flora
Epidemiology of cancer
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Van Leeuwen, Fred
Epigenetics in yeast
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Van Lohuizen, Maarten
Cell fate control by Polycomb silencers
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Van Steensel, Bas
Chromatin genomics
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Van ‘t Veer, Laura
Molecular profiles of breast cancer
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Verheij, Marcel
Apoptosis modulation and radiotherapy
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Wessels, Lodewyk
Bioinformatics
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Index
Basic research
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Psychosocial and behavioral oncology
Neil Aaronson
Neil Aaronson is certain that if you provide clear information about a patient’s quality of life,
SELECTED PUBLICATIONS
physicians and other carers become more attuned to the patient’s problems. Shortcomings
in treatment and care are redressed, and the patients are more satisfied with their treatment.
Madalinska, J., Van Beurden, M., Bleiker, E.,
Valdimarsdottir, H., Hollenstein, J., Massuger, L.,
With a background in clinical psychology, I have a keen interest in assessing how individuals
adjust to illness and therapy. I’m also trained in public health and so have a good grasp of
research based on large numbers of patients. For me, the NKI is the perfect place to do
Gaarenstroom, K., Mourits, M., Verheijen, R., Van
Dorst, et al. (2006). The limited role of hormone
replacement therapy in alleviating menopausal
symptoms after prophylactic salpingo-oophorectomy. J. Clin. Oncol. 22; 3576-3582.
high-quality academic work in an applied setting. It also gives me a base from which I link to
many international research groups.
Over the past 20 years I’ve championed the use of standardized questionnaires and
structured interviews, trialing them on large groups of cancer patients. We’ve learned how
cancer and its treatment affect patients and their families, and how survivors cope in the
Schagen, S.B., Muller, M.J., Booger, W.,
Mellenberg, G.H., and Van Dam, F.S. (2006).
Deterioration in cognitive function after
chemotherapy: a study in breast cancer patients.
J. Natl. Cancer Inst. in press.
long term. The questionnaires were initially created for research, and it’s been exciting to
Bleiker, E.M.A., Menko, F.H., Taal, B.G., Kluijt,
see them move into the clinic. Patients can now complete the questionnaire on a touch-
I., Wever, L.D.V., Gerritsma, M.A., Vasen, H.F.A.,
screen computer and take a printout to their consultation, which helps patient and clinician
use their time together more productively.
In another line of research, my colleagues Frits van Dam and Sanne Schagen found that a
small, but significant, group of people who have had chemotherapy find it harder to perform
mental tasks. The research started after a chance conversation with a nurse over lunch
one day, and led to a systematic assessment of the nature and scope of this problem. For
and Aaronson, N.K. (2005). Screening behaviour
of individuals at high risk for colorectal cancer.
Gastroenterology 128; 280-287.
Detmar, S.B., Muller, M.J., Schornagel, J.H.,
Wever, L.D.V., and Aaronson, N.K. (2002). A
randomized study of the value of health-related
quality of life assessments in daily clinical
practice. JAMA 288; 3027-3034.
patients with brain cancer, we are testing ways of helping them to recover cognitive skills or
to learn to cope with their new limitations.
My group is also studying people’s responses to counseling and genetic testing for cancers
that run in families, in particular colorectal and ovarian cancer. Led by Eveline Bleiker and
myself, this research line investigates the emotional implications of undergoing testing,
and examines how it affects the person’s anxiety about cancer, their family relationships, and
their efforts to remain in good health.
[email protected]
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RNAi, microRNAs and cancer
Reuven Agami
Reuven Agami came to the NKI in 1998 and develops tools that can reveal the functions of
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individual genes in the chain of events that transforms a healthy cell into a cancer cell.
Voorhoeve, P.M., Le Sage, C., Schrier, M., Gillis,
Our most exciting work at present is developing the tiny RNAs called microRNAs to
manipulate the expression of genes we suspect of playing a role in cancer. These 20-base
RNAs are part of a cell’s normal controls on gene activity.
The potential of microRNAs as research tools is vast. On the one hand we can change
A.J.M., Stoop, H., Nagel, R., Liu Y., Van Duijse,
J., Drost, J., Griekspoor, A., et al. (2006).
A genetic screen implicates miRNA-372 and
miRNA-373 as oncogenes in testicular germ cell
tumors. Cell. 124; 1169-1181.
gene regulation by introducing a microRNA that the cell does not produce; on the other
Duursma, A., and Agami, R. (2005). p53-
we can introduce so-called antisense microRNAs that effectively wipe out their counterpart
depen­dent regulation of Cdc6 protein stability
microRNAs in the cell.
controls cellular proliferation. Mol. Cell Biol. 25;
6937-6947.
We’ve made a unique set of viruses containing the genetic code for the 500 known human
microRNAs; we use them to force cells to make a specific microRNA. A first use of our
viruses was to identify cancer-causing microRNAs. Among these, we implicated two in
the rare but curiously easily treatable type of testicular cancer suffered by cyclist Lance
Armstrong in 1996. The vast majority of these tumor cells have a functional p53 tumor
Kolfschoten, I., Van Leeuwen, B., Berns, K.,
Beijersbergen, R., Bernards, R., Voorhoeve, P.M.,
and Agami, R. (2005). A genetic screen identifies
PITX1 as a suppressor of RAS activity and tumorigenicity. Cell. 121; 849-858.
suppressor gene, so they should be protected from becoming cancerous. But we discovered
Brummelkamp, T.R., Bernards, R., and Agami, R.
they also contain two microRNAs that prevent p53 from working properly. Intriguingly, these
(2002). A system for stable expression of short
microRNAs also make the tumor cells highly vulnerable to DNA damage, explaining why this
interfering RNAs in mammalian cells. Science.
296; 550-553.
cancer is easy to treat by therapies that attack DNA.
We’ve also discovered that these microRNAs are involved in helping some cancers resist
therapy. This raises the exciting possibility of using antisense microRNAs medically to tackle
this problem.
In previous work at the NKI on RNA interference — another way of silencing gene expression
— I, and my colleagues devised a system, marketed as pSUPER RNAi™, that can silence
almost any known gene in mammalian cells. This technology is now used in labs all over
the world.
[email protected]
Basic research
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p27
Individualization of radiotherapy
Adrian Begg
Adrian Begg arrived at the NKI 22 years ago, drawn from the UK by an invitation to develop
SELECTED PUBLICATIONS
a site of excellence in radiobiology research. He stayed on as the institute grew and the
work kept getting more interesting.
Hoebers, F.J., Pluim, D., Verheij, M., Balm, A.J.,
Bartelink, H., Schellens, J.H., and Begg, A.C.
The main thrust of my work is predicting how tumors respond to radiotherapy, which is
critical for improving cancer treatment. Our goal is to create a test that can accurately
predict the ideal treatment for a patient before they begin therapy.
(2006). Prediction of treatment outcome by
cisplatin-DNA adduct formation in patients with
stage III/IV head and neck squamous cell carcinoma, treated by concurrent cisplatin-radiation
(RADPLAT). Int. J. Cancer 119; 750-756.
In the past, such assessments could only be made by drawing inferences from parameters
such as tumor growth rate or oxygen levels, and was never very satisfactory. The arrival
of DNA microarrays opened up new horizons for us. We can now determine which of the
tumor cells’ genes are operating normally, which are overexpressed, and which are underrepresented. Having these genetic profiles is a huge step forward, and we should soon
Sprong, D., Janssen, H.L., Vens, C., and Begg,
A.C. (2006). Resistance of hypoxic cells to
ionizing radiation is influenced by homologous
recombination status. Int. J. Radiat. Oncol. Biol.
Phys. 64; 562-572.
be able to link a tumor’s profile with particular therapeutic recommendations and more
Janssen, H.L., Ljungkvist, A.S., Rijken, P.F.,
accurate prediction of outcome.
Sprong, D., Bussink, J., Van der Kogel, A.J.,
A valuable resource at the NKI is the tissue bank, where doctors have archived tumor tissue
Haustermans, K.M., and Begg, A.C. (2005).
Thymidine analogues to assess microperfusion in
taken over many years. We use this tissue to compare gene profiles of tumors taken from
human tumors. Int. J. Radiat. Oncol. Biol. Phys.
patients who were treated five years ago with the outcome of their treatment. We have
62; 1169-1175.
already found gene profiles that correlate with outcome — but we are still in an early stage.
Vens, C., Dahmen-Mooren, E., Verwijs-Janssen,
We’re also working on a more lab-based project on DNA repair. Ionizing radiation kills cells
M., Blyweert, W., Graversen, L., Bartelink, H.,
by damaging their DNA, and is most effective when the cell’s DNA repair mechanism is
and Begg, A.C. (2002). The role of DNA polymerase beta in determining sensitivity to ionizing
faulty — which is often the case for tumor cells. We want to understand the DNA repair
radiation in human tumor cells. Nucleic Acids
mechanism well enough to find agents that can disable it, and to identify the genetic profile
Res. 30; 2995-3004.
of cells in which DNA repair is weak.
The attraction of this approach is that cancer cells with mutations in one or more DNA repair
pathways will be vulnerable to therapy that disables the remaining pathway, while normal
cells with intact DNA repair will be unharmed. We hope that this approach will lead to a
therapy that hits tumors hard, but causes few side effects.
[email protected]
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Scientific brochure NKI
The RNAi strategy in cancer research
Roderick Beijersbergen
After his post-doctoral position at the Whitehead Institute for Biomedical Research in
SELECTED PUBLICATIONS
the United States, Roderick Beijersbergen moved to the NKI in 1999. He now uses his
imagination and innovative skills to develop and apply new research tools with the goal to
Bernards, R., Brummelkamp, T.R., and
identify key genes associated with cancer.
Beijersbergen, R.L. (2006). shRNA libraries and
their use in cancer genetics. Nat. Methods. 3;
701-706.
My main interest is to identify novel targets that can be used for the treatment of cancer.
With the elucidation of the humane genome we can now examine the role of each individual
Brummelkamp, T.R., Fabius, A.W., Mullenders,
J., Madiredjo, M., Velds, A., Kerkhoven, R.M.,
gene in important cellular processes. We make use of the technique of RNA interference
Bernards, R., and Beijersbergen, R.L. (2006).
(RNAi) to silence gene expression and monitor their role in cell growth, survival and
An shRNA barcode screen provides insight into
transformation. We have created large sets of so-called hairpin RNAs that can knock down
cancer cell vulnerability to MDM2 inhibitors.
Nat. Chem. Biol. 2; 202-206.
specific human and mouse genes. By making use of our own robotic high throughput system
to perform large scale automated cell based screens we can assess what happens when
each of these genes is turned off in a cell. By doing so we can also study how anti-cancer
drugs work and identify genes involved in resistance to cancer therapies.
A major challenge is to develop drugs that act only on tumor cells. We are using RNA
Berns, K., Hijmans, E.M., Mullenders, J.,
Brummelkamp, T.R., Velds, A., Heimerikx, M.,
Kerkhoven, R.M., Madiredjo, M., Nijkamp,
W., Weigelt, B., Agami, R., Ge, W., Cavet, G.,
Linsley, P.S., Beijersbergen, R.L., and Bernards, R.
(2004). A large-scale RNAi screen in human cells
interference to identify genes that upon inactivation only affect tumor cells and not normal
identifies new components of the p53 pathway.
cells. These genes are interesting candidates for the development of novel classes of more
Nature. 428; 431-437.
specific cancer therapies.
Behind all my work is a fascination with the complexity of biological systems. You often
start by working on a single gene, but soon you realize that the gene is part of an intricate
network or pathway. Understanding the complex processes involved in these networks will
allow us to develop better cancer drugs.
[email protected]
Basic research
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p29
Anticancer drug development
Jos Beijnen
Jos Beijnen oversees the NKI’s pharmacy department, which not only serves the Antoni
SELECTED PUBLICATIONS
van Leeuwenhoek hospital but also runs a small pharmaceutical facility, supplying new drug
formulations for research and treatment worldwide.
Engwegen, J.Y., Helgason, H.H., Cats, A.,
Harris, N., Bonfrer, J.M.G., Schellens, J.H.M.,
Besides our standard pharmacy work, preparing and dispensing drugs for the hospital,
and our research, we are very unusual for a pharmacy department in having a facility with
an official GMP (good manufacturing practice) license from the Dutch health authorities
to manufacture new investigational cytotoxic drugs. We make them for our own clinical
and Beijnen, J.H. (2006). Identification of serum
proteins discriminating colorectal cancer patients
and healthy controls using surface-enhanced
laser desorption ionisation-time of flight mass
spectrometry. World J. Gastroenterol. 12;
1536-1544.
research and for hospitals and biotech companies in Europe and the USA.
As we’re small, we can be quicker and more flexible than the pharmaceutical industry, and
will supply just a handful of ampoules of a new drug for a clinical trial. We’ve just installed
a ‘biotherapeutics unit’ that uses engineered Escherichia coli to produce DNA vaccines
for clinical trials by the NKI’s immunology division. The profits from our manufacturing are
Den Brok, M.W., Nuijen, B., Lutz, C., Opitz, H.G.,
and Beijnen, J.H. (2005). Pharmaceutical development of a lyophilised dosage form for the
investigational anticancer agent Imexon using
dimethyl sulfoxide as solubilising and stabilising
agent. J. Pharm. Sci. 94; 1101-1114.
invested into the NKI.
Our research is mostly on cancer, although we also work on HIV and drug addiction. The
Stokvis, E., Rosing, H., and Beijnen, J.H. (2005).
Liquid chromatography-mass spectrometry for
pharmacology group, which Jan Schellens also heads, has PhD students who work on the
the quantitative bioanalysis of anticancer drugs.
design of drug formulations, as well as analyzing the properties of drugs once they are
Mass Spectrom. Rev. 24; 887-917.
given to patients. We also specialize in mathematical analysis and modeling of drug effects,
Beijnen, J.H., and Schellens, J.H.M. (2004).
which we use to predict how a patient might react to a drug, as well as determining its
Drug interactions in oncology. Lancet Oncol. 5;
concentration in the body, and the risk of side effects.
We are just beginning to explore two new avenues. First, we are looking for mutations
that affect the distribution of drugs in tumors or tissues, and their side effects and activity.
Armed with this information, it may be possible to lower drug doses for individual patients
to minimize side effects. Second, our proteomics research aims to identify patterns of
proteins in biological samples that are specific for different types of cancer and may predict
a person’s response to chemotherapy. This is in the preliminary phase so far, but we hope it
will provide an alternative means of forecasting drug effects and a patient’s progress.
489-496.
[email protected]
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Scientific brochure NKI
Functional cancer genetics
René Bernards
René Bernards joined the NKI in 1992 to develop new molecular approaches to cancer
SELECTED PUBLICATIONS
diagnosis and treatment. He is co-founder of the spin-off company Agendia, and in 2005 he
won the prestigious Spinoza prize from the Dutch scientific organization NWO.
Epping, M.T., Wang, L., Edel, M.J., Hernandez,
M., and Bernards, R. (2005). The human tumor
Our group is using the latest genetic tools to systematically determine which of the 30,000
antigen PRAME is a dominant repressor of retinoic acid receptor signaling. Cell. 122; 835-847.
or so human genes can be involved in cancer. The popular approach in the past was to
make a gene more active and see how this changed cell behavior. We’re now pioneering the
Nijman, S.M.B., Huang, T.T., Dirac, A.M.G.,
Brummelkamp, T.R., Kerkhoven, R.M., D’Andrea,
opposite approach, using RNA interference (RNAi) to silence genes.
A.D., and Bernards, R. (2005). A genetic screen
In one project we use RNAi to investigate resistance to anticancer drugs. A staggering two
identifies the de-ubiquitinating enzyme USP1 as
out of every three cancer patients don’t respond to the first drug they’re given. By the time
a regulator of Fanconi Anemia D2 mono-ubiquitination. Mol. Cell. 17; 331-339.
the right drug is found, the tumor has often become too advanced for us to win the battle.
We inactivate genes one at a time in tumor-cell cultures to see which ones, when they’re
not working, render the cells resistant to a particular drug. If we find mutations in one of
these genes in tumors of patients who are unresponsive to that drug, mutations in that gene
become potential predictive biomarkers for unresponsiveness.
Berns, K., Hijmans, E.M., Mullenders, J.,
Brummelkamp, T.R., Velds, A., Heimerikx,
Kerkhoven, R.M., Madiredjo, M., Nijkamp, W.,
Weigelt, et al. (2004). A large-scale RNAi screen
in human cells identifies new components of the
p53 pathway. Nature. 428; 431-437.
We are doing this for current and experimental drugs, and have already identified a
biomarker in melanoma patients that predicts their response to a new type of drug called
histone deacetylase inhibitors.
Our other big project is to identify new targets for so-called ‘smart drugs’ that aim to treat
cancer more effectively than standard chemotherapy.
Our assumption is that tumor cells carrying certain mutations are likely to be more
vulnerable than normal cells to further damage. Inactivating a second gene in the same
pathway might kill the tumor cell, revealing a target for new drugs.
To find such genes, we use RNAi to inactivate genes one at a time in human tumor cells that
have common mutations, such as p53. We have identified some candidates, and are about
to test the concept in an animal model.
Brummelkamp, T.R., Nijman, S.M.B., Dirac,
A.M.G., and Bernards, R. (2003). Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB. Nature. 424; 797-801.
[email protected]
Basic research
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p31
Mouse models for cancer
Anton Berns
Anton Berns became director of the NKI in 1999, but still maintains solid links with day-to-
selected publications
day research. His passion is to quicken the pace of basic research with the aim of getting the
benefits to patients sooner.
Mikkers, H., Allen, J., Knipscheer, P., Romeyn,
L., Hart, A., Vink, E., and Berns, A. (2002). High
I like to see primary data — it prevents me becoming detached from the actual research. My
personal interest is in mouse models, particularly for lung cancer and mesothelioma, two of
the deadliest cancers.
throughput retroviral tagging to identify components of specific signaling pathways. Nat. Genet.
32; 153-159.
Meuwissen, R., Linn, S. C., Linnoila, R. I.,
About eight years ago I set out to develop mice that mimicked human cancers. Our
Zevenhoven, J., Mooi, W. J., and Berns, A.
conditional knockout mice have since been a great success, and we have a number of strains
(2003). Induction of small cell lung cancer by
that produce tumors that really resemble human disease. We can study the stem cells from
which we believe tumors develop, and define the steps involved. We try to identify which
pathways have to become defective for a healthy cell to become transformed into a tumor
cell. Then we can start designing and testing rational interventions, and hopefully move
rapidly to developing more effective treatments for these cancers in people.
Creating mouse models is time-consuming, however. Even if we have a mouse that closely
somatic inactivation of both Trp53 and Rb1
in a conditional mouse model. Cancer Cell. 4;
181-189.
Van Amerongen, R., Nawijn, M., Franca-Koh, J.,
Zevenhoven, J., van der Gulden, H., Jonkers,
J., and Berns, A. (2005). Frat is dispensable for
canonical Wnt signaling in mammals. Genes Dev.
19; 425-430.
resembles the human disease, as with our model of small-cell lung cancer, experiments
can take a painfully long time. To get things moving faster, we are now culturing cells from
the mouse tumors and putting them into the lungs of new mice, giving us a rapid way of
Meuwissen, R., and Berns, A. (2005). Mouse
models for human lung cancer. Genes Dev. 19;
643-664.
studying underlying mechanisms and testing potential therapies.
Looking ahead, we hope that once we can cure a cancer in mice, we can apply similar
approaches in humans. We know that mouse tumors vary greatly in their response to
the therapies used medically. Each tumor has to be characterized in detail to design the
best intervention. Undoubtedly, this needs also to be done for patients, who can then be
grouped according to the genetic features of their tumors. Such a group will give more
uniform results in clinical trials and fewer patients will be needed to provide statistically
valid answers.
[email protected]
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Scientific brochure NKI
Cell survival and death pathways
Jannie Borst
Jannie Borst has devoted her career to studying T cells – key cells of the immune system
selected publications
that fight infection and help destroy cancer cells. She studies the proteins that tell T cells
to become fully operational, and is starting to be able to manipulate both these signals
Werner, A.B., Tait, S.W.G., de Vries, E., Eldering,
and the T cells in ways that should help the development of better vaccines and new
E., and Borst, J. (2004). Requirement for aspar-
cancer therapies.
tate-cleaved Bid in apoptosis signalling by DNAdamaging anti-cancer regimens. J. Biol. Chem.
279; 28771-28780.
We work on the ‘co-stimulation’ signals that kick-start T cells into action when they are
Hendriks, J., Xiao, Y. and Borst, J. (2003). CD27
needed to fight an infection or destroy cancer cells. The co-stimulatory molecules are
promotes survival of activated T cells and
proteins on the T-cell surface that dock onto partner proteins on other white blood cells.
complements CD28 in generation and establish-
We know they’re important as we’ve shown that mice lacking co-stimulatory molecules are
ment of the effector T cell pool. J. Exp. Med.
198; 1369-1380.
unable to react properly against the influenza virus.
This work involves elaborate technology and can only be done in an institute such as the
NKI where there are good facilities and a lot of dedicated people with different expertise.
We are excited about the prospect of applying our findings in the clinic, for example,
by using antibodies to block co-stimulation and switch off the damaging action of T
Werner, A.B., de Vries, E., Tait, S., Bontjer, I., and
Borst, J. (2002). Bcl-2 family member Bfl-1/A1
sequesters truncated Bid to inhibit its collaboration with pro-apoptotic Bak or Bax. J. Biol.
Chem. 277; 22781-22788.
cells in autoimmune disease. Conversely, we are designing new types of cancer vaccines
Hendriks, J., Gravestein, L.A., Tesselaar, K., van
that provide strong co-stimulation, so that the patients’ T cells can destroy tumors more
Lier, R.A.W., Schumacher, T.N.M., and Borst,
effectively.
We are also excited by another project that uses a protein called TRAIL to kill cancer cells
by triggering cell suicide or apoptosis. TRAIL is attractive as it leaves most healthy cells
unaffected. Other groups outside of NKI are testing the effects of TRAIL in clinical trials.
Our group is taking another approach and combining TRAIL with radiotherapy. Animal
studies show that injecting TRAIL into mice at the same time as irradiating the tumor kills
far more tumor cells than either method alone. We believe this could be important in the
clinic, particularly as the precision of radiotherapy enables the effect to be confined to
the tumor site.
J. (2000). CD27 is required for generation and
long-term maintenance of T cell immunity.
Nature Immunol. 1; 433-440.
[email protected]
Basic research
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p33
Drug resistance and DNA base J
Piet Borst
Piet Borst’s early success as a biochemist led him to a professorship at the University
SELECTED PUBLICATIONS
of Amsterdam at the age of 30. In 1983 he became director of the NKI, introducing a
streamlined style of management. He handed over to Anton Berns in 1999, but has retained
Borst, P., and Genest, P.A. (2006). Parasitology:
his laboratory at the Institute.
switching like for like. Nature 439; 926-927.
Genest, P.A., Ter Riet, B., Dumas, C.,
I originally brought to the NKI my work on trypanosomes — parasites that can change
their surface coat, enabling them to remain ‘invisible’ to antibodies and thus evade human
Papadopoulou, B., Van Luenen, H.G.A.M., and
Borst, P. (2005). Formation of linear inverted
repeat amplicons following targeting of an
immune defenses. During this work we discovered a previously unknown DNA base, base J,
essential gene in Leishmania. Nucleic Acids Res.
which is unique to trypanosomes and related parasites, and comprises around 0.2 per cent
33; 1699-1709.
of their DNA. Now we are trying to understand how base J forms and how it functions. Its
uniqueness also makes it a potential target for new anti-trypanosomal drugs.
Base J turns out to be derived from thymine through the actions of two hydroxylases.
Discovering these enzymes has opened up new possibilities for interfering with base J
formation as a possible means of attacking trypanosomes. In collaboration with Charles
Weissmann at the Scripps Institute in Palm Beach, Florida, we are screening for potential
Zelcer, N., Van de Wetering, J.K., Hillebrand,
M., Sarton, E., Kuil, A., Wielinga, P.R., Tephly,
T., Dahan, A., Beijnen, J.H., and Borst, P. (2005).
Mice lacking multidrug resistance protein 3
show altered morphine pharmacokinetics and
morphine-6-glucuronide antinociception. Proc.
Natl. Acad. Sci. USA 102; 7274-7279.
drugs that inhibit the hydroxylases.
Reid, G., Wielinga, P., Zelcer, N., Van der
In an entirely different project at the NKI, my team has helped identify some of the
Heijden, I., Kuil, A., De Haas, M., Wijnholds, J.,
molecular pumps in cancer-cell membranes that remove drugs from the cells, making them
resistant to treatment. These are members of the ABC transporter family. We’ve made cell
lines that overproduce the pumps and also ‘knockout’ mice lacking one or more pumps.
and Borst, P. (2003). The human multidrug resistance protein MRP4 functions as a prostaglandin
efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc. Natl. Acad. Sci.
USA 100; 9244-9249.
The mice show us that the pumps often prevent the uptake of drugs from the gut and their
penetration into the brain. These resources are being used by the pharmaceutical industry
to screen for candidate drugs that do not interact with the pumps.
We are also very excited about the first proper animal model for drug resistance in an
epithelial tumor. These mice, engineered by Jos Jonkers (see page 41), lack the BRCA1
protein and spontaneously develop breast cancer. The tumors respond to high doses of
drugs, but eventually become resistant. How, we are now trying to find out.
[email protected]
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Scientific brochure NKI
Tiam1-Rac signaling and cancer
John Collard
Fifteen years ago, John Collard set out to find genes that influence the spread, or
SELECTED PUBLICATIONS
metastasis, of cancer in the body. He soon discovered a gene called Tiam1, and has since
concentrated on revealing its complex functions in cancer cells.
Mertens, A.E., Pegtel, D.M., and Collard, J.G.
(2006). Tiam1 takes PARt in cell polarity. Trends
Cell Biol. 16; 308-316.
Tiam1 is an intriguing gene. To start with, it is involved in making cells stick together in cell
sheets and organs. Cells that carry mutant versions of the gene tend to break away from
each other, because the adhesion protein cadherin, which binds cells together, cannot work
properly without Tiam1. Cell detachment from primary tumors is a key part of metastasis,
the process that allows cancer cells to migrate through the body and grow at sites far away
from the original tumor.
To study the effects of Tiam1 we made ‘knockout’ mice that don’t express the gene.
Generating these mice is intriguing in itself, but the real excitement comes from seeing what
Hamelers, I.H.L., Olivo, C., Mertens, A.E., Pegtel,
D.M., Van der Kammen, R.A., Sonnenberg, A.,
and Collard, J.G. (2005). The Rac activator Tiam1
is required for α3β1-integrin-mediated laminin 5
deposition, cell spreading and cell migration. J.
Cell Biol. 171; 871-881.
Mertens, A.E., Rygiel, T., Olivo, C., Van der
Kammen, R.A., and Collard, J.G. (2005). The
Rac activator Tiam1 controls tight junction bio-
the Tiam1 protein can do, and unraveling its effects in various pathways leading to tumor
genesis in keratinocytes through binding to and
initiation and progression.
activation of the Par polarity complex. J. Cell
One of our very first experiments revealed that Tiam1 knockout mice were remarkably
resistant to carcinogens. But while most did not get tumors at all, in the few that did, the
tumors were small but highly aggressive and metastatic. So Tiam1 seems to have several
Biol. 170; 1029-1037.
Malliri, A., Van der Kammen, R.A., Clark, K.,
Van der Valk, M., Michiels, F., and Collard, J.G.
(2002). Mice deficient in the Rac activator Tiam1
functions in addition to controlling cell–cell adhesion.
are resistant to Ras-induced skin tumours.
Preventing programmed cell death, or apoptosis, appears to be one function of Tiam1. Cells
Nature. 417; 867-871.
lacking Tiam1 are more sensitive to apoptosis, so that even if they become cancerous, most
of them die. The few that survive, however, are more aggressive and rapidly metastasize, as
a result of the loss of Tiam1’s effects on cell adhesion and cell migration.
In tracking down Tiam1’s role we have knocked out its gene in mouse strains that already
develop tumors spontaneously, a task that was made much easier because of the many such
strains at NKI. These mice are providing a fast track to validate findings from cultured cells
and to elucidate how Tiam1 expression could be influenced in order to treat cancer.
[email protected]
Basic research
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p35
Cancer cells: PIPed at the post
Nullin Divecha
With a PhD from Sheffield, UK, Nullin Divecha worked at the Babraham Institute in
SELECTED PUBLICATIONS
Cambridge, UK, before moving to the NKI in 1998. He currently studies the way that PIP
lipids in cell membranes transmit signals and thus help determine the cell’s immediate fate.
Jones DR, Bultsma Y, Keune WJ, Halstead JR,
Elouarrat D, Mohammed S, Heck AJ, D’Santos
Cells frequently find they have a message-bearing molecule on one side of a membrane
that needs to cause an effect on the other side. Many operate by influencing signaling
systems within the membrane I study the phosphatidylinositol (PI)-based systems. These
CS, Divecha N. (2006). Nuclear PtdIns5P as a
transducer of stress signaling: an in vivo role for
PIP4Kbeta. Mol Cell. 23, 685-695.
Jonathan R. Halstead, Jacco van Rheenen,
involve lipids that are present not only in the external membrane, but also in many different
Mireille H.J. Snel, Sarah Meeuws, Shabaz
membrane compartments within cells.
Mohammed, Clive S. D’Santos, Albert J. Heck,
Part of the task is seeing where in the cell these pathways are located, and what situations
bring them into existence. We place fluorescently labeled probes inside the cell, in the
cytosol, and observe them move to the PIs when they are generated in the membrane – you
Kees Jalink, and Nullin Divecha. (2006). A role
for PtdIns(4,5)P2 and PIP5Ka in regulating
stress-induced apoptosis. Current Biology 16,
1850-1856.
can watch that occur in real time. These probes are very popular because different probes
Halstead JR, Jalink K, Divecha N. (2005). An
can target different compartments within the cell. Our aim is to understand the orchestrated
emerging role for PtdIns(4,5)P2-mediated signal-
activity of all of the PIs in their various locations.
ling in human disease. Trends Pharmacol Sci. 26;
654-660.
The relevance to cancer is that some PIs are part of the p53 cancer suppression system.
If DNA is damaged, or the cell is under stress, then p53 activity usually increases and
prevents the cell from dividing. Removing PI, which we can do by overexpressing an enzyme
that uses it, reduces p53’s power to act. This is a real problem for the cell and can lead to
the development of cancer. Interestingly, the enzyme that uses this PI is also overexpressed
in human tumors.
One other piece in the puzzle is that when cells are about to undergo suicide they
downregulate the amount of a different PI. As this PI is involved in regulating many cellular
functions the cell is immediately in trouble. It would appear that downregulation of this
PI is one of the very early stages in apoptosis. We have found that one of the enzymes
responsible for making this lipid is upregulated in human cancers and may therefore points
to an appealing target for cancer therapies.
Motta MC*, Divecha N*, Lemieux M, Kamel
C, Chen D, Gu W, Bultsma Y, McBurney M,
Guarente L. (2004). Mammalian SIRT1 represses
forkhead transcription factors. Cell. 116; 551563. *joint co-authourship.
[email protected]
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Scientific brochure NKI
Transactions at the nuclear envelope
Maarten Fornerod
Maarten Fornerod likes to operate at borders where, he believes, some of the most
SELECTED PUBLICATIONS
interesting things happen. His challenge is to understand how events at the border between
the nucleus and cytoplasm regulate cell activity.
Bernad, R., Engelsma, D., Sanderson, H.,
Pickersgill, H., and Fornerod, M. (2006). The
My group’s interest is the nuclear membrane, the boundary between the nucleus and the
cytoplasm. It contains pores through which RNAs and proteins, including those that switch
genes on and off, move into and out of the nucleus as the cell responds to different signals.
Nup214/Nup88 nucleoporin subcomplex is
required for CRM1 mediated 60S preribosomal
nuclear export. J. Biol. Chem. 281; 19378-19386.
Pickersgill, H., Kalverda, B., De Wit, E., Talhout,
As an analogy, I think of the old Roman border between Leiden and Nijmegen, where all
W., Fornerod, M.*, and Van Steensel, B.* (2006).
sorts of exchanges took place: artifacts from all over the empire have been found there.
Characterization of the Drosophila genome at
So the border reflects the dynamics of the entire system, while at the same time remaining
the nuclear lamina. Nat. Genet. 38; 1005-1014.
* joint corresponding authorship
relatively stable.
In the same way, movement over the nucleus–cytoplasm boundary reflects what’s going
on in the whole cell. Our biggest challenge is to find the most important interactions at
this border, as these are often the most difficult to detect. We use a variety of techniques
— biochemistry, confocal and electron microscopy, and DNA microarrays. Knockout mice
Hendriksen, J., Fagotto, F., Van der Velde, H.,
Van Schie, M., Noordermeer, J., and Fornerod,
M. (2005). RanBP3 enhances nuclear export of
active beta-Catenin independently of CRM1. J.
Cell Biol. 171; 785:797.
that lack certain proteins also help us understand the relevance of the various players.
Engelsma, D., Bernad, R., Calafat, J., and
We have also collaborated with Bas van Steensel (see page 62) to use the DamID technique
Fornerod, M. (2004). Supraphysiological nuclear
to track interactions between chromatin (DNA bound by histone proteins) and proteins
called lamins that line the inside of the nuclear membrane. We find in particular that DNA
that does not contain genes binds to this inner shell, implying that the DNA between genes,
the so-called ‘junk’ DNA, is important in determining the arrangement of the genome within
the nucleus.
These experiments are beginning to cast light on how the position of a gene in the nucleus
is linked to its activity, which in turn may be crucial to ensuring that cells keep functioning
correctly.
export signals bind CRM1 independently of
RanGTP and arrest at Nup358. EMBO J. 15;
3643-3652.
[email protected]
Basic research
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Attacking cancer with T-lymphocytes
John Haanen
John Haanen is a medical oncologist who devotes half his time to the hospital and half to
SELECTED PUBLICATIONS
research at the NKI. His dream is to see novel therapies in the clinic that harness the ability
of the immune system to fight cancer.
De Witte, M.A., Coccoris, M., Wolkers, M.C., Van
den Boom, M.D., Mesman, E.M., Song, J.Y., Van
The immune system recognizes at least some tumors as ‘foreign’ and mounts an immune
response against them. My research group works on developing immunotherapies to
strengthen this response, in particular for the skin cancer melanoma and the penile and
der Valk, M., Haanen, J.B., and Schumacher, T.N.
(2006). Targeting self-antigens through allogeneic TCR gene transfer. Blood. 108; 870-877.
Overwijk, W.W., De Visser, K.E., Tirion, F.H., De
cervical cancers caused by the human papilloma virus (HPV).
Jong, L.A., Pols, T.W., Van der Velden, Y.U., Van
A therapeutic vaccine for cervical cancer will be different from the recently developed
den Boorn, J.G., Keller, A.M., Buurman, W.A.,
preventive cervical cancer vaccines, which are intended to prevent virus infection. They elicit
antiviral antibodies that mop up HPV before it can infect its target sites and trigger cancer.
In contrast, a therapeutic anticancer vaccine will need to activate the killer T cells of the
immune system to attack the cancer cells themselves.
We collaborate closely with Ton Schumacher on two vaccine delivery strategies. One is a
tattoo machine that we use to inject a DNA-based vaccine into the upper layers of the skin.
Theoret, M.R. et al. (2006). Immunological and
antitumor effects of IL-23 as a cancer vaccine
adjuvant. J. Immunol. 176; 5213-5222.
Bins, A.D., Jorritsma, A., Wolkers, M.C., Hung,
C.F., Wu, T.C., Schumacher, T.N., and Haanen,
J.B. (2005). A rapid and potent DNA vaccination
strategy defined by in vivo monitoring of antigen
expression. Nat. Med. 11; 899-904.
It’s a simple device for a high-tech vaccine, but it is a great way of delivering up to 30,000
tiny shots all at once, to an animal or person, and spreading the exposure to antigen over a
wider area of skin than would be achieved with a traditional needle.
The epidermis is packed with cells that help generate a strong immune response, including
the dendritic cells that present tumor antigens to the immune system. Killer T cells with the
appropriate receptors ‘see’ the tumor antigens on the surface of the dendritic cell, become
Van Oijen, M., Bins, A., Elias, S., Sein, J.,
Weder, P., De Gast, G., Mallo, H., Gallee, M.,
Van Tinteren, H., Schumacher, T., and Haanen,
J. (2004). On the role of melanoma-specific
CD8+ T-cell immunity in disease progression of
advanced-stage melanoma patients. Clin. Cancer
Res. 10; 4754-4760.
activated, and then seek out and destroy the real tumor cells. We are producing clinicalgrade DNA vaccines against cervical tumors and hope to begin phase 1 clinical trials in 2007.
The second delivery strategy modifies gene therapy procedures. The idea is to take T cells
of any specificity from the patient’s blood, and insert DNA coding for receptors designed to
latch tightly onto the tumor antigens. We would then inject the T cells back into the patients,
where they should be able to attack the tumor more strongly.
[email protected]
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Scientific brochure NKI
Breast cancer genes
John Hilkens
Having arrived at the NKI in 1975, John Hilkens has extensive experience in cancer research.
SELECTED PUBLICATIONS
He uses the development of mammary tumors in mice to track down genes involved in the
progression of breast cancer and its spread to other tissues.
Hilkens, J. (2006). Recent translational research:
oncogene discovery by insertional mutagenesis
The dream of cancer research is to find all the genetic pathways that make cells cancerous,
and to find how they interact – then you can develop drugs to hit specific targets. But I’m
a realist, and I know that we first need to find those genes that play outstanding roles in
gets a new boost. Breast Cancer Res. 8; 102-106.
Theodorou, V., Boer, M., Weigelt, B., Jonkers, J.,
Van der Valk, M., and Hilkens, J. (2004). Fgf10
is an oncogene activated by MMTV insertional
cancer. These will give us clues to the rest.
mutagenesis in mouse mammary tumors and
The NKI provides one of the best environments in the Netherlands to pursue this aim
overexpressed in a subset of human breast carci-
because of its excellent resources and strong research teams.
A powerful tool for revealing genetic pathways in cancer is a technique called insertional
mutagenesis. Mice are infected with retroviruses, which randomly insert their DNA into the
chromosomes of infected cells. Control regions in the retroviral DNA insert can turn on an
adjacent mouse gene, and if that gene is an oncogene, the infected cell may give rise to a
tumor. Finding where the viral DNA is inserted then points to the cancer-causing gene.
Our immediate goal is to use our observations in mice to identify equivalent genes in human
breast cancer.
To discover genes involved in cancer spread, or metastasis, we have developed our own
in vivo assay. For instance, we take lungs from a mouse that has a mammary tumor and
inject the lung cells under the skin of a genetically similar mouse. If metastatic cells from
the mammary tumor are present in the lungs they will give rise to a tumor at the site of
injection. By comparing the genes expressed in the primary and the secondary tumors we
discover genes involved in metastasis.
We’re now studying a newly discovered gene family called the R-spondins. There are four
known members, two of which we have found to be involved in breast cancer. Now all we
have to do is find out how they work!
nomas. Oncogene. 23; 6047-6055.
Thingstad, T., Vos, H.L., and Hilkens, J. (2001).
Biosynthesis and shedding of epiglycanin: a
mucin-type glycoprotein of the mouse TA3Ha
mammary carcinoma cell. Biochem. J. 353;
33-40.
[email protected]
Basic research
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Programmed mutagenesis
Heinz Jacobs
Heinz Jacobs began research at the NKI in 1987 as a graduate student, and drawn by its
SELECTED PUBLICATIONS
excellent research environment he returned to the NKI in 2002. He is now a group leader in
molecular immunology and programmed mutagenesis.
Jansen, J.G., Langerak, P., Tsaalbi-Shtylik, A., Van
den Berk, P., Jacobs, H., and De Wind, N. (2006).
My group is interested in programmed mutagenesis and its causal relationship to cancer
development. Programmed mutagenesis is part of the normal development of specialized
immune-cells known as B lymphocytes. However, B cells can give rise to cancers known
Strand-biased defect in C/G transversions in
hypermutating immunoglobulin genes in Rev1deficient mice. J. Exp. Med. 203; 319-323.
Langerak, P., Nygren, A., Schouten, J., and
as lymphomas, and we suspect a link between the natural mutation-creating process and
Jacobs, H. (2005). Rapid and quantitative
lymphoma development.
detection of homologous and non-homologous
B cells produce antibodies, the proteins that latch onto and help destroy invading bacteria,
recombination events using three oligonucleotide MLPA. Nucleic Acids Res. 33; 188.
viruses and parasites. B cells stimulated by these invaders activate an enzyme called AID,
which creates lesions in the genes that code for antibodies. This damage is repaired, but
errors are introduced, which results in B cells that produce antibodies slightly different to
the previous ones. Some of these bind more strongly to the invader, so that the immune
response becomes more efficient over time. The downside to this beneficial process, we
Bross, L., Muramatsu, M., Kinoshita, K., Honjo,
T., and Jacobs, H. (2002). DNA double-strand
breaks: prior to but not sufficient in targeting
hypermutation. J. Exp. Med.195; 1187-1192.
Jacobs, H., and Bross, L. (2001). Towards an
believe, is that the AID enzyme sometimes targets other genes, and so B cells undergoing
understanding of somatic hypermutation. Cur.
this programmed mutagenesis are at risk of acquiring potentially cancer-causing mutations.
Opin. Immunol. 13; 208-218.
We are using the DamID technique (see Bas van Steensel page 62) to identify all genes
Bross, L., Fukita, Y., McBlane, F., Démollière,
that AID can bind to and damage. The special error-prone DNA polymerases called TLS
C., Rajewsky, K., and Jacobs, H. (2000). DNA
polymerases that repair the AID damage are recruited to the lesions in DNA. We are trying
to understand what regulates when these DNA polymerases act, and when other, more
double-strand breaks in immunoglobulin genes
undergoing somatic hypermutation. Immunity.
13; 589-597.
precise, repair processes act instead to restore the exact original DNA sequence. We think
that this regulation is what keeps the balance between permitting mutations to persist in
antibody genes and eliminating lesions in other genes that might lead to cancer.
We hope that eventually the insights we gain into lymphoma development will provide
us with markers that can be used in the clinic to predict the course of a lymphoma and to
select the best treatments.
[email protected]
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Scientific brochure NKI
Biophysics of cell signaling
Kees Jalink
Kees Jalink is a biophysicist who loves to tinker. He brings new technology to the NKI, and
SELECTED PUBLICATIONS
is an advisor to three companies on the creation of new devices. He often builds prototypes
in the lab using individual pieces and sticky tape and then invites industry in to make them
Jalink, K. (2006). Spying on cGMP with FRET.
user-friendly.
Nat. Methods 3; 11-12.
Van Rheenen, J., Achame, E.M., Janssen, H.,
My group spends half of its time getting techniques running and serving as a biophysical
nerve center for the whole of the NKI, collaborating and publishing jointly with others. With
Calafat, J., and Jalink, K. (2005). PIP2 signaling in
lipid domains: a critical re-evaluation. EMBO J.
24; 1664-1673.
the other half of our time we focus on our own research.
Our expertise is in following cells individually by light microscopy. This allows us to see
important events that would otherwise be missed by biochemistry on, say, 10,000 cells.
A big challenge is overcoming the resolution of light microscopes, in which we can only see
things bigger than a quarter of a micrometer across. Individual proteins, for example, being
50 times smaller, are invisible to us. One option is to tag a protein with a fluorescent dye
which indicates where a protein is.
It does not, however, reveal interactions between proteins. To do this we employ another
Michalides, R., Griekspoor, A., Balkenende, A.,
Verwoerd, D., Janssen, L., Jalink, K., Floore, A.,
Velds, A., Van ‘t Veer, L., and Neefjes, J. (2004).
Tamoxifen resistance by a conformational arrest
of the estrogen receptor alpha after PKA activation in breast cancer. Cancer Cell 5; 597-605.
Van Rheenen, J., Langeslag, M., and Jalink, K.
(2004). Correcting confocal acquisition to optimize imaging of fluorescence resonance energy
trick known as FRET (fluorescence resonance energy transfer). In this we tag different
transfer by sensitized emission. Biophys. J. 86;
proteins with different fluorescing molecules. When the proteins come within 5 nanometers
2517-2529.
of each other, energy transfers between the tags. This causes changes in the light that
each molecule is emitting. We can put these into a single cell, watch both proteins and see
whether they are interacting.
We also monitor the rate of intracellular reactions and can use these fluorophores to watch
proteins change shape. Collaborating with Rob Michalides, for example, has revealed
that resistance to tamoxifen treatment in some breast cancer patients is linked to a lack of
conformational change by the estrogen receptor in their tumors. In our own research, we
study the ion channel TRPM7 that is involved in cell adhesion and metastasis. This sits in the
membrane of extended processes, invadopia, that are used by metastatic cancer cells to
squeeze out between the cells lining blood vessels and into surrounding tissues.
[email protected]
Basic research
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Mouse models of breast cancer
Jos Jonkers
After working at the NKI as a PhD student and postdoc, Jos Jonkers spent six months in the
SELECTED PUBLICATIONS
Sanger Centre in Cambridge, UK. In 2002, he was drawn back to the dynamic research base
at the NKI by the prospect of being able to rapidly translate basic research into clinical tools
Derksen, P.W., Liu, X., Saridin, F., Van der Gulden,
for diagnosis, prognosis or therapies.
H., Zevenhoven, J., Evers, B., Van Beijnum,
J.R., Griffioen, A.W., Vink, J., Krimpenfort, et al.
(2006). Somatic inactivation of E-cadherin and
Here at the NKI we have created new strains of mice that will improve laboratory studies of
breast cancer considerably. The overall aim was to alter a few carefully selected genes so
p53 in mice leads to metastatic lobular mammary
carcinoma through induction of anoikis resistance and angiogenesis. Cancer Cell. in press.
that the mice spontaneously generate tumors that resemble those seen in humans.
If mice carry too many mutations, however, they cannot breed, and cells don’t grow
properly. To just mutate the genes in the cells we are interested in, we use a genetic
recombination system called Cre-LoxP recombination, which enables us to turn off defined
sets of genes in just a few cells within a particular tissue. This mimics much better the way
that cancer arises in humans, and we now have a world-beating colony of mice with different
Chung, Y.J., Jonkers, J., Kitson, H., Fiegler,
H., Humphray, S., Scott, C., Hunt, S., Yu, Y.,
Nishijima, I., Velds, A., et al. (2004). A wholegenome mouse BAC microarray with 1-Mb resolution for analysis of DNA copy number changes
by array comparative genomic hybridization.
Genome Res. 14; 188-196.
combinations of mutations in genes associated with breast cancer, such as BRCA1, BRCA2,
P53, and E-cadherin.
We are using these mice to identify novel cancer genes and to learn how breast cancers
grow and metastatise. We are also using them to test novel tumor intervention strategies.
The genetic make-up of these mice is so well known that we no longer need to run tens
of replicates for each experiment. This increases the pace at which we can work and
reduces the numbers of animals needed to reach useful conclusions. These mice have huge
Jonkers, J., and Berns, A. (2002). Conditional
mouse models of sporadic cancer. Nat. Rev.
Cancer ;: 251-265.
Jonkers, J., Meuwissen, R., Van der Gulden,
H., Peterse, H., Van der Valk, M., and Berns, A.
(2001). Synergistic tumor suppressor activity of
BRCA2 and p53 in a conditional mouse model
for breast cancer. Nat. Genet. 29; 418-425.
potential, and it is made even greater by our new ‘mouse clinic’, which lets us treat each
mouse as if it were a human patient. We’ve already shown in these mice that platinumbased drugs have distinct promise as chemotherapeutic drugs for BRCA1-associated breast
cancers. It will be exciting to see whether this holds true in human trials.
I am fascinated by the intellectual challenge of working in cancer research. Our task now is
to speed up the process of translating understanding of the science into therapies, and our
mouse models will be important links in that chain of discovery.
[email protected]
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Scientific brochure NKI
Estrogen receptor and breast cancer
Rob Michalides
Since arriving at the NKI in 1975, Rob Michalides has pursued many lines of cancer research.
SELECTED PUBLICATIONS
He now has resistance to the cancer drug tamoxifen in his sights, and is focusing his efforts
on understanding tamoxifen’s target — the estrogen receptor.
Griekspoor, A., Zwart, W., Rondaij, M., Verwoerd,
D., Neefjes, J., and Michalides, R. A FRET profile
Estrogen hormones often stimulate the growth of breast cancers, and so anything that
prevents this is a potential therapy. The drug tamoxifen is a good example — it works
by inhibiting the estrogen receptor on breast cancer cells. This receptor only becomes
of modifications in Estrogen Receptor a associated with resistance to anti-estrogens. Submitted
for publication.
Griekspoor, A., Zwart, W., Neefjes J., and
activated when both estrogen and other molecules (cofactors) bind. Tamoxifen works by
Michalides, R. Visualizing the action of steroid
blocking both estrogen and cofactor binding.
hormone receptors in living cells. Curr. Med.
However, tamoxifen prevents only half of the recurrences in breast cancer. The recurrences
that do occur are either resistant or the tamoxifen makes their cancer grow faster. They
would be better served by, for instance, fulvestrant, a drug that blocks the estrogen
receptor in a different way. So we want to find out two things: what is going on at the
estrogen receptor to cause these effects, and can we determine beforehand who will
benefit from tamoxifen?
Chem. in press.
Zwart, W., Griekspoor, A., Mancini, M., Lakeman,
K., Jalink, K., Neefjes, J., and Michalides,R.
Protein Kinase A-induced resistance to tamoxifen
through altered orientation of Estrogen Receptor
 towards co-activator SRC-1. Submitted for
publication.
We’ve found that a cellular enzyme called protein kinase A (PKA) can promote tamoxifen
Michalides, R., Griekspoor, A., Balkenende, A.,
resistance. When PKA is active, the cofactor-binding pocket remains open even when
Verwoerd, D., Janssen, L., Jalink, K., Floore, A.,
tamoxifen binds to the receptor. If cofactor binds, the receptor is activated and sends a
growth signal to the cell. To confirm this we engineered estrogen-dependent tumor cells
that also overproduce PKA. True to expectation, they continued to grow in the presence of
tamoxifen.
To tackle our second question, we’ve worked with the American company Upstate to
develop an antibody that sticks only to PKA-modified receptors. At the hospital we are
screening a panel of 200 breast cancer patients with these antibodies to see whether the
tumors with PKA-modified receptors are also the ones that do not respond to tamoxifen.
If so, we’ll have a valuable new test to guide therapy.
Velds, A., Van ’t Veer, L., and Neefjes, J. (2004).
Tamoxifen resistance by a conformational arrest
of the Estrogen Receptor  after PKA activation
in breast cancer. Cancer Cell 5; 597-605.
[email protected]
Basic research
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LPA, a multifunctional growth factor
Wouter Moolenaar
In the early 1990s, Wouter Moolenaar’s discovery of a lipid called LPA set the course of his
SELECTED PUBLICATIONS
career. Intrigued by its potential role in cancer, he has devoted his energies to defining its
actions and discovering potential anticancer drugs that inhibit its formation.
Van Meeteren, L.A., Ruurs, P., Stortelers, C.,
Bouwman, P., Van Rooijen, M.A., Pradere J.P.,
Most people think of lipids as just the boring building blocks of cell membranes, but
lysophosphatidic acid (LPA) is far from boring. It’s made outside cells and transported
throughout the body in the bloodstream and, unusually for a lipid, it stimulates cell growth,
Pettit, T.R., Wakelam, M.J., Saulnier-Blache,
J.S., Mummery, C.L., et al. (2006). Autotaxin, a
secreted lysophospholipase D, is essential for
blood vessel formation during development.
Mol. Cell Biol. 26; 5015-5022.
proliferation and migration.
As this activity is important in both normal development and cancer formation, we decided
to look at how LPA alters a cell’s behavior in these ways. We’ve found that LPA switches on
activities such as cell proliferation and migration through a variety of molecular switches
that stimulate intracellular signaling pathways. We also discovered that LPA is produced
following injury and blood clotting, which points to an important role in wound healing.
In collaboration with the NKI clinicians, we have found that levels of LPA are extremely high
in peritoneal fluid from patients with ovarian cancer, suggesting a role for LPA in the spread
of ovarian cancer to the peritoneum.
Our current focus is on an enzyme called autotaxin, which makes LPA. To investigate its
action, we’ve made mice that lack autotaxin, and so cannot make LPA. These mice have
shown us that one role of LPA is in the formation of blood vessels during development. That
gives us its link to cancer, as tumors need to make new blood vessels if they are to grow.
Our great motivation is that patients will benefit from our discoveries. Autotaxin is an ideal
drug target as it is found outside cells and is easily accessible to drugs in the bloodstream:
several pharmaceutical companies are looking at it as a drug target. At the NKI we are
screening more than 20,000 chemical compounds to identify autotaxin inhibitors, which
we’ll then use to test our ideas about how autotaxin and LPA work in the body. Compounds
that block angiogenesis by blocking autotaxin might be the route to new, more specific,
cancer therapies.
Van Meeteren, L.A., Ruurs, P., Christodoulou, E.,
Goding, J.W., Takakusa, H., Kikuchi, K., Perrakis,
A., Nagano, T., and Moolenaar, W.H. (2005).
Inhibition of autotaxin by lysophosphatidic acid
and sphingosine 1-phosphate. J. Biol. Chem.
280; 21155-21161.
Moolenaar, W.H., Van Meeteren, L.A., and
Giepmans, B.N. (2004). The ins and outs of
lysophosphatidic acid signaling. BioEssays 26;
870-881.
Mills, G.B., and Moolenaar, W.H. (2003). The
emerging role of lysophosphatidic acid in cancer.
Nat. Rev. Cancer 3; 582-591.
[email protected]
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Scientific brochure NKI
Improving immune responses to tumors
Jacques Neefjes
Jacques Neefjes trained in chemistry at the Free University Amsterdam and did his PhD at
SELECTED PUBLICATIONS
the NKI on the cell biology of antigen presentation in the immune system. After a postdoc
at the DKFZ in Heidelberg, Germany, he joined the NKI in 1993, and in 1999 became head
Reits, E.A., Hodge, J.W., Herberts, C.A.,
of the Division of Tumor Biology.
Groothuis, T.A., Chakraborty, M., Wansley,
E.K., Capmhausen, K., Luiten, R.M., deRu,
A.H., Neijssen, J., Griekspoor, A., Mesman, E.,
We aim to understand how the immune system recognizes and responds to cancer cells in
general, and then find ways of encouraging a patient’s immune system to attack their own
Verreck, F.A., Spits, H., Schlom, J., van Veelen,
P., and Neefjes, J. (2006). Radiation modulates
the peptide repertoire, enhances MHC class I
cancer. Immunotherapy might be used by itself, or it could supplement treatments such as
expression, and induces successful antitumor
radiotherapy.
immunotherapy. J. Exp. Med. 203; 1259-71.
These therapies will involve the white blood cells known as T lymphocytes. We know that T
cells can recognize tumor cells as abnormal and eliminate them, but at some point, tumors
develop the ability to evade them. Our task is to find a way round this.
We are exploring two main strategies. One is to render tumors more visible to the immune
system. We’ve found that low doses of radiation increase the production of abnormal
proteins by tumor cells, which sends a stronger signal to the immune system, and we are
currently testing the effects of this treatment in mice.
The second strategy is to increase the numbers and range of T cells that can attack the
tumor. We can grow a patient’s T cells outside the body to expand their numbers and then
inject them back into the patient. We’re also developing ways of stimulating T-cell expansion
inside the body, using bacteria as the stimulant to boost the specific immune response to
Dantuma, N.P., Groothuis, T.A.M., Salomons,
F.A. and Neefjes, J. (2006). A dynamic ubiquitin
equilibrium couples proteasomal activity to chromatin remodeling. J. Cell Biol. 173; 19-26.
Neijssen, C. Herberts, J. W. Drijfhout, E. Reits, L.
Janssen and J. Neefjes. (2005). Cross-presentation by intercellular peptide transfer through gap
junctions. Nature. 434; 83-88.
W. Zwart, A. Griekspoor, C. Kuijl, M. Marsman,
J. van Rheenen, H. Janssen, J. Calafat, M.
van Ham, L. Janssen, M. van Lith, K. Jalink
and J. Neefjes. (2005). Spatial Separation of
HLA-DM/HLA-DR Interactions within MIIC and
tumor proteins. We would then use radiotherapy to increase the tumor signal and so direct
Phagosome-Induced Immune Escape. Immunity.
large numbers of T cells to the tumor. We want to test whether this sort of treatment will be
22; 221-233.
sufficient to enable the immune system to recognize and eliminate metastases. If successful,
it will give us a new combination therapy to be introduced into the clinic.
We hope to try out these ideas first in patients with melanoma or kidney cancer, for which
we already have encouraging evidence that tumors can spontaneously shrink and disappear
– which may be due to immune attack.
[email protected]
Basic research
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UV > 350 nm
NH2
Chemical tools for cancer research
Huib Ovaa
After a PhD in organic chemical synthesis at Leiden University and three years at Harvard
SELECTED PUBLICATIONS
University, Huib Ovaa arrived at the NKI in 2005. Although one of the newest members of
staff, he has already built up a strong team of chemists within the Institute.
Groll, M., Berkers, C.R., Ploegh, H.L., and Ovaa,
H. (2006). Crystal structure of the boronic acid-
My aim is to use my chemical skills to make new research tools that will allow others to
tackle previously intractable problems in cancer research.
My group’s collaboration with Ton Schumacher’s lab (see page 52) is a good example of
based proteasome inhibitor bortezomib in complex with the yeast 20S proteasome. Structure.
14; 451-456.
Rodenko, B., Toebes, M., Reker Hadrup, S.,
how we work. Together we’re looking at ways of detecting and characterizing the T cells
Van Esch, W.J.E., Molenaar, A.M., Schumacher,
of the immune system, which are the cells that cancer vaccines will need to stimulate. We
T.N.M., and Ovaa, H. (2006). Generation of
characterize T cells by finding out which antigen they recognize — which is always a small
peptide of some kind. We mix the T cells with ‘tetramers’ of four MHC proteins complexed
with a given peptide — and see if they bind.
But there was one big problem. To make this screening system really practical we needed to
be able to ‘mass-produce’ the MHC tetramers on their own, so that they could be stored,
and then combined with whatever peptide antigen was needed. But we couldn’t do that
at first, because MHC proteins only assemble and remain stable if they’ve already got a
peptide to bind.
This is where my group’s chemical expertise came in. We’ve made MHC tetramers carrying
a ‘temporary’ cargo of specially designed molecules. These tetramers are stable and can
be stored. The trick is that we made this cargo sensitive to UV light. When we want to use
peptide-MHC class I complexes through UVmediated ligand exchange. Nat. Protocols. 1;
1120-1132.
Toebes, M., Coccoris, M., Bins, A., Rodenko, B.,
Gomez, R., Nieuwkoop, N.J., Van de Kasteele,
W., Rimmelzwaan, G.F., Haanen, J.B., Ovaa, H.,
and Schumacher, T.N. (2006). Design and use of
conditional MHC class I ligands. Nat. Med. 12;
246-251.
Berkers, C.R., and Ovaa, H. (2005).
Immunotherapeutic potential for ceramidebased activators of iNKT cells. Trends Pharmacol.
Sci. 26; 252-257.
the tetramers, we put them into a solution containing the required peptides. UV illumination
Berkers, C.R., Verdoes, M., Lichtman, E.,
breaks the old cargo in shorter fragments: they drift free and the peptide takes their place
Fiebiger, E., Kessler, B.M., Anderson, K.C.,
— it really works!
Now that we’ve shown how quick and simple this method is, it’s available for others to
exploit in their research.
Ploegh, H.L., Ovaa, H., Galardy, P.J. (2005).
Activity probe for in vivo profiling of the
specificity of proteasome inhibitor
bortezomib. Nat. Methods. 2; 357-362.
[email protected]
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Scientific brochure NKI
Identifying novel cancer genes
Daniel Peeper
Molecular biologist Daniel Peeper came to the NKI in 1995, after a PhD in Leiden and a
SELECTED PUBLICATIONS
postdoc in Boston. He is fascinated by how deregulated genes cooperate to cause cancer,
with the aim of finding new drugs that block this process.
Peeper, D.S., and Mooi, W.J. (2006). Oncogeneinduced cell senescence: halting on the road to
My group is identifying novel genes involved in cancer, some of which might correspond
to specific targets for new therapy. We use functional genomics, which entails screening
the 30,000 genes in the human genome for specific, cancer-relevant functions. Our focus is
cancer. N. Engl. J. Med. 355; 1037-1046
Rowland, B.D., and Peeper, D.S. (2006). KLF4,
p21 and context-dependent opposing forces in
cancer. Nat Rev Cancer. 6; 11-23.
on defining genes involved in two phenomena that protect us against cancer: ‘oncogeneinduced senescence’ (premature cell aging) and ‘anoikis’ (a form of cell death). We aim to
identify the genes which, when mutated, interfere with these processes and cause cancer.
It may seem paradoxical that activation of an oncogene can cause cells to undergo
senescence, as oncogenes were defined by their ability to contribute to tumor formation.
What happens, however, is that ‘tumor suppressor’ genes become activated and serve as
protective brakes on proliferation. Only in the presence of additional mutations do cells
start proliferating. We have discovered several senescence genes that play a role in cancer.
Michaloglou, C., Vredeveld, L.C.W., Soengas,
M.S., Denoyelle, C., Kuilman, T., Van der Horst,
C.M.A.M., Majoor, D.M., Shay, J.W., Mooi, W.J.,
and Peeper, D.S. (2005). BRAFE600-associated
senescence-like cell cycle arrest of human nevi.
Nature. 436; 720-724.
Rowland, B.D., Bernards, R., and Peeper,
D.S. (2005). The KLF4 tumor suppressor is a
transcriptional repressor of p53 that acts as a
But senescence is more than just a powerful tool: we found that human melanocytic
context-dependent oncogene. Nat. Cell Biol. 7;
naevi (‘moles’) are in a state of active senescence. They express a mutant oncogene, have
1074-1082.
activated tumor suppressors and are in a stable state of growth arrest. Thus, senescence
Douma, S., Van Laar, T., Zevenhoven, J.,
protects us against cancer; only rarely does the senescence program become deficient,
Meuwissen, R., Van Garderen, E., and Peeper,
allowing malignant melanomas to emerge. Our second major research theme corresponds
to the identification of genes causing tumor cells to spread, a major cause for the death
D.S. (2004). Suppression of anoikis and induction
of metastasis by the neurotrophic receptor TrkB.
Nature. 430; 1034-1039.
of cancer patients. Upon detachment from their natural environment cells die by anoikis.
Thus, tumor cells must resist anoikis when they metastasize to other parts of the body.
In a genomic screen for anoikis resistance genes we recently identified the neurotrophic
receptor TrkB, which we demonstrated to act as an enzyme capable of rendering cells
anoikis-resistant, giving rise to highly metastatic tumors. We are currently exploiting the
intriguing possibility that TrkB represents a novel target in cancer therapy.
[email protected]
Basic research
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Structural biology
Anastassis Perrakis
Anastassis Perrakis received his PhD in 1996. For the next two years he was an EMBO post-
SELECTED PUBLICATIONS
doctoral fellow at the NKI. Following a three-year appointment as staff scientist at the EMBL
Grenoble outstation, in 2000 he moved back to the NKI to set up a new research team in
Romier, C., et al. and Perrakis, A. (2006). Co-
structural biology.
expression of protein complexes in prokaryotic
and eukaryotic hosts: experimental procedures,
database tracking and case studies. Acta
My interests are split two ways.
On the one hand I develop ways of moving rapidly from X-ray crystallography data to a
Crystallogr D Biol Crystallogr., 62, 1232-42.
Cohen, S.X., Morris, R.J., Fernandez, F.J., Ben
detailed knowledge of a protein’s 3D atomic structure. The data is in the form of diffraction
Jelloul, M., Kakaris, M., Parthasarathy, V., Lamzin,
patterns, which then have to be interpreted to determine the protein structure. In the early
V.S., Kleywegt, G.J., and Perrakis, A. (2004).
days of crystallography, researchers built real models with metal sticks, nuts and bolts, and
colored ribbons. More recently, they’ve had to sit for hours in front of the computer screen
manipulating their structure. But we’ve developed software, called ARP/wAPP, where you
simply enter the X-ray data and the protein’s amino-acid sequence, and then press ‘run’.
A couple of hours later, you have the structure! Around 90 per cent of X-ray
crystallographers now use this software, and it has featured in some 2,500 scientific papers.
Towards complete validated models in the next
generation of ARP/wARP. Acta Crystallogr. D.
Biol. Crystallogr. 60; 2222-2229.
Weichenrieder, O., Repanas, K., and Perrakis, A.
(2004). Crystal structure of the targeting endonuclease of the human LINE-1 retrotransposon.
Structure 12; 975-86.
We are now exploring further concepts in statistical pattern recognition to make our
Perrakis, A., Morris, R.J., and Lamzin, V.S. (1999).
software work even better.
Automated protein model building combined
My other interest is in structural biology itself. In our team we are trying to sort out the
with iterative structure refinement. Nat. Struct.
Biol. 6; 458-463.
relationship of structure to function of proteins involved in critical control points in the
cell-division cycle. One of the proteins we are trying to understand is geminin, which
controls both cell proliferation and differentiation — two opposing cell fates with enormous
implications in the development of cancer. We also study the Polo kinases, enzymes that are
often referred to as the ‘choreographers of the cell cycle’.
Our constant aim is to understand how the chemical structures of complicated
macromolecules enable them to do their job, and what has gone wrong at this level when
they stop doing it properly. Others can then use this information to develop better cancer
therapies.
[email protected]
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Scientific brochure NKI
Cryo-electron tomography in the cell
Peter Peters
With a passion for invention, Peter Peters has worked in a range of jobs from technician
selected publications
to professor. His ingenuity is driving developments literally at the cutting edge of electron
microscopy.
Mironov A Jr, Latawiec D, Wille H, BouzamondoBernstein E, Legname G, Williamson RA, Burton
I want to see how molecular machines operate inside cells. Some cells have pits in their
membranes that accept growth factors, for example, and when these structures get altered
it can lead to cancer. One can guess how all the proteins in the pit work together by looking
D, DeArmond SJ, Prusiner SB, Peters PJ. (2003).
Cytosolic prion protein in neurons. J Neurosci.
23; 7183-93.
Peters PJ, Mironov A Jr, Peretz D, van Donselaar
at the structures of individual proteins determined by X-ray crystallography, but being able
E, Leclerc E, Erpel S, DeArmond SJ, Burton
to see how the proteins really fit together in the cell would remove a lot of uncertainty.
DR, Williamson RA, Vey M, Prusiner SB. (2003).
This is where electron microscopy (EM) comes in. After 25 years experience I’ve developed
ideas and scientific contacts that could make this dream come true. My aim is to devise
a way of doing cryo-electron tomography. This will give us a 3D view of a cell’s internal
structure. The principle is rather like a CAT scan, but at the nanoscale and at very low
temperature — it’s not going to be easy.
The low temperature overcomes one problem, distortion. In cryo-EM, cells are flash frozen
Trafficking of prion proteins through a caveolaemediated endosomal pathway. J Cell Biol. 162;
703-17.
Van der Wel NN, Sugita M, Fluitsma DM, Cao X,
Schreibelt G, Brenner MB, Peters PJ. (2003). CD1
and major histocompatibility complex II molecules follow a different course during dendritic
cell maturation. Mol Biol Cell. 14; 3378-88.
to –180°C. This vitrifies them — the cells become a ‘solid’ liquid (like glass). Another
obstacle is getting thin enough slices. Working with the Swiss company Diatom we’ve
developed a diamond knife with a tip just 2 Ångstroms across (two ten-millionths of a
millimeter), which cuts slices 20–150 nanometers thick (a nanometer is a millionth of a
millimeter) at –160°C.
For cryo-electron tomography we take 100 images, slowly tilting the specimen through a
140° arc. We do this twice, along three axes. The result is a 3D map of the electron density
within the specimen. The electron density is the raw data from which protein structures are
deduced, so our map potentially shows the locations of all the proteins within a slice. By
putting a series of slices together we can get a 3D view right through the cell. The next step
will be to identify the proteins by matching their electron densities to those determined
by X-ray crystallography. The end result will be a tool that could revolutionize cell biology.
Peters PJ, Ning K, Palacios F, Boshans RL,
Kazantsev A, Thompson LM, Woodman B,
Bates GP, D’Souza-Schorey C. (2002). Arfaptin 2
regulates the aggregation of mutant huntingtin
protein. Nature Cell Biol. 4; 240-5.
[email protected]
Basic research
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Metastasis: tumor cells on the move
Ed Roos
When Ed Roos embarked on the study of metastasis in 1975 it was “a crazy time” with
SELECTED PUBLICATIONS
few technical tools - no monoclonal antibodies, no recombinant DNA technology, and
no concept of oncogenes. Inspired by what he could see under the microscope, he set
Meijer, J., Zeelenberg, I.S., Sipos, B., and Roos,
out to understand the processes by which tumor cells invade tissues and grow in new
E. (2006). The CXCR5 chemokine receptor is
environments.
expressed by carcinoma cells and promotes
growth of colon carcinoma in the liver. Cancer
Res. 19; 9576-9582.
My group is trying to find out why some tumors spread easily - a process known as
Stroeken, P.J., Alvarez, B., Van Rheenen, J.,
metastasis - and others do not. For a long time we focused on lymphoma because it’s a
Wijnands, Y.M., Geerts, D., Jalink, K., and Roos,
highly invasive cell type: the tumor cells travel via the blood, then squeeze out between
E. (2006). Integrin cytoplasmic domain-associat-
the cells that line blood vessels into the surrounding tissues. This is similar to how white
blood cells normally behave when they patrol the body looking for infection. We study this
invasion process in cell culture with mixtures of normal cells and tumor cells.
In particular, we are investigating two groups of proteins that we believe are important.
One group is the adhesion receptors that enable cells to stick to the vessel wall. The
other comprises the chemokines. These can attract cells to move when they bind to
ed protein-1 (ICAP-1) interacts with the ROCK-I
kinase at the plasma membrane. J. Cell Physiol.
208; 620-628.
Opdam, F.J.M., De Bruijn, R., and Roos, E.
(2004). Jak kinase activity is required for lymphoma invasion and metastasis. Oncogene 23;
6647-6653.
their receptors on the cell surface. We have recently made progress on a molecule called
Zeelenberg, I.S., Ruuls-Van Stalle, L., and Roos,
synaptotagmin, which controls the levels of some chemokine receptors on lymphoma cells.
E. (2003). The chemokine receptor CXCR4 is
Chemokine receptors are present on a wide variety of tumors, including the common
required for outgrowth of colon carcinoma
micrometastases. Cancer Res. 63; 3833-3839.
carcinomas. We found that if we block the receptor CXCR4 on carcinoma cells, they are
unable to metastasize in animals. Without the action of CXCR4 and other chemokine
receptors, the tumors cannot grow beyond a certain size. Currently, we are investigating the
hypothesis that the blocked cells are unable to adapt to the lack of oxygen and nutrients
within these tumors.
[email protected]
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Scientific brochure NKI
Pharmacology of anticancer drugs
Jan Schellens
Jan Schellens is qualified in both medical oncology and clinical pharmacology, enabling him
SELECTED PUBLICATIONS
not only to diagnose and treat cancer, but also to do research into making anticancer drugs
more effective.
Kruijtzer, C.M.F., Beijnen, J.H., Rosing, H.,
Ten Bokkel Huinink, W.W., Schot, M., Jewell,
The NKI is probably the largest center in Europe conducting phase 1 and phase 2 clinical
trials of anticancer drugs, with around 120 trials in progress. We test very new drugs, and
different combinations of existing ones. These trials serve to monitor a drug’s side effects,
R.C., Paul, E.M., and Schellens, J.H.M. (2002).
Increased oral bioavailability of topotecan in
combination with the Breast Cancer Resistance
Protein (BCRP) and P-glycoprotein (P-gp) inhibitor GF120918. J. Clin. Oncol. 20; 2943-2950.
measure how much gets into, and stays in the body for a period of time (pharmacokinetics),
and assess its effectiveness against tumors (pharmacodynamics).
The trials involve close collaborations between the NKI’s divisions of medical oncology and
experimental therapy, and the pharmacy department, and a trial office that coordinates the
gathering of clinical data. We also conduct large-scale phase 3 clinical trials. A current one
is comparing two drugs’ abilities to relieve physical and emotional side effects of patients
Maliepaard, M., Van Gastelen, M.A., De Jong,
L.A., Pluim, D., Van Waardenburg, R.C.A.M.,
Ruevekamp-Helmers, M.C., Floot, B.G.J., and
Schellens, J.H.M. (1999). Overexpression of
the BCRP/ MXR/ABCP gene in a topotecanselected ovarian tumor cell line. Cancer Res. 59;
4559-4563.
(most often with breast cancer) whose treatment has brought on an early menopause.
A key goal of my own research is to improve the body’s uptake of drugs taken by mouth
Meerum Terwogt, J.M., Beijnen, J.H., Ten Bokkel
Huinink, W.W., Rosing, H., and Schellens, J.H.M.
— up to now most anticancer drugs have to be injected intravenously. We have to find
(1998). Co-administration of oral cyclosporin A
ways of overcoming the gut’s natural defenses against poisons in food, as these hamper the
enables oral therapy with paclitaxel. Lancet 325;
passage of anticancer agents across the gut wall. Uptake from the gut is often prevented by
the actions of drug pumps, the ABC transporters, in the membranes of cells lining the gut.
We are testing compounds that can temporarily block these transporters, enabling larger
285.
Schellens, J.H.M., Planting, A.S.Th., Van Acker,
B.A.C., Loos, W., De Boer-Dennert, M., Van der
Burg, M.E.L., Koier, I., Krediet, R., Stoter, G., and
amounts of anticancer drugs to get into the body. Using these inhibitors, we can increase
Verweij, J. (1994). Phase I and pharmacologic
the availability to the internal tissues of the ovarium cancer drug topotecan from 30 to
study of the novel indoloquinone bioreductive
100%, and paclitaxel from 5 to approximately 50%. This raises the possibility of giving drugs
alkylating cytotoxic drug EO9. J. Natl. Cancer
Inst. 86; 906-912.
more frequently but at lower doses, which could make for safer and more active therapy.
[email protected]
Basic research
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p51
Improving anticancer drug efficacy
Alfred Schinkel
Alfred Schinkel has a broad interest in the genes and proteins responsible for resistance
SELECTED PUBLICATIONS
to anti-cancer drugs. Using knockout and transgenic mouse models his team is providing
a broader understanding of drug resistance and the way the body handles drugs, thus
Van Herwaarden, A.E., and Schinkel, A.H. (2006).
supporting optimization of clinical chemotherapy.
The function of breast cancer resistance protein
in epithelial barriers, stem cells and milk secretion of drugs and xenotoxins. Trends Pharmacol.
We study how drugs move around the body, which is a very important aspect of how
efficiently they treat disease. One of the main problems in the cancer field is the resistance
Sci. 27; 10-16.
Jonker, J.W., Merino, G., Musters, S., Van
that arises in tumors to drugs. Once this has occurred in a patient, the tumor is often
Herwaarden, A.E., Bolscher, E., Wagenaar,
resistant to many different drugs, including ones to which the patient has not yet been
E., Mesman, E., Dale, T.C., and Schinkel, A.H.
exposed.
It was found that this can be due to overexpression of molecules named multidrug
transporters that can occur in the membranes of tumor cells. These proteins can actively
(2005). The breast cancer resistance protein
BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nat. Med. 11;
127-129.
pump large numbers of drugs from the cell. We and other researchers discovered that they
Jonker, J.W., Wagenaar, E., Van Eijl, S., and
are present in normal tissues too, for example in the gut.
Schinkel, A.H. (2003). Deficiency in the organic
A typical example, P-glycoprotein, is present in the small blood vessels of the brain
where it prevents toxins and other substances crossing from the blood into brain tissue.
Consequently P-glycoprotein will normally prevent drugs from getting to small cancer
metastases in the brain. In the gut lining, P-glycoprotein and other pumps protect the body
against food toxins. This can prevent certain drugs from being absorbed at high enough
concentrations to work against tumors, and forces them to be administered intravenously.
cation transporters 1 and 2 (Oct1/Oct2 [Slc22a1/
Slc22a2]) in mice abolishes renal secretion of
organic cations. Mol. Cell. Biol. 23; 7902-7908.
Jonker, J.W., Buitelaar, M., Wagenaar, E., van der
Valk, M.A., Scheffer, G.L., Scheper, R.J., Plösch,
T., Kuipers, F., Oude Elferink, R.P.J., Rosing, et
al. (2002). The breast cancer resistance protein
protects against a major chlorophyll-derived
Blocking these pumps might thus improve chemotherapy in various ways.
dietary phototoxin and protoporphyria. Proc.
Drugs that block these pumps have been developed, and our collaborators, Jan Schellens
Natl. Acad. Sci. USA 99; 15649-15654.
(page 50) and Jos Beijnen (page 29), are now testing them in clinical trials to see if these can
safely allow anti-cancer drugs such as topotecan and paclitaxel to enter the body via the
oral route.
We are currently extending our research to drug-uptake and drug-metabolizing systems, as
these may be equally important for drug efficacy, and can be inhibited as well.
[email protected]
p52
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Scientific brochure NKI
Immunotechnology & immunotherapy
Ton Schumacher
Ton Schumacher’s early career included a period as a postdoc among chemists and
SELECTED PUBLICATIONS
physicists. This enabled him to become an inventor of new technologies, which he’s now
using to answer biological questions.
Toebes, M., Coccoris, M., Bins, A., Rodenko, B.,
Gomez, R., Nieuwkoop, N.J., Van de Kasteele,
Our lab’s activities all revolve around measuring or manipulating immune responses that
involve T lymphocytes, or T cells. These are cells with a key role in fighting infection and
— in some cases — cancer. In one project we insert unique DNA barcodes into individual
W., Rimmelzwaan, G.F., Haanen, J.B.A.G., Ovaa
H., and Schumacher, T.N.M. (2006). Design and
use of conditional MHC class I ligands. Nat.
Med. 12; 246-251.
T cells, using retrovirus carriers, so that we can follow T-cell differentiation during and
Bakker, A.H., and Schumacher, T.N.M. (2005).
after an immune response. This will help us find out, for example, precisely what type of
MHC multimer technology: Current status and
T cell gives rise to the memory cells that linger after an immune response and provide
future prospects. Curr. Opin. Immunol. 17;
428-433.
long-term immunity.
In collaboration with Huib Ovaa (page 45), we’ve developed a novel technology for
high-throughput detection of T cells, as an aid to analyzing T-cell responses. This involved
creating large ‘libraries’ of tetramers of MHC proteins that bind a vast range of peptide
antigens. These libraries can be used to detect T cells in a wide range of situations,
Bins, A., Jorritsma, A., Wolkers, M.C., Hung,
C.F., Wu, T.C., Schumacher, T.N.M., and Haanen,
J.B. (2005). A rapid and potent DNA vaccination
strategy defined by in vivo monitoring of antigen
expression. Nat. Med. 11; 899-904.
including the evaluation of vaccine trials.
Wolkers, M.C., Brouwenstijn, N., Bakker, A.H.,
One day we hope our MHC tetramers will benefit patients undergoing bone marrow
Toebes, M., and Schumacher, T.N.M. (2004).
transplants for leukemia or lymphoma. At present, the transplant is accompanied by an
Antigen bias in T cell cross-priming. Science 304;
1314-1317.
injection of donor white blood cells, including T cells, in the hope that these will attack any
remaining tumor cells. But it’s a haphazard procedure, as there’s no way of predicting what
tissues the cells might attack. Our MHC tetramers could be used to select donor T cells
specific for tumor-cell antigens that aren’t shared with other tissues. We could then inject
the purified T cells into patients. If we are unable to select T cells with a useful reactivity we
aim to create them by gene therapy, engineering patients’ T cells so that they bind to tumor
antigens at high affinity.
[email protected]
Basic research
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p53
Structural biology
Titia Sixma
Titia Sixma enjoys the beauty and solidity of protein structures. She is a crystallographer
SELECTED PUBLICATIONS
who combines biochemical analysis with structural studies in order to understand how
proteins work.
Buchwald, G., Van der Stoop, P., Weichenrieder,
O., Perrakis, A., Van Lohuizen, M., and Sixma,
Protein structures are more than beautiful. They show us how one protein activates another
and how two different regions of a protein interact. The structure helps explain biochemical
data and the role of the protein in cellular pathways leading to cancer. Structural and
T.K. (2006). Structure and E3-ligase activity of the
Ring-Ring complex of polycomb proteins Bmi1
and Ring1b. EMBO J. 25; 2465-2474.
Lebbink, J.H., Georgijevic, D., Natrajan, G., Fish,
biochemical data together can help us design new drugs.
A., Winterwerp, H.H., Sixma, T.K., and De Wind,
Much of what we study is basic biology, understanding how proteins collaborate in
N. (2006). Dual role of MutS glutamate 38 in
complexes, and to do so we are tackling a technically challenging goal — crystallizing
DNA mismatch discrimination and in the authorization of repair. EMBO J. 25; 409-419.
complexes of different proteins rather than a single type of protein from pure solution.
We have three main projects. The first is aimed at understanding how mistakes in DNA
replication are detected and corrected. Such mistakes would lead to frequent genetic
mutations were it not for an active mismatch repair system. If mutations occur in the repair
system itself, however, then other mutations can go unchecked, and lead to cancer. We are
Ulens, C., Hogg, R.C., Celie, P.H., Bertrand, D.,
Tsetlin, V., Smit, A.B., and Sixma, T.K. (2006).
Structural determinants of selective alpha-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP. Proc. Natl. Acad. Sci. USA
103; 3615-3620.
especially interested in the protein MutS, which checks for the insertion of the wrong bases.
A second project focuses on the process of modification by two proteins — ubiquitin and
SUMO, especially in DNA repair and chromatin regulation.
Thirdly, in collaboration with the Free University in Amsterdam, we are working on the
structure of a relative of the nicotinic acid receptor. It’s fun to study because it’s the only
high-resolution crystal structure currently available of an entire class of pharmaceutically
interesting proteins. Forty years of biochemistry have been made visible through our
structural work, which in the long term may help in the design of compounds that combat
nicotine addiction and smoking.
Much of our effort goes into studying the properties of our proteins and their complexes.
This tells us a lot about the proteins and their interactions, and gives insight in their
mechanisms.
Pichler, A., Knipscheer, P., Oberhofer, E., Van
Dijk, W.J., Korner, R., Olsen, J.V., Jentsch, S.,
Melchior, F., and Sixma, T.K. (2005). SUMO modification of the ubiquitin-conjugating enzyme
E2-25K. Nat. Struct. Mol. Biol. 12; 264-269.
[email protected]
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Scientific brochure NKI
Cell-matrix adhesion
Arnoud Sonnenberg
As well as carrying out his own research and heading a group, Arnoud Sonnenberg is an
SELECTED PUBLICATIONS
editor for the Journal of Cell Science. He believes that to understand what goes wrong in
cancer, you have to start by finding out how healthy cells work.
Litjens, S.H.M., De Pereda, J.M., and
Sonnenberg, A. (2006). Current insights into the
In our group we focus on finding out how cells know where they are in the body and know
formation and breakdown of hemidesmosomes.
Trends Cell Biol. 16; 376-383.
how they should develop. Interactions between the cell-surface proteins called integrins and
the extracellular matrix that surrounds cells are crucial to this. Depending on the particular
Sachs N., Kreft M., Van den Bergh Weerman,
M.A., Beynon A.J., Peters, T.A, Weening, J.J.,
integrins present and the composition of the matrix, cells can behave in very different ways,
and Sonnenberg, A. (2006). Kidney failure in
with implications for tumor development.
mice lacking the tetraspanin Cd151. J. Cell Biol.
We are currently excited about our work on an integrin called 64, which helps attach the
self-renewing stem cells of the epidermis to a layer of matrix that keeps them from invading
underlying tissues. Because they are naturally programmed to be capable of continued cell
division, stem cells are prime candidates for cells that could relatively easily be transformed
175; 33-39.
Wilhelmsen, K., Litjens, S.H.M., and Sonnenberg,
A. (2006). Multiple functions of the integrin 64
in epidermal homeostasis and tumorigenesis.
Mol. Cell. Biol. 26; 2877-2886.
into cancer cells, and stem cells are thought to be the source of many cancers. Integrin 64
seems to be particularly important in normally restricting the epidermal stem cells to their
Danen, E.H.J., Van Rheenen, J., Franken, W.,
Huveneers, S., Sonneveld, P., Jalink, K., and
correct niche and limiting their ability to grow.
Sonnenberg, A. (2005). Integrins control motile
We think that a mutation that causes the loss of 64 could allow a stem cell to leave its
strategy through a Rho-cofilin pathway. J. Cell
normal niche and start proliferating rapidly; this would encourage the accumulation of more
mutations that could eventually transform these cells into full-blown cancer cells. Complete
transformation probably entails the production of other integrins. When wounds heal,
Biol. 169; 515-526.
Wilhelmsen, K., Litjens, S.H.M., Kuikman, I.,
Tshimbalanga, N., Janssen, H., Van den Bout,
I., Raymond, K., and Sonnenberg, A. (2005).
for example, skin cells make a new set of integrins that lets them migrate and settle in a
Nesprin-3, a novel outer nuclear envelope
different place. If our ideas on integrins turn out to be true, one could view skin cancer as an
protein, associates with the cytoskeletal linker
uncontrolled version of wound healing — a normal process gone wrong.
So far, most research on integrins uses cell cultures. The next big challenge is to establish
good animal models in which we can apply our knowledge and discover the full role of
integrins in cancer.
protein plectin. J. Cell Biol. 171; 799-810.
[email protected]
Basic research
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Vascular damage after radiotherapy
Fiona Stewart
After working at the Gray Cancer Institute in London, UK, radiation biologist Fiona Stewart
SELECTED PUBLICATIONS
came to the NKI in 1984. Planning to stay for just a short time, she found the Institute so
inspiring that she is still here.
Dorresteijn, L.D., Stewart, F.A., and Boogerd,
W. (2006). Stroke as a late treatment effect of
I mainly work on the damage that occurs to normal tissues during radiotherapy. More
than half of the patients who are cured of their cancer have received this therapy, and we
are becoming more and more concerned about its long-term effects. In the early years of
Hodgkin’s disease. J. Clin. Oncol. 24; 1480.
Stewart, F.A., Heeneman, S., Te Poele, J. Kruse,
J., Russell, N.S., Gijbels, M., and Daemen, M.
(2006). Ionizing radiation acelerates the develop-
radiotherapy, people were just relieved to have their cancer treated, but with survivors now
ment of atherosclerotic lesions in ApoE-/- mice
living 30 years or more, we need to prevent serious long-term side effects.
and predisposes to an inflammatory plaque phe-
We now know that people who have had radiation therapy are at increased risk of
notype prone to hemorrhage. Am J. Pathology.
168; 649-658.
cardiovascular disease and stroke. Using mice that have been genetically engineered
so that, like humans, they are susceptible to atherosclerosis, my group at the NKI has
found that radiation accelerates its onset. It also makes blood vessels more likely to make
thrombotic plaques, which are more likely to rupture and block an artery than are plaques
formed in unirradiated vessels.
Krüse, J.J.C.M., Te Poele, J.A.M., Russell,
N.S., Boersma, L.J., and Stewart, F.A. (2004).
Microarray analysis to identify molecular mechanisms of radiation-induced micro vascular damage in normal tissue. Int. J. Radiat. Oncol. Biol.
Physics. 58; 420-426.
Radiation seems to trigger plaque formation by damaging the cells that line blood vessels.
I’m now trying to work out why the atherosclerosis pathway keeps progressing rather
than dying down once therapy stops. We are comparing biopsies from irradiated and
unirradiated tissues in patients undergoing surgery many years after cancer treatment. I’m
also using mice to test drugs that could improve the situation.
Krüse, J.J.C.M., Te Poele, J.A.M., Velds, A.,
Kerkhoven, R., Boersma, L.J. Russell, N.S., and
Stewart, F.A. (2004). Identification of differentially expressed genes in mouse kidney after
irradiation using microarray analysis. Radiat. Res.
161; 28-38.
Damage to small blood vessels is also a serious issue. After radiotherapy, people can be left
with reddened skin in which capillaries have become fragile. The skin breaks down easily,
leading to bleeding and infection. Capillaries in internal organs also become damaged.
In prostate cancer, bleeding from the rectum after radiotherapy can be so severe that the
patient requires surgery. We urgently need to understand why the body doesn’t restore this
tissue damage, and then try to block these unwanted reactions to aid recovery, or provide
supportive therapies.
[email protected]
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Scientific brochure NKI
Gene modification: subtle is the oligo
Hein te Riele
Over the 18 years that Hein te Riele has worked at the NKI his original simple desire to beat
SELECTED PUBLICATIONS
cancer has matured into a determined effort to understand how most cells avoid becoming
cancerous by repairing the mutations that can lead to uncontrolled cell proliferation.
Aarts, M., Dekker, M., De Vries, S., Van der
Wal, A., and Te Riele, H. (2006). Generation of
My team works at the molecular end of cancer research, on the systems that cells use to
prevent mutations. One way in which human cells protect the integrity of their 3 billion
bases of DNA is an error-checking system that spots and repairs mismatched bases. This
a mouse mutant by oligonucleotide-mediated
gene modification in ES cells. Nucleic Acids Res.
Accepted.
Dekker, M., Brouwers, C., Aarts, M., Van der
repair system also stops a cell with faulty DNA from dividing, and so prevents mutated
Torre, J., De Vries, S., Van de Vrugt, H., and
genes from being copied into new cells.
Te Riele, H. (2006). Effective oligonucleotide-
In around 15% of tumors this safeguard has failed, and this is probably a major cause of the
tumor. Making sense of what’s going on is complicated by the fact that we still do not fully
understand how mismatch repair works in healthy cells.
One approach to finding out is to subtly alter the genes that build the mismatch repair
system. To make these mutations we use a short single strand of DNA with a base sequence
that plugs on to the gene we want to alter, but has a few differences from it. Paradoxically,
mediated gene disruption in ES cells lacking the
mismatch repair protein MSH3. Gene Ther. 13;
686-694.
Foijer, F., Wolthuis, R.M.F., Doodeman, D.,
Medema, R.M., and Te Riele, H. (2005). Mitogen
requirement for cell cycle progression in the
absence of pocket protein activity. Cancer Cell.
8; 455-466.
we have to temporarily disable the mismatch repair system to do this, to stop it repairing
our changes. We stop the cell making repair proteins for a couple of days using a technique
known as RNA interference, which gives some cells time to accept the new mutation.
It’s a powerful technique, but not easy. Currently we’re the only lab in the world that can
pull it off. We make mutations in cultured embryonic stem cells, which we use to generate
mice with the desired mutations. We can then see if the mutation we’ve made predisposes
the mice to cancer. In this way we are teasing apart the individual roles of the mismatch
repair proteins.
Dekker, M., Brouwers, C., and Te Riele, H. (2003).
Targeted gene modification in mismatch-repairdeficient embryonic stem cells by single-stranded DNA oliogonucleotides. Nucleic Acids Res.
31; e27.
[email protected]
Basic research
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p57
Membrane rafts as gateways for drug
Wim van Blitterswijk
Coming to the NKI 36 years ago, Wim van Blitterswijk has spent most of his career here. He
SELECTED PUBLICATIONS
now concentrates on mechanisms of signal transduction, with a special interest in the role of
lipid rafts in the signaling pathways that lead to cell death.
Veldman, R.J., Koning, G., Van Hell, A., Zerp,
S., Vink, S.R., Storm, G., Verheij, M., and Van
Twenty years ago I first learnt that certain lipids congregate in cell membranes as
structures called ‘lipid rafts’. I also knew that an anticancer agent, the artificial lipid alkyllysophospholipid (ALP), kills cancer cells by acting on the cell membrane, but at that time
Blitterswijk, W.J. (2005). Co-formulated Noctanoyl-glucosylceramide improves cellular
delivery and cytotoxicity of liposomal doxorubicin. J. Pharmacol. Exp. Ther. 315; 704-710.
we lacked the tools to investigate further.
Van Blitterswijk, W.J., Van der Luit, A.H.,
We now have those tools, and ALP and lipid rafts have become hot research topics because
Veldman, R.J., Verheij, M., and Borst, J. (2003).
of their connection with apoptosis—the induced cell suicide that appears to play an
important role in the body’s natural defenses against cancer, and which is being explored as
a target for new treatments. Progress has been fast, and ALP is now being tested in clinical
trials at the NKI. My group’s research aims to provide an understanding of all its actions so
that treatment can be tailored to the individual patient.
ALP is taken up by lipid rafts and moves into the cell as small packets of membrane pinch
Ceramide: second messenger or modulator of
membrane structure and dynamics? Biochem. J.
369; 199-211.
Van der Luit, A.H., Budde, M., Verheij, M., and
Van Blitterswijk, W.J. (2003). Different modes of
internalization of apoptotic alkyl-lysophospholipid and cell-rescuing lysophosphatidylcholine.
Biochem. J. 374; 747-753.
off inwards. We’ve shown that, once inside, it blocks production of a major membrane lipid
— phosphatidylcholine. The cell becomes metabolically stressed and goes into apoptosis.
But if you disrupt the rafts, ALP cannot enter the cell and has no effect.
We also discovered that some cells can develop resistance to ALP by no longer making
sphingomyelin, one of the lipids needed for raft formation. We found that these cells are
Van der Luit, A.H., Budde, M., Ruurs, P., Verheij,
M., and Van Blitterswijk, W.J. (2002). Alkyllysophospholipid accumulates in lipid rafts and
induces apoptosis via raft-dependent endocytosis and inhibition of phosphatidylcholine
synthesis. J. Biol. Chem. 27;, 39541-39547.
also resistant to other agents that normally trigger apoptosis, such as gamma irradiation
and compounds that stimulate the so-called ‘death receptors’. These were thought to act by
different pathways, but our findings show that the rafts must be a common feature. The next
step will be to see if resistance against ALP develops in clinical trials.
[email protected]
p58
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Scientific brochure NKI
Genetic alterations in breast cancer
Marc van de Vijver
Marc van de Vijver interrupted his clinical training in the 1980s to spend more than four
SELECTED PUBLICATIONS
years doing basic research at the NKI. This led to an important contribution to breast
cancer research and inspired his present career, in which he combines research with clinical
Chang, H.Y., Nuyten, D.S., Sneddon, J.B.,
pathology. He encourages other MDs to follow suit.
Hastie, T., Tibshirani, R., Sorlie, T., Dai, H., He,
Y.D., Van ‘t Veer, L.J., Bartelink, H., et al. (2005).
Robustness, scalability, and integration of a
During my postgraduate studies I found that some breast cancer patients carry extra copies
of a gene called HER2. This turned out to encode a receptor (HER2) for a growth factor,
wound-response gene expression signature in
predicting breast cancer survival. Proc. Natl.
Acad. Sci. USA 102; 3738-3743.
which helped us understand why these breast cancers grow more rapidly. Subsequent
research, mainly by scientists in the United States, led to the development of the anticancer
drug Herceptin, which blocks the action of the HER2 protein.
My group now has two goals. First, we want to elucidate the biology of breast cancer
development by identifying the initial genetic changes that occur and determining how
these lead to the abnormal growth of breast tissue.
Second, we are trying to identify genetic profiles in breast cancers that tell us how long
a patient is likely to survive (their prognosis), and the likely effects of different drug
Hannemann, J., Oosterkamp, H.M., Bosch, C.A.,
Velds, A., Wessels, L.F., Loo, C., Rutgers, E.J.,
Rodenhuis, S., and Van de Vijver, M.J. (2005).
Changes in gene expression associated with
response to neoadjuvant chemotherapy in breast
cancer. J. Clin. Oncol. 23; 3331-3342.
Van de Vijver, M.J., He, Y.D., Van ‘t Veer, L.J.,
Dai, H., Hart, A.A., Voskuil, D.W., Schreiber, G.J.,
Peterse, J.L., Roberts, C., Marton, M.J., et al.
treatments. This will help guide clinical decision-making for each patient, enabling them not
(2002). A gene-expression signature as a predic-
only to live longer but also to avoid unnecessary treatment and its unpleasant side effects.
tor of survival in breast cancer. N. Engl. J. Med.
Targeted drugs like Herceptin are expensive, and there are many more in the pipeline,
making the ability to predict a patient’s response an extremely important future goal.
In collaboration with Laura Van ‘t Veer (see page 63) and René Bernards (see page 30), we
have already identified a profile composed of 70 genes whose pattern of expression seems
to be linked to longer survival in breast cancer patients. Before applying this routinely in
the clinic we need to test whether the association holds true for large numbers of patients.
Together with 15 other hospitals in the Netherlands, we are following up to 600 patients to
see if their progress matches with the presence or absence of this 70-gene signature. The
next step will be an international trial involving thousands of patients.
347; 1999-2009.
[email protected]
Basic research
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p59
Epidemiology of cancer
Flora van Leeuwen
Since arriving at the NKI in 1981, Flora van Leeuwen has studied the epidemiology of
SELECTED PUBLICATIONS
cancer, identifying risk factors from large-scale studies. She is also applying epidemiology to
identify those at risk from the late side effects of cancer treatment.
Van den Belt-Dusebout, A.W., Nuver, J, De Wit,
R., Gietema, J.A., Ten Bokkel Huinink, W.W.,
Epidemiological studies help identify factors affecting health and disease that may not be
immediately obvious. Once these links are known, they can help people avoid disease and
may also help us improve treatment.
Rodrigus, P.T.R., Schimmel, E.C., Aleman, B.M.P.,
and Van Leeuwen, F.E. (2006). Long term risk
of cardiovascular disease in 5-year survivors of
testicular cancer. J. Clin. Oncol. 24; 467-475.
I’m currently interested in hormone-related cancers in women — breast and ovarian cancers.
Van Asperen, C.J., Brohet, R.M., Meijers-
My group recently carried out a systematic review of the literature that strongly suggests
Heijboer, E.J., Hoogerbrugge, N., Verhoef, S.,
that women who take more exercise are less likely to get breast cancer. We believe this
could be because exercise influences hormone levels. If our theory is correct, this is very
exciting. Many risk factors that influence a woman’s chance of breast cancer are either out
Vasen, H.F., Ausems, M.G., Menko, F.H., Gomez
Garcia, E.B., Klijn, J.G., et al. (2005). Cancer risks
in BRCA2 families: estimates for sites other than
breast and ovary. J. Med. Genet. 42; 711-719.
of her control or are an intrinsic part of her lifestyle. But if exercise protects, then women
Klaren, H.M., Van ‘t Veer, L.J., Van Leeuwen, F.E.,
could help themselves by deciding to take more. Other hormone-related choices that
and Rookus, M.A. (2003). Potential for bias in
women make are their use of oral contraceptives and hormone-replacement therapy, and
we are looking to see if these change the risk of cancer. Part of this study involves following
a group of women who had hormone stimulation as part of fertility treatment.
As more people survive cancer, we are realizing that 20 or 30 years after receiving
treatment, they are at increased risk of new tumors and cardiovascular disease. One study
we are doing in this field is following 3,500 patients treated for Hodgkin’s lymphoma in the
studies on efficacy of prophylactic surgery for
BRCA1 and BRCA2 mutation. J. Natl. Cancer
Inst. 95; 941-947.
Van Leeuwen, F.E., Kokman, W.J., Stovall, M.,
Dahler, E.C., Van ‘t Veer, M.B., Noordijk, E.M.,
Crommelin, M.A., Aleman, B.M.P., Broeks, A.,
Gospodarowicz, M., Travis, L.B., and Russell, N.S.
(2003). Roles of radiation dose, chemotherapy,
1960s through to the 1990s — it’s already found that female survivors are at a high risk of
and hormonal factors in breast cancer follow-
developing breast cancer.
ing Hodgkin’s disease. J. Natl. Cancer Inst. 95;
To get the most out of epidemiology I collaborate with experts in molecular biology. At the
NKI this is easy because we know each other, and everyone’s offices and labs are close by.
My group is working with Laura Van ’t Veer to put together her genetic profiles of patients
with epidemiological data on cancer survivors. Combining the two should help us predict
which patients are most at risk of this late-onset cancer.
971-980.
[email protected]
p60
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Scientific brochure NKI
Epigenetics in yeast
Fred van Leeuwen
Beginning his scientific career at the NKI by working on African trypanosomes, Fred van
SELECTED PUBLICATIONS
Leeuwen became fascinated by epigenetics – the process by which genes are permanently
switched on or off. This took him to Seattle, USA, and back to the NKI in 2003.
Van Leeuwen, F., and Van Steensel, B. (2005).
Histone modifications: from genome-wide maps
We’re interested in how cells maintain their identity and pass a memory of which genes are
switched on or off to daughter cells through cell division. Understanding the mechanisms
will give us insights into how some cancers may arise.
to functional insights. Genome Biol. 6; 113.
Schubeler, D., MacAlpine, D.M., Scalzo, D.,
Wirbelauer, C., Kooperberg, C., Van Leeuwen,
F., Gottschling, D.E., O’Neill, L.P., Turner, B.M.,
Every cell in the body has the same genes, but varies according to which ones are switched
Delrow, J., Bell, S.P., and Groudine, M. (2004).
on or off. And this pattern of gene activity is passed on to future cell generations. The
The histone modification pattern of active genes
process by which this happens – known as epigenetics – involves ‘packaging’ of DNA, in the
nucleus by wrapping it around proteins called histones. Small changes in this packaging can
affect the ease with which the cellular machinery can ‘read’ its sequence.
As well as being caused by mutations, certain cancers can arise from epigenetic changes.
For example, patients with an inherited form of colon cancer often have a mutation in
MLH1, a protein involved in DNA repair. In contrast, people who develop the disease
revealed through genome-wide chromatin
analysis of a higher eukaryote. Genes Dev. 18;
1263-1271.
Van Leeuwen, F., Gafken, P.R., and Gottschling,
D.E. (2002). Dot1p modulates silencing in yeast
by methylation of the nucleosome core. Cell.
109; 745-756.
spontaneously, with no family history, usually have a normal version of the gene. But it is
Van Leeuwen, F., and Gottschling, D.E. (2002).
often switched off, rather than inactivated by mutation.
Genome-wide histone modifications: gaining
We would like to be able to revert the epigenetic state of a tumor cell to a normal cell. But
specificity by preventing promiscuity. Curr. Opin.
Cell Biol. 14; 756-762.
before we can do that we need to understand the epigenetics of normal cells.
As an experimental system we are studying budding yeast. We use reporter genes that
give the cells a color to reveal which parts of the genome are turned on or off as the yeast
Van Leeuwen, F., and Gottschling, D.E. (2002).
Assays for gene silencing in yeast. Methods
Enzymol. 350; 165-186.
colonies grow. These colors let us watch the pattern of gene activity as it propagates
through the generations. We have two broad aims: first, to find new players – enzymes that
introduce modifications on the histone proteins that cause genes to become ‘silent’, and
second, to understand how such modifications are passed on to new cells.
[email protected]
Basic research
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p61
Cell fate control by Polycomb silencers
Maarten van Lohuizen
Maarten van Lohuizen has come full circle since gaining a PhD at the NKI in 1992 studying
SELECTED PUBLICATIONS
oncogenes with Anton Berns. After a postdoc on cell-cycle genetics at the University of
California, San Francisco, he returned to the NKI in 1995 and is now head of the Division of
Tolhuis, B., Muijrers, I., De Wit, E., Teunissen,
Molecular Genetics.
H., Talhout, W., Van Steensel, B., and Van
Lohuizen, M. (2006). Genome-wide profiling of
PRC1 and PRC2 Polycomb chromatin binding in
I’m fascinated by the master switches that control cell and tissue development, and how
these go wrong in cancer. Our group is working on one set of these switches, the Polycomb-
Drosophila. Nat. Genet. 38; 694-699.
Bruggeman, S.W.M., Valk-Lingbeek, M.E., Van
group proteins, which control cell fate and identity both during embryonic development and
der Stoop, P.P.M., Jacobs, J.J.L., Kieboom, K.,
throughout the rest of your life. We know these proteins are involved in tumor formation.
Tanger, E., Hulsman, D., Leung, C., Arsenijevic,
Understanding this in detail could lead to entirely new types of drugs that act in more
precise ways than simply killing rapidly dividing cells.
The role of Polycomb proteins is to keep genes that control cell differentiation switched
Y., Marino, S., and Van Lohuizen, M. (2005). Ink4a
and Arf differentially affect cell proliferation and
neural stem cell self-renewal in Bmi1 deficient
mice. Genes Dev. 19; 1438-1443.
on or off as appropriate. If Polycomb proteins fail to work, tumors can develop. We are
Leung, C., Lingbeek, M., Shakhova, O., Liu, J.,
focusing in particular on how Polycomb proteins control the fate of stem cells, such as
Tanger, E., Saremaslani, P., Van Lohuizen, M., and
those that continually renew the skin and the gut lining. We suspect that many cancers are
the result of stem cells losing their normal response to their immediate environment and
continuing to divide when they should be starting to differentiate. At the beginning of this
process, however, these cells may divide too slowly to be killed by many of the current
cancer drugs, which only act on rapidly proliferating cells.
In collaboration with Anton Berns (see page 31) and the Sanger Institute in the UK, we are
using large-scale screens for mutations caused by retrovirus insertion to systematically find
genes and pathways involved in cancer. With these screens we have already identified one
Polycomb gene, BMI1, with a role in tumor formation and stem-cell regulation.
These screens are also uncovering many possible targets for a new generation of anticancer
drugs, and are providing insight into which combinations of mutated oncogenes and tumor
suppressor genes act together to cause cancer.
Marino, S. (2004). Bmi1 is essential for cerebellar
development and is overexpressed in human
medulloblastomas. Nature. 428; 337-341.
Valk-Lingbeek, M.E., Bruggeman, S.W.M., and
Van Lohuizen, M. (2004). Stem cells and cancer:
the Polycomb connection. Cell. 118; 409-418.
[email protected]
p62
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Scientific brochure NKI
?
?
Chromatin genomics
Bas van Steensel
Bas van Steensel envisages the thousands of genes that make up a genome as musicians
SELECTED PUBLICATIONS
in an orchestra. Each gene has to act in perfect coordination with all others, and correct
timing and levels of expression are essential. Unlike an orchestra, however, the genome
Moorman, C., Sun, L.V., Wang, J., De Wit,
is not controlled by a single conductor, but by several hundreds. Chromatin proteins and
E., Talhout, W., Ward, L.D., Greil, F., Lu, X.J.,
transcription factors are these ‘conductors’ of the genome.
White, K.P., Bussemaker, H.J., and Van Steensel,
B. (2006). Hotspots of transcription factor
colocalization in the genome of Drosophila
Our lab wants to know how proteins work together to coordinate the expression of
melanogaster. Proc. Natl. Acad. Sci. USA. 103;
12027-12032.
thousands of genes. We have developed a genome-wide technique named DamID that can
identify genes which are directly controlled by a chromatin protein or transcription factor.
The technique works by linking the protein of interest to an enzyme from E. coli bacteria.
When the protein binds to a gene the enzyme adds a unique chemical tag to the region.
This tag can be subsequently mapped in the genome using special microarrays, and the
Tolhuis, B., De Wit, E., Muijrers, I., Teunissen, H.,
Talhout, W., Van Steensel, B., and Van Lohuizen,
M. (2006). Genome-wide profiling of PRC1 and
PRC2 Polycomb chromatin binding in Drosophila
melanogaster. Nat. Genet. 38; 694-699.
genes by the protein can thus be identified.
Vogel, M., Guelen, L., De Wit, E., Peric Hupkes,
So far we have created genome-wide maps of DNA binding of around 30 proteins. These
D., Lodén, M., Talhout, W., Feenstra, M., Abbas,
maps offer us a more general view of how things work compared to traditional methods
B., Classen, A.K., Van Steensel, B. (2006). Human
heterochromatin proteins form large domains
examining single genes individually. For example, analysis of these maps using advanced
containing KRAB-ZNF genes. Genome Res. in
bioinformatics techniques tells us how each protein may contribute to the coordination of
press.
gene expression, and by which mechanism this is done. By comparing the binding maps
Pickersgill, H., Kalverda, B., De Wit, E., Talhout,
of the different proteins, we are also starting to see relationships between proteins that no
W., Fornerod, M., and Van Steensel, B. (2005).
one has seen before. This lets us see which proteins form complexes together, and which
complexes control which genes. We think of this as a kind of combinatorial code that we
Characterization of the Drosophila melanogaster
genome at the nuclear lamina. Nat. Genet. 38;
1005-1014.
hope to decipher in the future. We work with cells from fruit flies and humans. Fruit flies
have a much smaller and simpler genome than humans and are therefore an easier model
system for the development of new techniques and concepts. The skills and insights that we
obtain from working with this organism make it much easier to do genome-wide mapping
studies in human cells.
[email protected]
Basic research
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p63
Molecular profiles of breast cancer
Laura van ‘t Veer
Trained in molecular biology, Laura van ‘t Veer applies her expertise to cover the whole
selected publications
range from cancer diagnostics and genetic counseling in the NKI’s family cancer clinic to
research into understanding the roles that genes play in cancer.
Fan, C., Oh, D.S., Wessels, L., Weigelt, B.,
Nuyten, D.S.A., Nobel, A.B., Van ‘t Veer, L.J.,
Most of our research focuses on breast cancer – identifying the genetic factors that make
women susceptible to the disease and also fine-tuning diagnostic tests to predict outcome
more accurately, and make better decisions about therapy.
Perou, C.M. (2006). Concordance among geneexpression-based predictors for breast cancer.
New Engl J Med. 355; 560-569.
Weigelt, B., Peterse, J.L., Van ‘t Veer, L.J. (2005).
We are part of large international collaborations, the Breast Cancer Association Consortium,
Breast cancer metastasis - markers and models.
which involves around 50,000 patients and an equal number of controls, and the
Nat Rev Cancer. 5; 591-602.
International BRCA-1/2 Carrier Cohort Study. Our focus is to look at the DNA that is passed
to future generations in sperm and egg to identify new gene mutations that confer a high or
moderate risk of developing breast cancer. And we look at how different genes interact with
each other and with environmental factors to promote disease.
Predicting the clinical course of breast cancer based on improved molecular assessment
of the tumor biology and the presence of circulating tumor cells is the other main focus of
our research. Especially large-scale gene expression analysis has helped us to dissect breast
cancer into therapeutically meaningful subgroups.
I am one of the co-founder’s of the NKI’s spin-off biotech company Agendia, which develops
the research findings into diagnostic tests for breast cancer and other diseases. The first
commercial test, the 70-gene ‘signature’ or pattern of gene activity, can indicate the chance
Van de Vijver, M.J., He, Y.D., Van ‘ t Veer, L.J.,
Dai, H., Hart, A.A.M., Voskuil, D., Schreiber, G.J.,
Peterse, J.L., Roberts, C., Marton, M.J., Parrish,
M., Atsma, D., Witteveen, A., Glas, A., Delahaye,
L., Van der Velde, T., Bartelink, H., Rodenhuis, S.,
Rutgers, E.Th., Friend, S.H., Bernards, R. (2002).
A gene expression signature predicts survival in
lymph node negative and positive breast cancer
patients. New Engl J Med. 347; 1999-2009.
Van ‘t Veer, L.J., Dai, H., Van de Vijver, M.J., He,
Y.D., Hart, A.A.M., Mao, M., Peterse, J.L., Van
der Kooij, K., Marton, M.J., Witteveen, A.T.,
Schreiber, G.J., Kerkhoven, R.M., Roberts, C.,
Linsley, P.S., Bernards, R., Friend, S.H. (2002).
of future metastasis. Physicians can use this to decide if a patient should embark upon
Gene expression profiling of breast cancer
chemotherapy, and weigh-up the likely benefits over side effects.
predicts clinical outcome of disease. Nature.
615, 530-536.
[email protected]
p64
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Scientific brochure NKI
Apoptosis modulation and radiotherapy
Marcel Verheij
Marcel Verheij spends half his time as a radiotherapy specialist at the Antoni van
selected publications
Leeuwenhoek Hospital and the rest in three different labs. This helps him keep his
laboratory work focused on clinical need, and his clinical work scientifically up to date.
Vink SR, Lagerwerf S, Mesman E, Schellens JHM,
Begg AC, Van Blitterswijk WJ, Verheij M. (2006).
After gaining my medical degree, I started a residency in radiation oncology at the NKI,
and also spent two years at the Memorial Sloan-Kettering Cancer Center in New York.
There I got interested in apoptosis, or cell suicide, and started to investigate the signaling
Radiosensitization of Squamous Cell Carcinoma
by the Alkylphospholipid Perifosine in Cell
Culture and Xenografts. Clin Cancer Res. 12;
1615-1622.
mechanisms by which radiation induces it. I returned to the Netherlands with enough data
Jansen EPM, Boot H, Verheij M, Van de Velde
for my PhD and to establish a new line of research at the NKI.
CJH. (2005). Optimal locoregional treatment in
I have three main areas of research, all of which have the aim of making apoptosis a more
powerful weapon against cancer. Working with Wim van Blitterswijk (see page 57), we have
brought a new group of anticancer lipids into potential clinical use as radiosensitizers. We
are also investigating how lipid rafts in cell membranes sense apoptosis-related signals and
how they pass this information into the cell. In collaboration with Jannie Borst (page 32), we
are developing a promising therapeutic combination of radiation and a drug that binds to
gastric cancer. J Clin Oncol. 23; 4509-4517.
Haas R, De Jong D, Valdés Olmos RA, Zerp SF,
Van den Heuvel I, Bartelink H, Verheij M. (2004).
In vivo imaging of radiation-induced apoptosis
by 99mTc-annexin-V scintigraphy in follicular
lymphoma patients. Int J Radiat Oncol Biol Phys.
59; 782-787.
the ‘death receptors’ to trigger apoptosis.
Van der Luit AH, Budde M, Ruurs P, Verheij M,
In collaboration with Renato Valdés Olmos we have introduced an imaging method that can
Van Blitterswijk WJ. (2002). Alkyl-lysophospho-
detect radioisotope-labeled proteins that specifically bind to the surface of cells about to
undergo apoptosis. This will enable us to judge whether therapies are working. We already
have indications that tumors with a high proportion of apoptotic cells are more susceptible
to therapy than those with fewer suicidal cells.
As a third line of assault, I’m focussing on combinations of chemotherapy and radiotherapy,
because we know that these increase the chance of survival for patients with some certain
tumors. With scientific and clinical facilities close by, and keen to collaborate, the NKI is a
great place to make advances in this type of therapy.
lipids induce apoptosis via raft-mediated endocytosis and inhibition of phosphatidylcholine
synthesis. J Biol Chem. 277; 39541-39547.
[email protected]
Basic research
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Bioinformatics
Lodewyk Wessels
Lodewyk Wessels brings an unusual perspective to the NKI. He trained first as an electrical
selected publications
engineer and worked in machine learning (ML) at the Technical University of Delft before
joining the NKI in 2006 as a full-time bioinformatician.
Fan, C., Oh, D.S., Wessels, L.F.A., Weigelt, B.,
Nuyten, D.S.A., Nobel, A.B., Van ‘t Veer, L.J., and
My first project at the NKI was to adapt computer algorithms I’d helped develop for ML,
and use them to predict the mutation status of breast cancers from comparative genomic
hybridization data. The aim was to produce an alternative means of identifying carriers of
Perou, C.M. (2006). Different gene expressionbased predictors for breast cancer patients are
concordant. N. Engl. J. Med. 355; 560-569.
Lai, C., Reinders, M.J.T., Van ‘t Veer, L.J., and
germline mutations in the BRCA1 gene from a high-risk population.
Wessels, L.F.A. (2006). A comparison of univari-
We compiled a ‘predictive classifier’ — a set of chromosomal regions where the number of
ate and multivariate gene selection techniques
copies present indicates the mutation status of known cancer-causing genes.
for classification of cancer datasets. BMC
Bioinformatics. 7; 235.
Our ultimate goal is to build classifiers that make reliable predictions on data from new
cases, not just cases on which the predictors were trained. We are now concentrating on
incorporating data on whole pathways, rather than single genes, to make prediction more
accurate. This ties in with our group’s other research, which is on systems biology — the
study of how all the components of a cell work together.
As well as our own research on systems biology we provide statistical and bioinformatics
expertise to other groups at the NKI. Often, such projects require tailor-made bioinformatics
solutions, which open up new topics for bioinformatics research. For example, we’re
collaborating with the teams of Jos Jonkers’s, Anton Berns and Maarten van Lohuizen (page
61) to interpret data from insertional mutagenesis studies in mice.
Our task is to develop algorithms for deciding which insertions lead to cancer and which
have no effect. In the meantime, the approaches we developed for insertional mutagenesis
proved to be applicable to a wide range of other genomic datasets.
Another challenging, but exciting collaboration is with Jos Beijnen — using proteomics
to detect cancer in its early stages by the proteins present in easily sampled tissues such
as blood. We’re calibrating his measurement techniques and our algorithms, using known
proteins, to ensure reliability and reproducibility of results.
Wessels, L.F.A., Reinders, M.J.T., Hart, A.A.M.,
Veenman, C.J., Dai, H., He, Y.D., Van ‘t Veer, L.J.
(2005). A protocol for building and evaluating
predictors of disease state based on microarray
data. Bioinformatics 21; 3755-3762.
[email protected]
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Clinical research
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Scientific brochure NKI
Medical Oncology
The Division of Medical Oncology is at the clinical end of the NKI’s emphasis on translating laboratory results
into clinical practice. The staff is devoted to improving cancer diagnosis and making treatment more effective
for the individual patient.
Developing new therapies and
cancer to which the NKI has access for
Immunocytochemistry can then reveal
procedures is a two-way process —
research. The NKI also specializes in
whether or not the tumor is carrying
many new concepts and tools originate
research into and treatment of head
high levels of the estrogen receptor
in the NKI’s laboratories, but their
and neck tumors, as well as cancer of
or of another receptor, Her-2. Patients
clinical usefulness is uncertain until
the stomach, colon, kidney and skin.
can be accordingly assigned treatment
tested in clinical trials. At the same
with either hormones or the drug
time, questions arise in clinical practice
The right diagnosis
Herceptin, but these techniques do
that inspire new laboratory studies,
Having an accurate diagnosis is
not actually predict whether individual
to improve treatment protocols,
crucial to making the best treatment
patients will or will not respond to their
for example, or find new disease
decisions. Cancer diagnosis involves
treatment. Only one in four patients
markers and drugs. The success of the
identifying not just the tissue of
with advanced breast cancer and who
division’s research is due to extensive
origin, such as breast or lung, but
test positive for Her-2 will respond to
collaborations both within the NKI,
also the tumor subtype. And even
treatment with Herceptin alone, and
with the departments of pathology,
within a single subtype there can be
there is currently no way of predicting
molecular pathology, radiotherapy and
many variants — and which one the
who they are at diagnosis. The drug is
surgical oncology, and elsewhere.
patient has will affect their response to
often combined with another for better
treatment.
results. But it would be preferable to
The head of the Division of Medical
know in advance who is most likely to
Oncology, Sjoerd Rodenhuis, is
Even in cancers affecting the same
benefit, so as to avoid treating patients
responsible for the diagnosis and
tissue there is often a diversity in
unnecessarily.
management of cancer, and for
genetic and biological properties that
devising treatment protocols for
is only beginning to be understood.
The Division of Medical Oncology is
the division’s clinical trials. His
In breast cancer, for example,
working closely with the Division of
particular interest in breast cancer
traditional histology provides a useful
Diagnostic Oncology (page 82) to
has helped turn the AVL hospital
indication of whether the tumor
make cancer diagnosis more precise
into a major referral center for this
has originated from the basal cells
than is currently possible. More precise
disease. Consequently, there is a large
of the milk duct epithelium, or the
diagnoses would help clinicians choose
population of patients with breast
cells lining the lumen of the duct.
drug combinations that better suit
Clinical research
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| Sjoerd Rodenhuis, head of the division
individual patients, thus avoiding
course of non-small-cell lung cancer,
as alkylating agents, for example,
unnecessary treatments and side
while another genetic study is
was once considered effective, until
effects. In the race against time before
looking for the presence or absence
it was found that only a minority of
a cancer spirals out of control, this
of mutations in a growth factor
patients benefited, while the majority
could make the difference between life
receptor, EGFR. This information
could suffer severe side effects. In
and death.
indicates which patients may benefit
collaboration with the Department
in future from a new drug aimed at
of Pathology, the Medical Oncology
A major collaboration between NKI
this receptor. Meanwhile, the group
Division is testing to see which patients
scientists, pathologists, surgeons
is also investigating other methods
have tumors that are most susceptible
and medical oncologists has led
for improving the diagnosis of various
to these drugs, and whether lower
to pioneering work on the use of
types of lung cancer, such as the use
and safer doses could be used. To do
microarray technology for defining
of fluorescently activated markers that
so, they are using various molecular
patterns of gene expression in breast
are preferentially taken up by tumor
techniques and magnetic resonance
cancer that can be used to predict
tissue, and immunocytochemistry for
imaging (MRI).
the chance that a patient’s disease
detecting the presence of a particular
is likely to metastasize. The success
maker called HTERT in the lung
Quality drugs
of the collaboration has led to the
tissue of smokers, which might
Another important area of research
setting up of a commercial company
indicate those most at risk of
in medical oncology is clinical
within the NKI, Agendia, to provide
developing smoking-related cancer
trials to test different treatment
molecular diagnostic tests and services
and who could receive chemotherapy
combinations, using both existing
for other clinicians and researchers.
as a means of prevention.
and new pharmaceutical products.
Medical oncology specialists are
Currently, the NKI is involved in
now closely involved in taking the
Tailoring treatment
around 120 different clinical trials with
use of microarrays further to predict
A crucial decision in medical
collaborators in the Netherlands and
responses to drug treatment.
oncology is when to switch a patient
abroad.
The thoracic oncology group within
to another drug combination if the
Underpinning this, the Department
the division is investigating whether
first appears not to be working. The
of Pharmacy and Pharmacology led
microarrays can help predict the
use of high doses of drugs known
by Jos Beijnen (page 29) provides
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Scientific brochure NKI
an extensive facility for designing,
Monitoring new treatments
Basic research by Alfred Schinkel
manufacturing and evaluating new
A vital part of assessing a new
(page 51) and others is contributing
pharmaceutical formulations. Besides
treatment strategy, with either existing
to our understanding of these drug
its routine work for the AVL, the
or new drugs, is monitoring their
transporters and our potential ability
department supplies top-quality
effects in patients. The Department of
to manipulate them.
preparations of new investigational
Pharmacy and Pharmacology monitors
drugs to hospitals and biotech
patients during clinical trials to
The Gastroenterology Department
companies around the world. The
determine, for example, which drugs
is investigating new treatments
profits from this are used to fund
can be taken orally, which doses are
aimed at controlling incurable forms
the department’s research, which
most effective and when, and how to
of cancer in the gut. These include
involves around 25 PhD students
minimize side effects. The department
cancer of the stomach and the mid-
working on improving drug design and
also conducts its own research into
gut, as well as tumors arising from
formulation, and bioanalysis of drug
improving cancer treatment. One
the neuroendocrine system — the
effects in patients.
project involves screening patients for
nervous tissue that lies alongside
genetic differences that could indicate
the gut. Different combinations of
The Department of Pharmacy has also
how long a drug persists in the body.
chemotherapy and radiotherapy are
recently established a Biotherapeutics
Ultimately, this information could help
being evaluated. The department is
Unit for the manufacture of DNA-based
guide different dose regimes for each
also using genetic studies to identify
products, including DNA vaccines
individual.
which patients are likely to experience
for the treatment of cervical cancer
treatment side effects.
and melanoma, in collaboration
Another project tackles a major
with medical oncologist and
problem that results when particular
The Division of Medical Oncology is
immunologist John Haanen (page 37).
transporter proteins in a patient’s
at the forefront of research in a wide
In a separate collaboration with the
gut wall block the uptake of drugs
range of clinical specialties, aimed
NKI’s bioinformatics expert Lodewyk
taken orally, and so prevent them
at improving both diagnosis and
Wessels (page 65), the department is
entering the bloodstream. To
treatment of many types of cancer.
exploring the potential of proteomics
receive an effective dose, these
The research involves the development
— the analysis of proteins in biological
patients must be given the drugs
and application of many different
samples — for the diagnosis and
intravenously, over a prolonged
technologies from the laboratory to
monitoring of breast cancer, colorectal
time in a hospital bed, rather than
the clinic, confirming the NKI’s position
cancer, renal cancer, and other solid
in more convenient pill form. To
as a leading European research
tumors.
address this problem, researchers
institute.
In addition the Division of Immunology
led by medical pharmacologist Jan
is investigating the effects of using
Schellens (page 50), in collaboration
cytokines to stimulate the immune
with the Division of Experimental
system before surgery for renal
Therapy, are investigating the use
carcinoma, to see whether this boosts
of new agents that block these drug
the action of the body’s T cells against
transporters, thus allowing anticancer
tumors.
drugs taken orally to enter the body.
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Bins A.D., Jorritsma A., Wolkers M.C., Hung
C.F., Wu T.C., Schumacher T.N., Haanen
J.B.A.G. (2005). A rapid and potent DNA vaccination strategy defined by in vivo monitoring
of antigen expression. Nat Med. 11: 899-904.
Bosch T.M., Kjellberg L.M., Bouwers A., Koeleman B.P., Schellens J.H.M., Beijnen J.H., Smits
P.H., Meijerman I. (2005). Detection of single
nucleotide polymorphisms in the ABCG2 gene
in a Dutch population. Am J Pharmacogenomics. 5: 123-131.
De Jonge M.E., Huitema A.D.R., Tukker A.C.,
Van Dam S.M., Rodenhuis S., Beijnen J.H.
(2005). Accuracy, feasibility, and clinical impact
of prospective bayesian pharmacokinetically
guided dosing of cyclophosphamide, thiotepa,
and carboplatin in high-dose chemotherapy.
Clin Cancer Res. 11: 273-283.
Hannemann J., Oosterkamp R., Bosch C.A.J.,
Velds A., Loo C., Rutgers E.J., Rodenhuis S.,
Van de Vijver M.J. (2005). Response to neoadjuvant chemotherapy in breast cancer results
in significant changes in gene expression. J
Clin Oncol. 23: 3331-3342.
Luiten R.M., Kueter E.W., Mooi W., Gallee M.P.,
Rankin E.M., Gerritsen W.R., Clift S.M., Nooijen
W.J., Weder P., Van de Kasteele W.F., Sein J.,
Van de Berk P.C., Nieweg O.E., Berns A.M.,
Spits H., De Gast G.C. (2005). Immunogenicity,
including vitiligo, and feasibility of vaccination
with autologous GM-CSF-transduced tumor
cells in metastatic melanoma patients. J Clin
Oncol. 23: 8978-8991.
Rademaker-Lakhai J.M., Horenblas S., Meinhardt W., Stokvis E., de Reijke T.M., Jimeno
J.M., Lopez-Lazaro L., Lopez Martin J.A., Beijnen J.H., Schellens J.H.M. (2005). Phase I clinical and pharmacokinetic study of kahalalide F
in patients with advanced androgen refractory
prostate cancer. Clin Cancer Res.
11: 1854-1862.
Breedveld P., Zelcer N., Pluim D., Sonmezer
O., Tibben M.M., Beijnen J.H., Schinkel A.H.,
Van Tellingen O., Borst P., Schellens J.H.M.
(2004). Mechanism of the pharmacokinetic
interaction between methotrexate and benzimidazoles: potential role for breast cancer
resistance protein in clinical drug-drug interactions. Cancer Res. 64: 5804-5811.
De Jonge M.E., Van den Bongard H.J., Huitema A.D., Mathôt R.A., Rosing H., Baas P.,
Van Zandwijk N., Beijnen J.H., Schellens J.H.
(2004). Bayesian pharmacokinetically guided
dosing of paclitaxel in patients with non-small
cell lung cancer. Clin Cancer Res. 10: 22372244.
Rodenhuis S., Bontenbal M., Beex L.V.A.M.,
Wagstaff J., Richel D.J., Nooij M.A., Voest E.E.,
Hupperets P., van Tinteren H., Peterse H.L.,
Ten-Vergert E.M., de Vries E.G.E. (2003).
High-dose chemotherapy with hematopoietic
stem cell rescue in high-risk breast cancer.
N Eng J Med. 349: 7-16.
Zuetenhorst J.M., Bonfrer J.M., Korse C.M.,
Bakker R., Van Tinteren H., Taal B.G. (2003).
Carcinoid heart disease: the role of urinary 5hydroxyindoleacetic acid excretion and plasma
levels of atrial natriuretic peptide, transforming
growth factor-beta and fibroblast growth
factor. Cancer. 97: 1609-1615.
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Surgical Oncology
The Division of Surgical Oncology is a large and diverse department, with over 50 academic staff and more
than 50 medical residents and research students. The division’s research interests reflect clinical reality and
extend far beyond surgery itself into areas such as diagnostics and therapies for inoperable tumors.
One of the largest projects the division
collects in; these nodes are then
Women at known high risk of
has undertaken is the development of
prime candidates for surgical removal.
developing ovarian cancer are
lymphatic mapping, which can identify
Lymphatic mapping can highlight those
screened twice a year, using vaginal
likely sites at which secondary tumors
nodes at greatest risk of developing
ultrasound and measurement of blood
will arise. The fluid within tissues drains
a tumor long before any lump can
levels of the ovarian protein CA125.
through lymphatic vessels to lymph
be felt, and the NKI has moved the
Research at the NKI has suggested,
nodes before being recirculated via the
procedure from research into clinical
however, that this screening has only
lymphatic system into the blood. This
use. A recently completed study of
limited success at detecting early-
fluid can carry cells from a tumor into
patients with penile cancer showed
stage cancer, and is collaborating
the lymph nodes, where they become
that lymphatic mapping improves long-
with the Amsterdam Medical Center
trapped and set up a secondary tumor.
term survival rates.
to develop a more reliable test that
A given tumor only drains into a few
will be based on a spectrum of blood
lymph nodes at most, and if these
Evaluating diagnosis and screening
proteins, not just a single one. A
‘sentinel nodes’ can be identified,
The division is continually evaluating
nationwide study coordinated from the
the surgeon can remove them to
current diagnostic and screening
NKI is also looking at the psychosocial
determine whether the cancer has
techniques for their reliability and
impact of removing a woman’s
spread. Effective treatment can then
validity. For example, the presence of
ovaries to reduce her risk of cancer, to
be given at an early stage, reducing
the protein S100B in the blood is used
determine whether the reduced fear
the chance of the cancer recurring.
as a diagnostic marker for melanoma.
of cancer balances out the hormonal
However, researchers in the division
disturbances caused by the loss of the
To carry out lymphatic mapping, the
have shown that this marker is of
ovaries.
doctor injects small volumes of a low-
limited use, and fails to predict the
level radioactive tracer at the site of
presence of non-palpable secondary
Heat treatments
the primary tumor — most commonly
tumors in lymph nodes. If patients have
for metastatic cancer
a breast tumor, skin tumor (melanoma)
S100B in their blood then their chance
A novel therapy being pioneered at
or penile tumor. The tracer’s
of recurrent melanoma is high, but a
the NKI is hyperthermic intraperitoneal
movement is followed with a gamma-
lack of S100B does not, unfortunately,
chemotherapy (HIPEC) to treat
ray camera to see which nodes it
rule out melanoma.
tumors that have arisen in, or tend to
Clinical research
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| Bin Kroon, head of the division
spread to, the abdominal cavity. All
thermal ablation (RFA). This involves
In thoracic surgery, such as that for
of the visible tumor is first removed,
inserting a miniature transmitter that
lung cancer, the division’s research
and the entire abdominal cavity is
has been placed inside a long needle
focuses on the use of radiotherapy
then perfused with a solution of
into the tumor. The transmitter acts
or chemotherapy before surgery,
chemotherapeutic drugs warmed
like a microwave oven and destroys
while also looking for ways to reduce
to 40–41°C. The combination of
cells around it. If the growths are not
postoperative pain. One project is
chemotherapy and heat is thought to
large, and can be completely removed
investigating whether CT-guided RFA
work better than drugs alone, because
by RFA, the treatment can improve
could replace surgery as a treatment
heat increases uptake of the drug into
long-term survival. RFA also leaves the
for some secondary or metastatic lung
the tumor cells and may even reverse
patient with less pain and discomfort
tumors.
the drug resistance that can arise
than surgery, and can sometimes be
during chemotherapy. In addition, heat
used when conventional surgery is
The division has pioneered the
itself can kill tumor cells. The world’s
impossible.
technique of isolated limb perfusion
first prospective randomized trial of
to treat melanoma and sarcoma
this treatment was carried out recently
Which treatment?
with chemotherapeutic drugs. Tubes
at the NKI, and showed significantly
Deciding the best treatment for each
lead into the major artery and vein
increased survival when compared with
patient is vital. To determine the best
supplying the affected limb, and are
conventional treatment. So far, HIPEC
treatment for some types of breast
connected by a pump, creating an
has been used to help patients with
cancer, the NKI is coordinating the
isolated circulation through which
certain colorectal tumors and there are
AMAROS trial (after-mapping of the
chemotherapeutics can be given at
plans to test it in women with ovarian
axilla: radiotherapy or surgery), an
a higher concentration than usual, as
cancer, which has a tendency to
international, multicenter phase III
they are kept within the limb.
reappear within the abdomen.
clinical trial in patients with operable
invasive breast cancer whose tumor
In 2004, the Antoni van Leeuwenhoek
Another approach to treating
has spread to the lymph nodes.
hospital started day-care surgery
metastatic cancer is to either surgically
Patients will be randomly assigned to
for breast cancer. Careful additional
remove the metastatic cells or to
receive either radiotherapy or surgical
local anesthesia can give thorough
destroy them using radiofrequency
removal of the nodes.
pain relief while avoiding many usual
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Scientific brochure NKI
postoperative problems such as the
nausea and vomiting associated with
strong painkillers such as opioids. In
addition, the Division has developed
the technique of ‘awake fibercapnic
intubation’ to make intubation easier in
patients with difficult airways, typically
patients with a tumor in the upper
airway.
function, with substitute bladders and
subcutaneous tissue and skin are
Maintaining function
the reinstatement of means of urine
transplanted from one site of the body
Cancer of the head or neck is
storage and evacuation.
to the part of the body that needs
particularly problematic to treat
restoring and provides an optimal
because it is so difficult to remove
To help rebuild disease-damaged
means of covering the defect. Getting
tumors surgically without damaging
areas, the NKI’s plastic surgeons
the flap to graft in the new location
vital tissues and organs. The division
recently investigated the risk of
requires that it contains a good set of
is engaged in many projects that aim
surgical complications of a method
blood vessels, and that these vessels
to spare healthy tissue or restore
that involves saving the breast’s skin
can be microsurgically fixed into an
function to areas damaged by surgery.
during a mastectomy and immediate
adequate blood supply. Unfortunately,
The head and neck department has
inserting implants to maintain the
radiotherapy used to treat the initial
a leading role in rehabilitating the
breast’s overall shape. They are now
tumor often damages blood vessels
voice and the airway after a total
able to offer guidance for patients with
in the area, and the Department of
laryngectomy. The head and neck
breast cancer or for those who have
Plastic and Reconstructive Surgery
department is also working closely
inherited a specific risk of developing
is collaborating with the Division
with the Division of Radiotherapy to
breast cancer. Working with the
of Radiotherapy to investigate the
develop combinations of radiotherapy
Department of Psychology, members
severity of damage to these vessels or
and cisplatin and other radiosensitizing
of the surgical staff are also developing
tissues and their clinical implications.
agents (page 78) with the aim of
methods that spare a woman’s nipple
helping people with large tumors while
during surgery. Other methods that
The NKI has played a pivotal role in
leaving as much function as possible.
aim to enhance the cosmetic result of
successfully developing the clinical
breast reconstruction include refining
application of photodynamic therapy.
Sparing healthy tissue is also important
lipofilling techniques, which involve
The patient is given an intravenous
in the case of bladder cancer, where
making use of the patient’s own fatty
photosensitizing chemical and then
removal of the bladder is sometimes
tissue. So far this looks promising.
red light from a laser is shone onto
the only chance of survival. The
the tumor. Only the combination of
department of urology has been in the
In reconstructive surgery that follows
the chemical and light kills cells, and
forefront of developing reconstructive
surgical removal of a tumor and
thus destroys the tumor while causing
surgery that aims to restore normal
surrounding tissues ‘free flaps’ are
minimal damage to surrounding
anatomy and sexual and urinary
frequently used. These flaps of muscle,
healthy tissue, leaving excellent
Clinical research
function and good cosmetic results.
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Another recent development is a
device that delivers light to tumors
Smeenk R.M., Verwaal V.J., Antonini N., Zoet-
Van Poelgeest, M.I., Van Seters, M., Van
that have infiltrated deep into tissue.
mulder F.A.N. Survival analysis of pseudomyxo-
Beurden, M., Kwappenberg, K.M., Heijmans-
These techniques are being tested in
ma peritonei patients treated by cytoreductive
Antonissen, C., Drijfhout, J.W., Melief, C.J.,
surgery and hyperthermic intraperitoneal
Kenter, G.G., Helmerhorst, T.J., Offringa, R.,
chemotherapy. Ann Surg, in press.
and Van der Burg, S.H. (2005) Detection of
nasopharyngeal cancer in collaboration
with universities in Jakarta and
Yogyakarta in Indonesia.
Robotic surgery
Reducing scarring is just one
advantage of the NKI’s latest piece
human papillomavirus (HPV) 16-specifi c CD4+
Van Rijk M.C., Peterse J.L., Nieweg O.E., Ol-
T-cell immunity in patients with persistent
denburg H.S.A., Rutgers E.J.Th., Kroon B.B.R.
HPV16-induced vulvar intraepithelial neoplasia
(2006). Additional axillary metastases and
in relation to clinical impact of imiquimod
stage migration in breast cancer patients with
treatment. Clin. Cancer Res. 11; 5273-5280.
micrometastatic and submicrometastatic sentinel lymph node disease. Cancer. 107:467-471.
Estourgie, S.H., Nieweg, O.E., Valdés Olmos,
R.A., Rutgers, E.J.Th., and Kroon, B.B.R.
Huitink, J.M., Buitelaar, D.R., and Schutte, P.F.
(2004). Lymphatic drainage patterns from the
of surgical technology — a remotely
(2006). Awake fibrecapnic intubation: a novel
breast. Ann. Surg. 239; 232-237.
controlled robotic surgeon. With
technique for intubation in head and neck can-
this da Vinci® Surgical System, the
cer patients with a difficult airway. Anaesthesia.
Noorda, E.M., Takkenberg, B., Vrouenraets,
61; 449-452.
B.C., Nieweg, O.E., Van Geel, A.N., Egger-
patient lies on a surgical table and
mont, A.M.M., Hart, A.A.M., and Kroon, B.B.R.
laparoscopy style instruments are
Van der Poel, H.G. (2006). Androgen receptor
(2004). Isolated limb perfusion prolongs the
inserted so that they reach the tumor.
and tgfbeta/smad signalling are mutually inhi-
limb recurrence-free interval after several
bitory in prostate cancer. Eur. Urol. 48;1051-
episodes of excisional surgery for locoregional
1058.
recurrent melanoma. Ann. Surg. Oncol. 11;
The surgeon moves to the other
side of the operating theatre and
491-499.
Smit L.H.M., Korse C.M., Hart A.A.M., Bonfrer
maneuvers the instruments using
J.M.G., Haanen J.B.A.G., Kerst J.M., Nieweg
Hopper, C., Kübler, A., Lewis, H., Tan, I.B.,
joysticks, watching what is happening
O.E., De Gast G.C. (2005). Normal values of
Putnam, G., and the Foscan 01 Study Group.
on a 3D computer display. This filters
serum S100-B predict prolonged survival for
(2004). MTHPC-mediated photodynamic
stage IV melanoma patients. Eur J Cancer.
therapy for early oral squamous cell carcinoma.
41:386-392.
Int. J. Cancer. 111; 138-146.
out any tremor in the surgeon’s hands,
and allows hand movements to be
Kroon B.K., Horenblas S., Lont A.P., Tanis P.J.,
Noorda, E.M., Vrouenraets, B.C., Nieweg,
scaled up to allow greater precision
Gallee M.P.W., Nieweg O.E. (2005). Penile
O.E., Van Coevorden, F., Van Slooten, G.W.,
than is possible manually. The patient
carcinoma patients benefit from immediate
and Kroon BBR. (2003). Isolated limb perfusion
resection of clinically occult lymph node me-
with TNF-alpha and melphalan for unresecta-
tastases. J Urol. 173: 816-9.
ble soft tissue sarcoma of the extremities.
benefits from an operation performed
with greater precision, minimizing the
chances of damaging surrounding
tissue. The NKI first used robot surgery
for prostate cancer, where removing
the tumor often damages nerves,
Cancer. 7; 1483-1490.
Jansen, M.C., Van Duijnhoven, F.H., Van Hillegersberg, R., Rijken, A., Van Coevorden, F., Van
Verwaal, V.J., Van Ruth, S., De Bree, E., Van
der Sijp, J., Prevoo, W., Van Gulik, T,M. (2005).
Slooten, G.W., Van Tinteren, H., Boot, H., and
Adverse effects of radiofrequency ablation of
Zoetmulder, F.A. (2003). Randomized trial of
liver tumours in the Netherlands. Br. J. Surg.
cytoreduction and hyperthermic intraperito-
92; 1248-1254.
neal chemotherapy versus systemic chemothe-
resulting in incontinence or impotence.
In the United States, surgeons use
robots to perform 30% per cent of
prostatectomies. Europe is likely to
catch up soon, and the NKI will be in
the forefront.
rapy and palliative surgery in patients with
Meij, V., Zuetenhorst, J.M., Van Hillegersberg,
peritoneal carcinomatosis of colorectal cancer.
R., Kroger, R., Prevoo, W., Van Coevorden,
J. Clin. Oncol. 21; 3737-3743.
F., and Taal, B.G. (2005). Local treatment in
unresectable hepatic metastases of carcinoid
tumors: Experiences with hepatic artery embolization and radiofrequency ablation. World J.
Surg. Oncol. 17; 75.
p78
|
Scientific brochure NKI
Radiotherapy
The NKI enjoys the privilege of being linked with one of the top radiotherapy departments in the world.
Not only does this have the latest commercially available equipment, but there is an integrated team of
technology experts, scientific researchers and healthcare providers who are constantly developing new ways
of making radiation treatments more effective. This means giving the right treatment to the right patient, and
then controlling the way that treatment is given.
Staff in the NKI’s radiotherapy
on tens of thousands of people
The problem with radiotherapy is
department take a four-pronged
worldwide. NKI has already made a
that this DNA damage will occur in
approach to making radiation
more than modest contribution.
any cell the radiation passes through,
treatment more effective at killing
whether cancerous or healthy. There is,
cancer cells while leaving healthy
This work builds on just over a century
however, some bias towards damaging
ones unscathed. First, is the search for
of innovation using radiation. Only a
tumor cells as these tend to be faster
chemical agents that, when combined
couple of years after German physicist
growing than normal cells, are often
with radiation, massively increase
Wilhelm Conrad Röntgen discovered
less equipped to deal with DNA
its efficacy. This involves trying to
X-rays in 1895 in Würzburg, Germany,
damage, and consequently are more
understand the underlying cellular
doctors started experimenting with
vulnerable to radiation injury.
biology. Secondly, they are developing
radiation to combat cancer, and by
new equipment that can deliver
the 1920s X-rays had become a major
Combination therapies
radiation to a tumor with greater
weapon in their armory. Although other
Department head Harry Bartelink’s
precision. Third they are looking to
types of treatment are now available,
involvement with combination therapy
increase the dose of radiation given to
radiotherapy is still the major therapy
goes back to 1992, when he and his
patients, and finally they are analyzing
for more than half of cancer patients.
co-workers published a pioneering
the genes in tumors to find profiles that
paper showing that adding the
will provide finely tuned, personalized
The underlying principle is simple. As
cytotoxic drug cisplatin to radiotherapy
therapy for future patients.
radiation penetrates cells it damages
dramatically improved the ability to
DNA — a cell’s store of genetic
control cancer. At the time the side-
The department’s overall strategy
information. While the damage is not
effects were so great that it did not
is to look for ways of improving the
so severe that the cell dies outright,
become a standard therapy, but since
outcome of therapy for patients with
its presence activates biochemical
then advances in supportive therapies
the most common tumors — those of
machinery that either halts cell growth
have turned cisplatin and radiotherapy
the breast, lung and prostate and, to a
and allows the DNA to be repaired, or,
into one of the most frequently used
lesser extent, the rectum. The rationale
if the damage is great enough, causes
therapeutic options for an increasing
is that even a modest improvement
the cell to commit suicide — to enter
number of solid tumors.
in these will have a dramatic effect
apoptosis.
Clinical research
|
p79
| Harry Bartelink, head of the division
The difference it makes is huge.
studies with mice, Verheij and van
radiation will still damage healthy
In anal cancer, for instance, giving
Blitterswijk have found that while
tissue. A team of almost 50 medical
chemotherapy alone cures no one,
treatment with ALP or radiation alone
physicists within the division is
while radiotherapy alone has the
has some effect, combining them
working on creating better ways of
possibility of curing around half of the
results in complete and long-lasting
determining exactly where a tumor is
patients. Combining the two leads to a
tumor regression. With the hospital
within the patient, and then directing
cure in around 8 out of 10 patients.
right next to the lab it is only a short
the radiation just to that region. This
step to move ALP into clinical trials.
would be a simple matter if the patient
Currently, clinician Marcel Verheij
and their internal organs never moved,
(page 64) and scientist Wim van
Immunologist Jannie Borst (see page
because you could measure where
Blitterswijk (page 57) are collaborating
32) is investigating the possibility of
the tumor was and then hit it perfectly
to take a close look at the synthetic
combining a protein called TRAIL with
— but in reality the patient is very
alkyl-lysophospholipids (ALPs) as a
radiation therapy. TRAIL latches onto
much alive and moving. Each breath,
combination therapy. These lipids are
and stimulates the so-called ‘death
heartbeat or movement of gas through
cytotoxic, that is they can kill cells.
receptors’ that trigger apoptosis, and
the intestines will alter the position
Unlike many other cytotoxic drugs,
once these receptors are stimulated
of internal organs, and thus shift the
however, ALPs do not attack a cell’s
the cell enters apoptosis and dies.
tumor.
DNA, but instead are taken up by
Laboratory studies showed that
rafts of lipids that float in the cell
TRAIL predominantly affects tumor
The conventional approach has been
membrane. Laboratory experiments
cells, and triggers apoptosis by a
to irradiate not only the zone where
have revealed much about how ALP
different pathway from that used
the tumor is predicted to be, but
then interferes with lipid metabolism
by DNA-damaging agents, making
also a sizeable margin around it. So
in the cell, throwing it into a state of
it particularly exciting as a new
even if the tumor moves, it will still
metabolic stress. The cell’s response to
therapeutic approach.
be irradiated. That approach causes
stress is to stop growing or to consider
considerable damage to surrounding
killing itself — add radiation-induced
Right on target
organs, and, depending on the
DNA damage to this and the cell is
While combining radiation with
position of the tumor, can lead to
very likely to undergo apoptosis. In
chemicals increases its punch, the
heart, lung, or rectal damage.
p80
|
Scientific brochure NKI
To avoid such damage, the NKI’s
A computer constantly matches this
as previously radiation frequently
medical physicists and computer
image with the pre-treatment high-
damaged the colon.
technologists have developed
resolution image, and drives the
The arrival of more careful targeting
equipment that can follow the tumor
platform on which the patient lies so
has triggered a global review of
at the same time as delivering the
that the tumor is held in the same
radiation doses, and many clinical
radiation. At the center of this advance
place even if the patient moves a little.
trials are looking at the effect of giving
is a technique called computer
In 2004, the NKI was the first institute
increasingly large doses. Until recently,
tomography-cone beam (CTCB)
in the world to use this technique
a dose of 60 gray was considered to be
guided radiotherapy. This involves
in clinical practice. By 2006 there
the maximum acceptable for patients
making a PET scan before starting
were about 20 machines using this
with lung cancer, but NKI clinicians are
therapy to determine the location of
technology around the world, with a
now considering doses of up to 100
the actively growing mass of cells,
10-fold increase expected each year.
gray. Initial results from trials at the
and carrying out CT scans that show
NKI show that high doses enable the
where this tumor is within the body.
Boosting the dose
cancer to be treated without having to
A computer then merges the two.
One consequence of this technology
resort to removing the whole organ,
When the patient lies on the platform
is that you can increase the dose of
which can make a huge difference to
to receive radiation, a third imaging
radiation, knowing that you are only
the patient’s life.
modality, also developed at the NKI,
hitting diseased cells. In the case of
comes into play. This generates a fairly
prostate cancer, this has significantly
Harry Bartelink has coordinated a
low-resolution image, but one that
reduced the number of patients
trial across Europe to determine the
can run while the radiation is given.
who experience rectal bleeding,
difference in outcome if patients with
Clinical research
|
p81
early breast cancer are given either the
from a particular intervention before
The bottom line
standard 50-gray dose or a 65-gray
exposing them to the inconvenience
Because of the headline-grabbing cost
dose. Early indications are that the
and risk of receiving it. By using
of new equipment, it is easy to make
higher dose gives a 50% reduction in
microarrays to search for specific
the false assumption that radiotherapy
local recurrence with only a minimal
gene mutations and patterns of gene
is expensive. But once installed, a
increase in side effects. Similarly,
activity, the NKI’s researchers are
machine runs for years, so that less
fellow researcher Joos Lebesque has
beginning to build a picture of the
than 5% of the total expenditure on an
coordinated a Dutch trial in prostate
genetic profiles of those who respond
individual patient’s care is down to the
cancer showing that an increase in the
well. The genes most likely to serve
radiotherapy. While the chemotherapy
radiation dose to the tumor from 68 to
as useful markers are those involved
elements may cost €100,000, outlay on
78 gray resulted in a 30% reduction of
in controlling cell growth and DNA
radiotherapy can be less than €20,000.
signs of recurrence.
repair. Currently, the Radiotherapy
department is conducting a trial
This means that radiotherapy is not
Prognosis profiling
that already includes more than 400
only clinically effective, it is also cost
Other trials are being carried out to
patients, comparing how people with
efficient, and therefore a valuable
determine whether there is a way of
different genetic profiles respond to
technology when well used. The work
predicting who is most likely to benefit
two different levels of radiotherapy.
at the NKI is increasing its impact.
Bijker N., Meijnen P., Peterse J.L., Bogaerts
lung tumour motion in anatomical and functio-
Ruiter G.A., Zerp S.F., Bartelink H., Van Blitters-
J., Van Hoorebeeck I., Julien J.P., Gennaro M.,
nal scans. Phys Med Biol. 50: 1569-1583.
wijk WJ, Verheij M. (1999). Alkyl-lysophosp-
SELECTED PUBLICATIONS
Rouanet P., Avril A., Fentiman I.S., Bartelink H.,
holipids activate the SAPK/JNK pathway and
Rutgers E.J. (2006). EORTC Breast Breast-
Sonke J.J., Zijp L., Remeijer P., van Herk M.
enhance radiation-induced apoptosis. Cancer
conserving treatment with or without radio-
(2005). Respiratory correlated cone beam CT.
Res 59: 2457-2463.
therapy in ductal carcinoma-in-situ: ten-year
Med Phys. 32: 1176-1186.
results of European Organisation for Research
Verheij M., Bose R., Lin X.H., Yao B., Jarvis
and Treatment of Cancer randomized phase
Smitsmans M.H., De Bois J., Sonke J.J.,
W.D., Grant S., Birrer M.J., Szabo E., Zon L.I.,
III trial 10853 - a study by the EORTC Breast
Betgen A., Zijp L.J., Jaffray D.A., Lebesque
Kyriakis J.M., Haimovitz - Friedman A., Fuks
Cancer Cooperative Group and EORTC Radio-
J.V., Van Herk M. (2005). Automatic prostate
Z., Kolesnick R.N. (1996). Requirement for
therapy Group. Cancer Cooperative Group.
localization on cone-beam CT scans for high
ceramide-initiated SAPK/JNK signalling in
J Clin Oncol. 24(21):3381-3387
precision imageguided radiotherapy. Int J
stress-induced apoptosis. Nature. 380: 75-79.
Radiat Oncol Biol Phys. 63: 975-984.
Peeters S.T.H., Heemsbergen W.D., Koper
Schaake C., Van der Bogaert W., Dalesio O.,
P.C.M., Van Putten W.L.J., Slot A., Dielwart
Bartelink H., Schellens J.H.M., Verheij M.
Festen J., Hoogenhout J., Van Houtte P., Kirk-
M.F.H., Bonfrer J.M.G., Incrocci L., Lebesque
(2002). The combined use of radiotherapy
patrick A., Koolen M., Maat B., Nijs A., Renaud
J.V. (2006). Dose-response in radiotherapy
and chemotherapy in the treatment of solid
A., Rodrigus P., Schuster-Uitterhoeve L., Sculier
for localized prostate cancer: results of the
tumours. Eur J Cancer. 38 : 216-222.
J.P., Van Zandwijk N., Bartelink H. (1992).
Effects of concomitant cisplatin and radio­
Dutch multicenter randomized phase III trial
comparing 68 Gy of radiotherapy with 78
Bartelink H., Horiot J.C., Poortmans P., Struik-
therapy on inoperable non-small-cell lung
Gy. J Clin Oncol. 24: 1990-1996.
mans H., Van den Bogaert W., Barillot I., Four-
cancer. N Eng J Med. 326: 524-530.
quet A., Borger J., Jager J., Hoogenraad W.,
Wolthaus J.W., Van Herk M., Muller S.H., Bel-
Collette L., Pierart M. (2001). Recurrence rates
derbos J.S., Lebesque J.V., De Bois J.A., Rossi
after treatment of breast cancer with standard
M.M., Damen E.M. ( 2005). Fusion of respira-
radiotherapy with or without additional
tion-correlated PET and CT scans: correlated
radiation. N Engl J Med. 345: 1378-1387.
p82
|
Scientific brochure NKI
Diagnostic Oncology
The Division of Diagnostic Oncology comprises the Departments of Radiology, Nuclear Medicine, Pathology,
Clinical Chemistry and the Family Cancer Clinic. Both clinical work and research in this division are carried out
by several independent groups with wide-ranging expertise but with a common focus on cancer diagnosis.
Each group has close ties to other departments at the NKI and is developing or applying different techniques
to the goal of improving a physician’s ability to determine exactly the type and extent of growth of each
tumor and to plan the most effective treatment.
Pathology goes molecular
to diagnose tumors of the breast,
and together with the Department
The Pathology Department
head and neck, and lungs.
of Epidemiology contributes data
performs both routine diagnosis
to several national and international
and translational research on human
The rapid expansion of genetic tests
research projects, such as GEO-
tissues removed at surgery with the
for cancer-related markers has led
HEBON (gene–environment
patient’s consent. Over the past 20
to an increasing demand for testing
interactions in hereditary breast and
to 30 years, the department has
and counseling for affected families,
ovarian cancer). This nation-wide
amassed a considerable bank of
particularly in relation to cancer of
study is looking at how genetic and
frozen tumors and normal tissues,
the breast, ovary, and lower gut. If a
other factors, such as lifestyle, diet,
which supports research across all
person is diagnosed with a form of
and hormonal changes such as during
departments of the NKI. Using the
cancer linked to a gene mutation, then
breast feeding, may alter the risk of
latest genetic techniques, DNA and
other family members can be screened
breast or ovarian cancer in people with
RNA samples isolated from the tumors
to see if they too carry the mutation.
a family history of these diseases.
are being investigated to expand our
Its presence may indicate that they
understanding of each type of cancer.
or their children are at high risk of
The Pathology Department has
developing the disease. In the case
pioneered the use of DNA microarray
The output of the division has
of breast cancer, for example, women
technology for detecting patterns of
grown as new techniques have been
carrying high-risk mutations in the
gene activity in a patient’s tumor that
introduced. In 1983, the molecular
BRCA1 or BRCA2 genes might wish to
can be used to predict the course
pathology group was founded, and
consider preventive mastectomy.
of the disease. Areas of prediction
began to use the then novel technique
not only include the likelihood of
of PCR to detect mutations in cancer-
To meet the growing demand for
disease spreading to other parts of
associated genes and chromosome
these tests, the NKI began the Family
the body, but also the response to
rearrangements in lymphoma. The
Cancer Clinic in 1995. This administers
different kinds of treatment. Analyzing
group continues to use a wide range
both tests and genetic counseling and
the results and making accurate and
of molecular techniques, particularly
has served more than 2000 families.
reliable predictions is a complex and
in hematology for the diagnosis of
The clinic also serves as a conduit for
specialized task that requires close
leukaemia and lymphoma, as well as
recruiting volunteers for research,
collaboration with members of the
Clinical research
|
p83
| Marc van de Vijver, head of the division
Bioinformatics Unit. So far, most
monitoring using radiological imaging,
graphy (PET) scanning after injection of
progress has been made in applying
which provides important information
radioactively labeled compounds such
this technology to breast cancer,
without invasive surgery. A special unit
as glucose or estrogen, for example,
with the identification of a 70-gene
within the Department of Radiology,
enables ‘functional imaging’, which
‘signature’ that predicts the likelihood
the Diagnostic Imaging Laboratory,
shows which area of a tumor is most
of metastasis. The department has
is devoted to the pursuit of new
active. Radiological imaging using
initiated a collaborative study with
imaging techniques, image processing
tracer compounds injected into breast
other hospitals in the Netherlands
and analysis. In particular, the unit
tumors is also proving extremely useful
(the RASTER study), to determine
is researching the use of magnetic
to guide surgery for those tumors that
the feasibility of introducing the test
resonance imaging (MRI) for different
have already invaded surrounding
into routine clinical practice. Similar
applications, such as measuring the
tissue.
research is ongoing for the diagnosis
local spread of breast tumors before
and prognosis of lymphoma, although
surgery, and monitoring the effect of
Computer tomography (CT) scans, on
this has yet to be translated into a
chemotherapy on tumor size. The unit
the other hand, indicate the impact
diagnostic test.
is also assessing whether computer-
of radiotherapy or chemotherapy by
aided enhancement of MRI images can
showing whether or not the tumor is
The Bioinformatics Unit also analyses
improve the accuracy of breast cancer
shrinking. Such information can spare
the data from animal experiments
diagnosis in women who are at a
months of treatment with the wrong
aimed at identifying new genes
greater risk of developing the disease.
drugs if a patient’s tumor is failing to
involved in cancer and understanding
respond and is instead continuing to
how they interact. These in turn could
The Department of Nuclear Medicine
grow. It enables a physician to switch
serve as targets for new drugs in
focuses on the use of imaging tech-
the patient rapidly on to different
future.
niques that involve the detection of
drugs.
radioactive substances injected in or
Diagnostic imaging
around tumors. This research aims to
Signs from biological fluids
Two departments within the Division
improve diagnosis, detect local spread
The Clinical Chemistry Department is
of Diagnostic Oncology are at the
of disease, monitor treatment and
involved in both pre-clinical research
forefront of cancer diagnosis and
guide surgery. Positron emission tomo-
on animal models and clinical
p84
|
Scientific brochure NKI
investigations on patients. Using
leptomeningeal metastasis. This occurs
tumors in the brain. The Department of
a wide variety of the most up-to-
in around one in twenty patients,
Clinical Chemistry is carrying out tests
date techniques, the department is
and can be devastating if it is not
in animals of new inhibitor drugs that
analyzing mostly fluids such as blood
detected and treated immediately.
block the drug transporters and allow
and cerebrospinal fluid for research
The problem is that current diagnostic
anticancer drugs such as topotecan to
aimed at improving diagnosis and
tests fail to detect the presence of
enter the brain, for the treatment of
treatment. For stomach cancer, for
the brain tumor in a high proportion
brain tumors and brain metastases.
example, the Clinical Chemistry
of cases. The department is exploring
Department is assessing blood tests
the possibility that proteomics — the
The Division of Diagnostic Oncology
for marker proteins that are produced
search for patterns of multiple proteins
is at the hub of interactions between
by the tumor cells and enter the blood.
in the cerebrospinal fluid using mass
many clinical departments of the
The concentration of these proteins
spectroscopic analysis — will give a
Antoni van Leeuwenhoek Hospital and
in the blood appears to predict how
more accurate early diagnosis.
research departments at the NKI. Its
quickly the tumor will grow and
activities aim to improve the diagnosis
spread, and hence the patient’s chance
As with the lining of the gut drug
and treatment of a number of types of
of survival.
transporters in the lining of the brain’s
cancer, using the latest technologies
blood vessels pump therapeutic drugs
and setting new standards for what can
Cerebrospinal fluid from patients with
out of the brain as fast as they enter.
be achieved in future.
breast cancer can yield information on
A project with the Department of
whether the disease has spread early
Pharmacology is focused on improving
to the brain, a condition known as
the access of anticancer drugs to
Clinical research
|
p85
SELECTED PUBLICATIONS
Chang H.Y., Nuyten D.S., Sneddon J.B., Hastie
benefit of computerised analysis. Eur J Cancer.
Glas A.M., Kersten M.J., Delahaye L.J., Wit-
T., Tibshirani R., Sorlie T., Dai H., He Y.D., Van
41: 1393-1401.
teveen A.T., Kibbelaar R.E., Velds A., Wessels
’t Veer L.J., Bartelink H., Van de Rijn M., Brown
L.F., Joosten P., Kerkhoven R.M., Bernards R.,
P.O., Van De Vijver M.J. (2005). Robustness,
Hannemann J., Oosterkamp H.M., Bosch C.A.,
Van Krieken J.H., Kluin P.M., Van ‘t Veer L.J.,
scalability, and integration of a wound-res-
Velds A., Wessels L.F., Loo C., Rutgers E.J.,
De Jong D. (2004). Gene expression profi-
ponse gene expression signature in predicting
Rodenhuis S., Van de Vijver M.J. (2005).
ling in Follicular Lymphoma to assess clinical
breast cancer survival. Proc Natl Acad Sci USA.
Changes in gene expression associated with
aggressiveness and to guide the choice of
102: 3738-3743
response to neoadjuvant chemotherapy in
treatment. Blood. 105: 301-307.
breast cancer. J Clin Oncol. 23: 3331-3342.
De Jong D. Molecular pathogenesis of
Kartachova M., Haas R.L., Valdes Olmos R.A.,
follicular lymphoma: a cross talk of genetic
Van Beers E.H., Van Welsem T., Wessels L.F., Li
Hoebers F.J., van Zandwijk N., Verheij M.
and immunologic factors. (2005). J Clin Oncol.
Y., Oldenburg R.A., Devilee P., Cornelisse C.J.,
(2004) In vivo imaging of apoptosis by 99mTc-
23: 6358-6363. Review.
Verhoef S., Hogervorst F.B., Van ’t Veer L.J.,
Annexin V scintigraphy: visual analysis in rela-
Nederlof P.M. (2005). Comparative genomic
tion to treatment response. Radiother Oncol.
Deurloo E.E., Muller S.H., Peterse J.L., Besnard
hybridization profi les in human BRCA1 and
72: 333-339.
A.P., Gilhuijs K.G.A. (2005). Clinically and mam-
BRCA2 breast tumors highlight differential
mographically occult breast lesions on MR
sets of genomic aberrations. Cancer Res. 65:
Kemper E.M., Verheij M., Boogerd W., Beijnen
images: potential effect of computerized
822-827.
J.H., van Tellingen O. (2004). Improved
assessment on clinical reading. Radiology.
234: 693-701.
penetration of docetaxel into the brain by coWeigelt B., Hu Z., He X., Livasy C., Carey L.A.,
administration of inhibitors of P-glycoprotein.
Ewend M.G., Glas A.M., Perou C.M., Van
Eur J Cancer. 40: 1269-1274.
Deurloo E.E., Peterse J.L., Rutgers E.J.,
’t Veer L.J. (2005). Molecular portraits and
Besnard A.P., Muller S.H., Gilhuijs K.G. (2005).
70-gene prognosis signature are preserved
Additional breast lesions in patients eligible for
throughout the metastatic process of breast
breastconserving therapy by MRI: impact
cancer. Cancer Res. 65: 9155-9158.
on preoperative management and potential
p86
|
Scientific brochure NKI
Facilities
Modern day biomedical research depends on expensive equipment and on techniques that can take years
of practice to do well. Individual researchers need to use a wide range of techniques in their work, however,
and it is impossible for anyone to master them all or be given the money to buy all the equipment they are
likely to need. The NKI has resolved this problem and used its funding in the most efficient way by creating
dedicated centralized technology facilities that serve the whole institute. All NKI scientists have direct access
to these facilities. Periodic review of the facilities ensures that they maintain a high standard.
Animal facility
range from weighing and routine sampling to performing
Much of the NKI’s research is carried out on cultured
complex operations and detailed tissue analyses at the end
mammalian cells and tissues, but cells act very differently in
of the experiment. They also help create the transgenic
culture to the way they behave in the body. Consequently,
and knockout mice that are now powerful tools in genetic
cancer research can only progress by using animals for
research. The animal facility has two pathologists and five
some experiments. Hundreds of strains of mice have been
technicians who sample 25,000 to 30,000 tissues per year,
bred with particular genetic traits that make them ideal for
a workload equivalent to that of a pathology laboratory in a
research into cancer genetics as well as efficient models for
medium-sized hospital.
testing new treatments.
A new development is the ‘mouse clinic’. This is
At any one time the NKI houses approximately 25,000 mice,
intended to house mice with mutations that influence
from almost 700 specially bred strains. Some mice are used
their responses to cancer and cancer therapy. The facility
for experiments, while others are held for breeding.
will be equipped with radiotherapy equipment and
advanced imaging systems, enabling scientists to treat
The animals’ living conditions are carefully controlled and the
and study the mice in ways comparable to treating
welfare of every mouse is monitored daily. A system of tags
humans in a clinic.
and barcodes combined with web-based communication
enables staff to alert a researcher immediately if an issue
The animal facility also houses zebrafish, which are
arises with an individual animal.
increasingly being used in genetic studies, and small
Along with day-to-day care of the animals, animal facility
colonies of the frog Xenopus, which has long-been used in
staff help researchers carry out their experiments. This can
developmental research.
Facilities
|
p87
Microarray facility
These include automation of the ‘hybridizing’ stage, when
High-throughput technologies for studying genes and gene
the sample to be tested is mixed with the microarray, and
expression are essential in today’s biomedical research, but
computer-aided scanners that read the results. The scanners
present huge challenges to the individual researcher. One of
are linked directly to a web-based database, so researchers
these technologies, DNA microarray, involves spotting many
can call up their data any time they need, even if they are
thousands of gene fragments onto a microscope slide which
away from the lab.
are then used to screen samples for genes that are being
expressed.
Any scientist wanting to use the facility is given basic
training in all the stages of the work, ensuring that they fully
The NKI’s microarray facility was set up in 1998, right at
understand the process. If an experiment requires a large
the start of this particular technological revolution, with
number of microarrays, the staff will train the researchers
substantial financial support from the Dutch Cancer Society.
to carry out the experiment themselves, but if it needs only
Rather than using a commercial platform, which is expensive
a few, the microarrays are processed by facility staff. This
and tends to be inflexible, staff at the NKI’s facility have
means that everyone gets high-quality data.
developed their own highly versatile system for printing
microarrays. Printing arrays in-house saves money, allowing
Microscopy facility
NKI researchers to carry out projects that are usually only
The hospital attached to the NKI is named after Antoni van
feasible for a large pharmaceutical company.
Leeuwenhoek, the 17th-century Dutch scientific pioneer who
was one of the first people to use microscopes. It is fitting,
The facility has automated many of the stages required to
then, that the NKI has an impressive microscopy facility, with
carry out a microarray experiment and analyze the results.
six digital microscopes, most of them capable of confocal
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microscopy. The facility trains researchers to use these
a day for complex cellular phenotypes. In combination with
complex instruments and maintains them.
robotics and followed by computer-assisted automated
image analysis, large-scale screens that test thousands of
Confocal microscopes produce amazingly high-definition
genes can be performed to look for genes that affect protein
images at high magnifications and have revolutionized
localization, chromosome separation, receptor activation, or
microscopy. By directing laser light through a series of lenses,
even the movement and migration of living cells.
mirrors, and diaphragms, confocal microscopes take a thin
‘optical slice’ through the sample. They can also make a
Flow Cytometry Facility
series of optical slices within an object, feeding the data to a
Flow cytometry plays an important role in many of the
computer to construct a 3D image.
research lines of the NKI.
A flow cytometer is able to measure the size and molecular
The six systems are tailored to different needs, from simple
characteristics of individual cells; thousands of cells can
fluorescence imaging of fixed cells and tissues to 3D analysis
be examined per second. Fluorescent labels mark specific
of living cells and organs. For instance, researchers at the
components on the cell surface or can be coupled to
NKI have started using confocal microscopes to look at the
particles inside the cell, thus elucidating their functional
skin of living mice. By bringing the mouse back on successive
characteristics.
days, they can follow the growth, development and
movement of cells within individual tumors. A simpler digital
The high-speed sorters have the ability to physically sort cells
microscope is used for monitoring changes in cells growing
or particles of interest. Both our sorters can make sorting
in multi-well plates. Aided by a robot, it can take images of
decisions at a speed of 20,000 cells per second, creating
cells at set time intervals over a period of a few days.
very pure cell populations that can be used for further study.
NKI researchers can also make use of the electron micros-
The Flow Cytometry Facility accommodates four bench-top
copy facilities present at the institute. Dedicated staff will
analyzers and two multicolor high-speed sorters, each of
operate the microscope and deliver high quality images. The
which can detect (depending on the number of detectors)
latest development in electron microscopy, 3D reconstruction
three to nine different fluorescent labels.
of protein complexes, will be introduced soon at the NKI.
The facility provides instrumentation and technical assistance
Robotics and Screening Center
for performing flow cytometric analysis and sorting. Every
As researchers build ever-larger collections of agents that
researcher who is interested in flow cytometric analysis is
perturb the expression of particular genes, they need tech-
offered an instructional session on flow cytometry basics and
nology that can rapidly perform the thousands of individual
special applications, and on the operation of the analyzers.
experiments required to test the effects of disrupting gene
expression in cells. To do this efficiently, the NKI has built a
All in all, this facility enables the researchers to find the
highly flexible, high-throughput automated facility that in-
cellular equivalent of a needle in a haystack, such as a single
cludes an automated liquid-handling system together with a
stem cell hidden among 100,000 other cells.
robotic arm that can also access an automated tissue culture
system, plate-washing station and plate readers. This robotic
Tissue and Serum Bank
set-up runs cell-based screens at a throughput of more than
Over the past 20 years the Antoni van Leeuwenhoek Hospital
10,000 samples per day. The facility is designed to accom-
has collected and stored tumor samples from patients. While
modate several different experimental set-ups to support the
identities are kept confidential, these samples can be linked
many different research lines pursued in the institute, ranging
to medical records. This means that researchers can study
from the construction of large collections of genomic tools,
the precise genetic nature of the tumor that a person had a
to small-molecule drug screens and yeast genetics.
decade or more ago, link it to the treatment they received,
and compare this information with the treatment outcome.
The robotic system includes an automated fluorescence
This tissue bank is a phenomenally valuable asset in the fight
confocal microscope that can analyze thousands of samples
against cancer.
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Technology Transfer
initiatives. The Biometrics Department serves as the data
The Technology Transfer Office (TTO) supports the NKI-
center of the institute and provides the infrastructure for
AVL by managing the protection and exploitation of
clinical and fundamental research on bio-statistical support,
intellectual property created by the institute’s scientists. This
centralized patient data collection and documentation, data
helps to advance the institute’s mission to improve cancer
processing and coordinated administration and monitoring
diagnosis and treatment for the benefit of cancer patients
of clinical trials. The statisticians and data managers collabo-
by transferring basic research discoveries to academia for
rate in clinical and research projects both within the institute
further research and to the marketplace for commercial
and for national and international multicenter studies. Sup-
development and broad implementation.
port for central administration, patient registration, and data
The TTO is organized to identify and protect the institute’s
collection of clinical trials is provided through the Trial Office
intellectual property without impeding scientific research,
of the department. The department also maintains a Tumor
and is responsible for patenting, licensing, consultancy, and
Register database containing information on patients with
scientific collaborations and research agreements. The TTO is
benign tumors, pre-malignant, and malignant tumors seen in
the first point of contact for licensing requests and research
the Institute since 1977. This database is a valuable resource
collaborations. When commercial partners are required in EU
for research and currently contains more than 120,000 regi-
or other research consortia, the TTO assists with consortium
strations.
agreements and project management.
Other facilities
Biometrics Department
Other NKI facilities include the central ICT department that
The NKI takes part in many clinical trials and other patient
provides general IT support for all research groups, as well
related clinical research projects; some of which are NKI
as specific ‘site-wide’ services (such as email facilities) for all
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personnel. Tasks include management of routers, Ethernet
In addition to departmental laboratories licensed for
switches, file servers, job-and-database servers, configuration
radioactive work, which are present on nearly each floor of
of network software on PCs and Apple Macintosh computers
the research building, there is a central radiochemistry facility
of end users and, if necessary, the development and
available for specific and general experimental use. The staff
maintenance of custom server and/or client-side software.
of the Radionuclide Laboratory offer help and advice on all
The Central Cancer Library serves the research, clinical,
aspects of radioactive work. The department is equipped
nursing, and paramedical departments of the institute.
with up-to-date gamma and scintillation counters, gamma
In recent years site licenses for a wide range of electronic
analyzers and HPLC apparatus. There are also separate
publications and services have been obtained, giving full-
facilities for animal experiments with radioactive tracers.
text, electronic access to key publications over the intranet.
Radiation safely courses are regularly organized for students
and scientists.
Synthetic peptides find wide use within the NKI. Peptides
have been synthesized on-site since 1988, making it possible
The Sequence Facility offers a service for DNA sequence
to obtain peptides with specific modifications in any quantity.
and fragment analyses to the research departments and the
The facility makes use of two synthesizers. One monitors
clinical DNA-diagnostics laboratory.
the complete reaction process while the other machine
can synthesize up to 60 peptides simultaneously. Peptides
The institute also has a central cryogenic storage facility, a
up to 40 amino acids in length can be synthesized.
glassware kitchen, an electro- and technical workshop and an
The quality and identity of all peptides is monitored by
audiovisual department.
HPLC or LCMS and peptides can be purified by
preparative HPLC to meet the highest-quality standards.
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Career and training
Faculty
website), which aims to make the institute an excellent
The NKI provides a unique and challenging environment
place to work for postdocs and to help them develop their
with state-of-the-art facilities for young and established
careers. One of its main tasks is to organize the annual
researchers. Although the NKI is an independent research
NKI-AVL postdoc retreat. Topics typically discussed during
institute, many staff scientist have professorships at Dutch
the retreat are: how to succeed as a scientist in academia or
universities.
outside; communication skills; setting personal expectations;
On a regular base we seek assistant professors. These AvL-
obtaining and negotiating a promotion; responsibilities
fellows are given the opportunity to start their own group,
beyond the laboratory; laboratory management; mentoring
building on their proven excellence as a postdoctoral fellow
and being mentored; project management; understanding
and having access to the NKI’s full range of facilities, and
the (inter)national funding process and getting funded;
financial support in the initial phase to appoint personnel.
getting published; technology transfer; and setting up
collaborations.
Established researchers and candidates for an AvL-fellowship
are invited to contact the scientific director.
Any postdoctoral fellows interested at training at the NKI are
invited to contact one of the group leaders or look at our
Postdoctoral fellows
website.
About 70 postdoctoral fellows are employed in the different
research groups at the NKI. The institute helps postdocs to
Graduate students
obtain their own funding and reach a more independent
Graduate students do research in a challenging environment
position that prepares them for a faculty position.
while following a PhD program offered by the Oncology
The NKI has a very active postdoc committee (see the NKI
Graduate School Amsterdam (OOA). This joint program
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between the oncology researchers from the NKI, the Free
the institute provided they have obtained a Bachelor’s
University Amsterdam and the University of Amsterdam
degree with a major in Biology, Medical Biology, Medicine,
offers detailed graduate courses. OOA graduate students
Pharmacy, Chemistry, or a closely related subject. In addition,
enjoy frequent opportunities to interact, including a three-
the Division of Psychosocial Research and Epidemiology
day annual retreat, where students present their work to
takes students with relevant theoretical backgrounds.
fellow students. Each graduate student has a PhD committee
Students with a background in informatics and/or physics
consisting of NKI faculty members who oversee the quality
can also join the research facilities or the Division of
and progress of the project, and which discusses the
Radiotherapy. English language is the teaching medium in
performance of both the supervisor and the student.
daily practice. Every Masters student who does a project
in the institute in the area of Biology/Medicine/Chemistry
Graduate students are welcome to check for positions
for more than 4 months is obliged to pursue a course and
that we advertise regularly on our website, and to contact
examination in experimental oncology.
directly either our group leaders or the dean of the graduate
students Prof. Dr. Titia Sixma (email: [email protected]).
Masters students interested in rotation projects are invited
to make direct contact with a research group at the NKI, or
Masters students
contact the dean of Master Education (onderwijscoördinator),
Masters students also have the opportunity to take part in
Prof. Dr. Jannie Borst (email [email protected], university
cutting-edge research and to enjoy its associated excitement
students) or Dr. John Collard (email: [email protected], HLO
and challenges. The NKI-AVL is happy to receive Masters
students). Information about clinical training is supplied by
students from universities and HLO schools for rotation
the heads of the clinical divisions or by the coordinator for
projects. University students may undertake projects in
medical students, Prof. Dr. Fons Balm (email: [email protected]).
Career and training
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Contact
Contact
The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital
Plesmanlaan 121
1066 CX Amsterdam
The Netherlands
www.nki.nl
General enquiries
Telephone: +31 (0)20 512 9111
Fax: +31 (0)20 617 2625
Public Relations
Telephone: +31 (0)20 512 2850
Email: pr&[email protected]
Technology Transfer
Telephone: +31 (0)20 512 1999
Email: [email protected]
Personnel Department
Telephone: +31 (0)20 512 2915
Email: [email protected]
Financial Department
Telephone: +31 (0)20 512 2367
Email: [email protected]
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Colophon
Text
Dr Julie Clayton and Dr Pete Moore
Editing
Eleanor Lawrence
Design
Room for ID’s
Photography
Jan Schot
Printing
Drukmotief
Coordination
Frederique Melman
Henri van Luenen
Copyright
The Netherlands Cancer Institute, 2006