Scientific Annual Report 2013 Scientific Annual Report 2013

249 Pages·2014·10.36 MB·English

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Scientific Annual Report 2013

Netherlands Cancer Institute
Plesmanlaan 121
1066 CX Amsterdam
The Netherlands
www.nki.nl
Scientific Annual Report 2013
Introduction
I am pleased to present our Scientific Annual Report for 2013, a special edition that
Director of Research
marks our 100th year anniversary. Hundred years in which we have combined our
René Medema
efforts in research, treatment and care, to bring the best possible treatments to
our patients. This report showcases the scientific achievements of the Netherlands
Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL) in 2013. More background
information on our research programs and principle investigators can be found on our
website (www.nki.nl) or in our Scientific Brochure that is available for download on our
website.
The Antoni van Leeuwenhoek is a Comprehensive Cancer Center, combining a dedicated
cancer hospital and cancer research institute in a single organization. This combination
was established in 1913 and therefore we celebrated our 100th anniversary on
October 10th 2013. Our hospital currently has 180 beds, an outpatient clinic and a
large radiotherapy department and an extensive infrastructure for clinical research
that includes clinical data management, a large array of diagnostic facilities, and a
pharmacy with a production unit for experimental drugs and clinical grade biologicals.
Over the years the hospital has built a large repository of patient data and a large
collection of tumor and normal tissues. Clinical research spans across medical, surgical
and diagnostic oncology, radiotherapy, pharmacology, epidemiology and psychosocial
oncology and research into cost effectiveness of health care and efficiency of planning
and organization. Our hospital has seen steady growth in patient numbers over the
last years, with an average annual growth of 7%. To facilitate this growth, construction
is underway to increase the capacity of our outpatient clinic, operating rooms and
intensive care. Construction is planned to be completed in 2015 and will give room to
4 additional operating rooms and the necessary expansion of our intensive care unit.
In 2013, a new office building was completed that provides office space for all 135
members of our medical staff and their support staff. In January 2013 the radiotherapy
satellite in Hoofddorp (Spaarne Ziekenhuis) was opened and this is now operational
at full capacity. Also, preparations to establish a cancer hospital in Utrecht in a joint
venture with the University Medical Center (UMC) Utrecht have seen continued progress
in 2013. In Utrecht, a separate financial unit was created that encompasses most of
the oncological activities that take place within the UMC Utrecht. The joint venture
AVL-Amsterdam/AVL-Utrecht that is to be formed in 2015, aims to improve the quality
of cancer care, and will bring together a large critical mass in areas such as radiology,
radiotherapy and personalized cancer treatment. This will facilitate further innovations
in minimally invasive and non-invasive interventions as well as in tailored therapies,
areas that hold great promise for further improvements in cancer care. At the end
of 2013, the neighboring Slotervaart Hospital became part of the MC group (www.
mcgroup.nl). As part of this acquisition, the Antoni van Leeuwenhoek purchased the
hospital pharmacy and its associated research activities. In addition, neuro-oncology
will transfer to the Antoni van Leeuwenhoek. As a consequence, the Netherlands
Cancer Institute will expand its research program to encompass a new division of
Pharmacological Oncology, an important addition to our drug development program.
This program was further strengthened by the formation of the Cancer Drug Discovery
Initiative (CDDI) in 2013. The CDDI aims to develop new bioactive compounds for drug
targets identified in the NKI for (pre-) clinical validation. Finally, we aim to establish a
proton therapy center next to the Antoni van Leeuwenhoek, in a joint venture with the
Academic Medical Center and the Free University Medical Center and as a collaborative
effort with the UMC Utrecht and the National Children’s Oncology Center (NKOC). The
proton therapy center is expected to be operational in 2016 and will treat the patients
of the NKOC requiring moderate to high irradiation, as well as a range of inoperable
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tumors in adult patients surrounded by radiation-sensitive healthy tissue.
We concluded 2013 with a profit for the hospital, but the growth in numbers of patients
continues to put pressure on the workload per employee and per square meter. An
important challenge for our institute is to accommodate this growth in order to provide
the required clinical care for the growing numbers of cancer patients. Yet, this growth
must not compromise the high level of quality care that we strive to provide.
Unfortunately, while we continue to see a steady growth in the number of patients that
visit our hospital, the increase in our research budget has been very limited. This is
in large part due to the fact that funding options at the Netherlands Organization for
Scientific Research have seen a steady reduction under previous governments. As a
result, it is becoming increasingly difficult for bottom-up research initiatives to secure
funding, despite the fact that project proposals from the Netherlands Cancer Institute
continue to rank well above the national average in funding percentile. On top of this
shrinkage in external funding sources, emphasis in our national funding schemes has
undergone a dramatic shift towards short-term valorization of scientific research.
While our institute performs very well in such projects, and serves as a role model for
clinical translation, we do foresee a serious bottleneck arise in the near future. The cuts
we are facing now in fundamental cancer research will become rate-limiting for further
innovation and progress in a few years from now.
TABLE 1
CORE RESEARCH FUNDING THE NETHERLANDS CANCER INSTITUTE - ANTONI VAN LEEUWENHOEK HOSPITAL
BY THE DUTCH CANCER SOCIETY AND THE MINISTRY OF HEALTH, WELFARE AND SPORT IN THE PERIOD
2003 – 2012 IN MILLION EUROS.
25 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
20
15
10
5
0
DUTCH CANCER SOCIETY
MINISTRY OF HEALTH, WELFARE & SPORT*
TOTAL
* EXCLUDED ARE THE REIMBURSEMENT FOR INTEREST
AND DEPRECIATION OF BUILDINGS
Fortunately, the Dutch Cancer Society (KWF) has increased the financial support for our
research by allowing a gradual increase of the core grant given by the Dutch Cancer
Society to the Netherlands Cancer Institute. This funding becomes ever more important
for our success, because the continuity of our research activities critically depends
on a healthy ratio between core funding and external funding. That ratio has steadily
shifted towards external grants, donations and short-term research agreements with
third parties. Currently 65% of our total research budget comes from such sources,
making it difficult to maintain sufficient manpower in the underlying infrastructure that
is increasingly important to deal with the complexity of present-day cancer research.
The dependence of our research activities on high-throughput screening facilities, next
generation sequencing, proteomics, bio-informatics, analysis and maintenance of large
datasets requires steady investments that cannot be easily accommodated by external
grants. In an attempt to deal with this problem, we, together with the Dutch Cancer
Society, have established a foundation (Antoni van Leeuwenhoek Foundation) that will
raise funds for the Netherlands Cancer Institute. In 2013, this foundation launched a
national campaign to raise funds and increase awareness for individualized treatment of
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cancer. The campaign received a lot of attention from national media and several third
parties organized fundraising activities for the campaign. The collected funds will be
used for our research on personalized treatment of cancer.
HIGHLIGHTS
It is impossible to provide a complete overview of the total impact generated by our
Institute in 2013 in this introduction. Many of the highlights can be found in the reports
of the individual group leaders further on in this annual report or on our website. I have
chosen to mention just a few highlights here, amongst which several new therapeutic
strategies that were validated in pre-clinical models, some of which will enter clinical
trials in our own hospital in 2014.
Joanna Kaplon in the group of Daniel Peeper has shown that oncogene-induced
senescence, a key mechanism protecting against cancer, is accompanied by an increase
in oxidative metabolism of glucose through suppression of pyruvate dehydrogenase
kinase (PDK1). She uncovered that inhibition of PDK1 causes regression of established
melanomas, highlighting PDK1 as a potential target in cancer treatment.
Chong Sun and Liqin Wang in the Bernards lab, found a molecular explanation of the
“drug holiday” effect seen in the clinic when patients are treated with selective BRAF
inhibitors for BRAF mutant melanoma. They found that the reprogramming of the cancer
cells during drug resistance development becomes a liability in the absence of drug,
explaining the response of tumours to drug withdrawal. Also, using a kinome-centred
synthetic lethality screen the Bernards group found that suppression of the ERBB3
Receptor Tyrosine Kinase is strongly synergistic with MEK inhibitors in KRAS mutant
lung and colon cancer cells. Small molecule inhibitors targeting both EGFR and ERBB2,
each capable of forming active heterodimers with ERBB3, are strongly synergistic with
MEK inhibitors in KRAS mutant tumours in vitro and in vivo. Based on this finding, a
clinical study will be initiated in the first quarter of 2014 at our hospital, highlighting the
short route from the bench to the bedside at our cancer center.
Peter Bouwman and Jos Jonkers functionally characterized 74 hitherto unclassified
mutations of the BRCA1 gene, thus providing more clarity concerning the risks of cancer
for patients and relatives carrying these mutations. The test that Bouwman and Jonkers
developed can also provide information for the tailored treatment of breast or ovarian
cancer patients with unclassified BRCA1 mutations. The Zwart group identified novel
biomarkers in primary breast cancer that are indicative of treatment outcome when
these patients develop metastasis many years later. This indicates that responsive
behavior of the metastatic tissue may already be imprinted in the primary lesion.
The Neefjes lab reported a new activity for the anthracyclin anti-cancer drugs. They
showed that DNA repair and epigenetics are all altered when cells, mice and cancer
patients are exposed to these anti-cancer drugs. This work provides an intriguing novel
rational to the activities of anthracyclins and sheds new light on the way their efficacy
could be optimized. The Ovaa group reported an unexpected reactivity for a chemical
warhead, unlike anything described thus far in the chemistry textbooks. This warhead
can be used in active-site directed probes that are powerful tools to trap enzyme
reactions and therefore extremely useful for future studies of enzymatic function. 
Gaetano Gargiulo and colleagues in the van Lohuizen group demonstrated the power
of focused shRNAi screens in vivo; they uncovered Atf3 and the ER-stress response
pathway as a key Polycomb target in Glioblastoma. Waseem Akhtar, in the van Lohuizen
group, joined forces with Alexey Pindurin (van Steensel group) and Johann de Jong
(Wessels group), to highlight the power of TRIP- thousands of reporters integrated in
parallel, a new method to study chromatin position effects genome-wide using bar-
coded transposon-reporters in ES cells. Jop Kind in the group of Bas van Steensel
showed that the contact sites between chromatin and the nuclear lamina are not
inherited during cell division but instead are stochastically reshuffled. Moreover, they
identified the H3K9 methyltransferase G9a as a regulator of association of chromatin to
the nuclear lamina.
The Schumacher group demonstrated that the averaging of the stochastic output of
single cells shapes cytotoxic T cell responses. In more applied work, this research group
used cancer exome information to reveal that T cell recognition of mutated epitopes is
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common in melanoma patients. These data provide a likely explanation for the effects of
cancer immunotherapies in this disease, and suggest that T cell recognition of mutated
antigens will also be of importance in other human cancers with similar mutation loads.
Yanling Xiao in the group of Jannie Borst discovered how immune activation can lead to
bone remodeling by inhibiting osteoclast formation from a novel precursor.
Lucas Jae in the group of Thijn Brummelkamp identified new genes involved in the entry
of Lassa virus, a virus that causes lethal hemorrhagic fever. In collaboration with Hans
van Bokhoven (Radboud Universiteit Nijmegen) they showed that mutations in several
of these genes leads to familial Walker-Warburg Syndrome, a disease characterized by
inappropriate glycosylation of alpha-dystroglycan. 
Carlos Melo and Jarno Drost in the group of Reuven Agami studied the role of enhancer
RNAs in controlling gene expression and in cancer. They demonstrated that the tumor
suppressor p53 binds enhancer domains and activates the expression of enhancer
RNAs. Intriguingly, those enhancer RNAs are key players in the tumor suppressor
function of p53. Fabricio Loayza, Ran Elkon and Koos Rooijers in the group of Reuven
Agami used Ribosome profiling and bioinformatics to study control of gene expression
at the level of protein translation. They demonstrated how p53 controls cell proliferation
and cell growth, as well as how disease-causing mutations in mitochondrial DNA affect
protein production at a nucleotide resolution.
The Epidemiology group (Flora van Leeuwen) and the Department of Radiation Oncology
(Berthe Aleman), together with the U.S. National Cancer Institute, led an international
study showing that stomach cancer is an important cause of excess morbidity and
mortality among Hodgkin lymphoma survivors. Stomach cancer risk not only increased
with increasing radiation dose to the stomach but also with increasing number of
alkylating agent-containing chemotherapy cycles, a novel finding. Also, a collaborative
effort of the group of Epidemiology and the division of Molecular Pathology uncovered 49
novel breast cancer susceptibility SNPs (Single Nucleotide Polymorphisms). This finding
has increased the explained familial relative risk for breast cancer with 15% for the
general breast cancer population, 6% for BRCA1 and 7% for BRCA2 mutation carriers.
Last but not least, Marijke Wevers in the group of Neil Aaronson reported on the first
randomized controlled trial of rapid genetic counseling and testing. She showed that
breast cancer patients with a suspected BRCA1/2 mutation who undergo genetic
counseling and receive DNA test results prior to surgery are more likely to opt for direct
bilateral mastectomy. Importantly, rapid testing and counseling did not increase levels of
psychological distress in this group of patients.
QUALITY OF RESEARCH
The quality of our research can be monitored in several ways. First of all, objective
bibliometric parameters (citations and impact of scientific articles published by NKI
staff) demonstrate that our scientific productivity is steadily increasing over time (see
table 2). The year 2013 is no exception to this trend and it is gratifying to note that we
managed to maintain our position at the international forefront of cancer research.
Secondly, our prominent international standing in cancer research is reflected by
the frequency with which our staff members are invited to present at international
meetings and in the awards and grants that they obtain. We score high on all of these
accounts. Karin de Visser was awarded an ERC Consolidator Grant, TOP grants were
given to Heinz Jacobs, to Huib Ovaa and Jacques Neefjes, and to Jannie Borst and René
van Lier of Sanquin. Jacques Neefjes coordinated a Gravity proposal that was awarded
27.8 million euros for the next 10 years. In this project several other groups from the
NKI, as well as groups from several academic institutions, will work together to combine
their expertise on chemistry and immunology to combat disease. In addition to these
awards, several NKI-postdocs have received competitive grants from national and
international organizations.
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TABLE 2
SHORT TERM CITATIONS AND IMPACT OF SCIENTIFIC ARTICLES PUBLISHED BY THE NETHERLANDS
CANCER INSTITUTE RESEARCH STAFF 2000 – 2010/2014
PUBLICATION PUBLICATIONS CITATIONS CITATIONS/ IMPACT
YEAR PUBLICATIONS
2000 284 3551 12,5 1659
2001 309 3991 12,9 1582
2002 384 7436 19,4 2455
2003 349 5094 14,6 2122
2004 302 5267 17,4 1882
2005 387 6350 16,4 2461
2006 400 6336 15,8 2608
2007 412 5605 13,6 2969
2008 419 5657 13,5 2590
2009 471 7904 16,8 3074
2010 457 8788 19,2 2841
2011 441 8654 19,6 3110
2012 512 3340
2013 539 3714
HONORS AND APPOINTMENTS
The NKI-AVL cannot award university degrees, but many of our staff members hold
special part-time chairs at Dutch Universities. This allows them to award PhD degrees
to graduate students who receive their training at the Netherlands Cancer Institute.
Currently, 35 staff members have professorships at one of the Dutch Universities.
In 2013, Arnoud Sonnenberg was appointed Professor of Cell Adhesion in Health and
Disease at the Science Faculty of the University of Leiden. Jos Jonkers was appointed
Professor of Molecular Experimental Oncogenetics and Cancer Therapeutics, also at
the Faulty of Science of the University of Leiden. Thijn Brummelkamp recieved the very
prestigious 2013 EMBO Gold Medal in acknowledgement of his outstanding work to
accelerate the genetic analysis of human disease. The Royal Netherlands Academy of
Arts and Sciences awarded René Bernards the 2013 Academy Professor Prize.
In 2013 there were a few changes in our staff. Peter Peters accepted a position as
Professor of Nanobiology at Maastricht University and Sach Muhkerjee accepted a
position within the MCR Biostatistics Unit of Cambridge University.
Staff of the NKI-AVL fulfilled numerous functions in national and international
organizations, on boards of scientific journals, as members of study sections, site visit
committees and as organizers or co-organizers of scientific meetings, workshops and
conferences.
OUTLOOK AND ACKNOWLEDGEMENTS
For the last decennia our Institute has been at the international forefront in cancer
research and innovative cancer treatments. It has demonstrated to be able to maintain
that position, despite the difficult economic situation of the last few years. We have
been very successful in obtaining external grants for our research and I am convinced
that we will continue to do so. Provided that we can match this with a healthy ratio
of core funding, I foresee that the Netherlands Cancer Institute can continue to
deliver important breakthroughs that will prove beneficial in the treatment of cancer.
Particularly in a time when our ever growing molecular understanding of cancer
meets up with a new generation of anti-cancer drugs that target well-defined nodal
points in the cancer cell. This calls for a more individualized treatment of cancer, in
which molecular pathology in the form of a genetic and/or immunological fingerprint
of the tumor is extensively used in making clinical decisions how to treat the individual
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patient. Success in this area will critically depend on a close collaboration between
basic and clinical research; where basic research can provide the concepts for new
drug combinations that can be taken to the clinic, and vice-versa, where response
failure of a genetically and immunologically defined tumor in the clinic can be taken
to the lab to identify alternative strategies. The integration of research and clinic in
a single Comprehensive Cancer Center provides us with the ideal setting to facilitate
this collaboration, and our first concrete steps in this area hold great promise for the
future. However, these promising developments bring new demands for our research
infrastructure that cannot be financed from external project grants. It is therefore
imperative that we raise additional funds through alternative routes to enable us to
maximize our research efforts in this area. This will receive high priority in the coming
years.
I want to end by thanking all of our employees and everyone that supported us; not only
in 2013, but all of those that supported us throughout the 100 years of our existence.
Ever since our creation in 1913 our organization has received enormous support from
our highly motivated employees, volunteers and sponsors. Ever since its creation
in 1948, the Dutch Cancer Society (KWF) has been a very significant sponsor of our
research; the Ministry of Health Welfare and Sport provides a substantial core grant
to our Institute and has provided the funds to renovate our research facilities; and all
of those individuals that provided us with financial, moral and practical support. Their
support is making it possible for us to continue to strive for better treatments to
improve the outlook of cancer patients. And last but not least, I would like to extend my
sincere gratitude to all of our patients willing to participate in our clinical studies; they
are vital to the progress that we can make.
René Medema
Director of Research

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