Scientific Annual Report 2016 Scientific Annual Report 2016

279 Pages·2017·6.7 MB·English

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Scientific Annual Report 2016
Netherlands Cancer Institute
Plesmanlaan 121
1066 CX Amsterdam
The Netherlands
www.nki.nl
Contents
2 Introduction 12 Board members
Director of Research
26 Group leaders
16 Neil Aaronson 54 Jacqueline Jacobs 92 Arnoud Sonnenberg
18 Reuven Agami 56 Kees Jalink 94 Hein te Riele
20 Roderick Beijersbergen 58 Jos Jonkers 96 Uulke van der Heide
22 Jos Beijnen 60 Pia Kvistborg 98 Michiel van der Heijden
26 André Bergman 62 Sabine Linn 100 Lonneke van der Poll
28 René Bernards 64 Rene Medema 102 Wim van Harten
30 Anton Berns 66 Gerrit Meijer 104 Flora van Leeuwen
32 Christian Blank 68 Wouter Moolenaar en Matti Rookus
34 Eveline Bleiker 70 Daniel Peeper 108 Fred van Leeuwen
36 Jannie Borst 72 Anastassis Perrakis 110 Maarten van Lohuizen
38 Piet Borst 74 Sven Rottenberg 112 Bas van Steensel
40 Thijn Brummelkamp 76 Sanne Schagen 114 Marcel Verheij
42 Karin de Visser 78 Jan Schellens 116 Emile Voest
44 Elzo de Wit 82 Alfred Schinkel 118 Jelle Wesseling
46 John Haanen 84 Marjanka Schmidt 120 Lodewyk Wessels
48 Michael Hauptmann 86 Ton Schumacher 122 Lotje Zuur
50 Metello Innocenti 88 Titia Sixma 124 Wilbert Zwart
52 Heinz Jacobs 90 Jan-Jakob Sonke
128 Division of 154 Division of 168 Division of
Diagnostic Oncology Medical Oncology Radiation Oncology
188 Division of 204 Biometrics 212 Research
Surgical Oncology Department facilities
214 Education in 220 Clinical 246 Invited
oncology trials speakers
248 Research 268 Personnel
projects index
Scientific Annual Report 2016
Introduction
I am pleased to present our Scientific Annual Report that contains an overview of
Director of Research
the scientific achievements of the Netherlands Cancer Institute in 2016. More
René Medema
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 Netherlands Cancer Institute is a Comprehensive Cancer Center, and the only Dutch
center to officially carry this title. We combine a dedicated cancer hospital and cancer
research institute in a single organization. Our hospital currently has 205 beds, 12 state
of the art operation theatres, an outpatient clinic with more than 100.000 visits a year,
a large radiotherapy department and an extensive infrastructure for clinical research
that includes clinical data management and a large array of diagnostic facilities. Over
the years, the hospital has built a large repository of patient data and a large collection
of tumor and normal tissues. Our clinical research spans across medical, surgical and
diagnostic oncology, radiotherapy, pharmacology, epidemiology, 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 5%.
To accommodate this growth, we have in recent years been expanding. Our building
activities have increased the capacity of our outpatient clinic and intensive care,
as well as the number of operation rooms. In 2016, our new Pathology wing was
finalized. It contains brand new laboratories to accommodate our rapidly expanding
pathology facilities. The construction of the building that will house our new Center for
Survivorship and Supportive Care was also finalized in 2016. It will become operational
during the course of 2017. To continue to accommodate our growth, we will need to plan
additional expansions of our clinical capacity. We foresee that new building activities (in
addition to the ones that are currently ongoing) will be required from 2018 onwards.
One of the biggest changes that took place in 2016 was that Marien van der Meer took
the place of Wim van Harten as our new financial director. Wim van Harten left our
institute at the end of 2015, after serving in our Board of Directors for almost 15 years.
I am confident that in Marien van der Meer we have found a worthy successor.
We managed to end 2016 with a profit for the hospital. But the sustained growth in
numbers of patients that come to our hospital continues to put a strain on our system.
Our excellent reputation is attracting more patients than we can possibly treat due to
limitations in physical space and personnel. This, combined with tighter budgets from
health insurance companies, are putting an increasing strain on all of our activities. Our
clinical research program suffers from the limited time that clinicians can dedicate to
research. Thus, an important challenge for our institute will be to allocate sufficient time
to our clinician researchers to be able to continue to develop better treatments and
provide the evidence that is necessary to make these new treatment options available
to patients throughout the Netherlands. We continue to see a growth in the number of
clinical studies in our Institute that are based on research performed at the NKI (tables
2 and 3). We want to continue to support this important development, essential for the
improvement of cancer therapies, but this will require additional funding capacity.
In 2016, we made additional investments in three of our research themes, molecular
oncology, immunotherapy and Image-guided interventions, but maintaining an
international competitive program requires continuous investments in infrastructure,
and it is challenging for us to find sufficient funding for this. Also, we run many projects
that produce very large datasets, but the long-term maintenance of these valuable
resources requires extensive management and storage costs. These challenges become
ever more difficult for us to overcome due to the fact that our research program is in
2
the largest part financed from project (short-term) funding. We are very thankful to
the Dutch Ministry of Health, Welfare and Sport and to the Dutch Cancer Society (KWF
Kankerbestrijding) for their generous institutional funding (table 1). However, our
funding 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 challenging to maintain sufficient manpower in
the underlying infrastructure.
HIGHLIGHTS
It is impossible to provide a complete overview of the total impact generated by our
institute in 2016 in this introduction. Many of the highlights can be found in reports of
the individual group leaders further on in this annual report and on our website. I have
chosen to mention a few highlights of our 5 research themes here.
Molecular Oncology
The lab of Reuven Agami developed a technique to detect metabolic vulnerabilities of
tumors, called DIRICORE. Postdoc Fabricio Loayza-Puch was one of the main inventors
of this new technique, and was awarded with the AVL prize for his groundbreaking work.
DIRICORE could lead to a whole new approach of fighting cancer based on exploiting
the specific amino acid requirements of individual tumors. Joris van Arensbergen and
colleagues in the lab of Bas van Steensel developed an ultra-high throughput method
to assay the transcriptional activity of more than 100 million DNA fragments in a single
experiment. This new approach will help to unravel how gene expression is controlled in
different cell types and in response to various signals.
In the department of Cell Biology, Wouter Molenaar’s group found that the
glycerophosphodiesterase GDE2 promotes neuroblastoma differentiation and is a
marker of the clinical outcome. An important discovery, because little is still known
about this type of childhood cancer. Femke Feringa, together with other members of
my lab, showed that the cellular response to DNA damage is dramatically different in
cells that are about to undergo cell division. Her work demonstrated that the capacity
to recover from a DNA damaging insult is lost as cells progress through the division
cycle. This discovery could help to improve the efficacy of DNA damaging therapies.
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
2005 – 2016 IN MILLION EUROS.
30 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
25
20
15
10
5
0
DUTCH CANCER SOCIETY
MINISTRY OF HEALTH, WELFARE & SPORT*
TOTAL
* EXCLUDED ARE THE REIMBURSEMENT FOR INTEREST
AND DEPRECIATION OF BUILDINGS
3
TABLE 2
THERAPEUTIC CONCEPTS THAT ARE THE PRODUCT OF FUNDAMENTAL AND TRANSLATIONAL RESEARCH
PERFORMED AT THE NETHERLANDS CANCER INSTITUTE, AND CURRENTLY IN CLINICAL DEVELOPMENT IN
OUR INSTITUTE
REFERENCE CLINICALTRIALS. AVL CODE NOVEL TREATMENT TUMOR TYPE
NUMBER** GOV
1 NCT01719380 M12LGX EGFRi + BRAFi ± PI3Ki Mutant BRaf Colorectal Cancer
1 NCT01750918 M13DPT EGFRi + BRAFi ± MEKi Mutant BRaf Colorectal Cancer
2 NCT02039336 M13DAP Pan-HERi + MEKi Mutant KRas Colorectal Cancer
2 NCT02230553 M14LTK Pan-HERi + MEKi Mutant KRas Colorectal Cancer
3-5 Registration M14REV Carboplatin + PARPi Advanced Breast Cancer with
pending BRCA mutation
6,7 NCT02285179 M14POS Tamoxifen + PI3Ki ER/PR+ and HER2- Breast Cancer
8-10 NCT01057069 M09TNM Neo-adjuvant Chemo Triple-Negative Breast Cancer
8-15 NCT01898117 M13TNB Paclitaxel ± VEGFi BRCA1-like Breast Cancer
16,17 NTC02278887 M14TIL TIL vs. Ipilimumab Metastatic Melanoma
18-20 NCT00407186 M06CRI Chemoradiotherapy + surgery Resectable Gastric Cancer
21 NCT02229656 N13ORH Radiotherapy + PARPi Laryngeal and HPV-Negative
Oropharyngeal SCC
21 NCT01562210 N11ORL Radiotherapy ± Cisplatin + Locally Advanced NSCLC
PARPi
21 NCT02227082 N13ORB Radiotherapy + PARPi Locally Advanced Triple-Negative
Breast Cancer
22 NCT01504815 M11ART Cisplatin + Adaptive High Dose Locally Advanced Oropharynx, Oral
Radiotherapy Cavity or Hypopharynx SCC
23 *NCT01024829 M09PBO FDG-PET-based Boosting RT Inoperable NSCLC
24 NCT01780675 M12PHA Hippocampus Avoidance PCI SCLC
25 NCT01933568 N12HYB Combined Stereotactic and Stage II-III NSCLC
Conventional Fractionated RT
26 *NCT01543672 M11VOL MLD-based SBRT Inoperable + Peripheral NSCLC
27 NCT01024582 M08PBI Partial Accelerated Early Stage Operable Breast
Preoperative Irradiation Cancer
28,29 NCT00582244 P07CB Cognitive Behavioral Therapy & Breast Cancer
Physical exercise
30 NCT00783822 P08TIM Rapid Genetics BRCA mutant Breast Cancer
31,32 NCT015622431 P11SIG Problem checklist Breast & Colon Cancer
REFERENCE NTR CODE AVL CODE NOVEL TREATMENT TUMOR TYPE
NUMBER
33 *NTR4607 N14HPV DNA vaccination HPV16+ Vulvar Neoplasia
34 NTR3539 M11TCR MART-1 TCR gene therapy Metastatic Melanoma
35 NTR2159 P09PHY Physical Exercise Breast & Colon Cancer
37 M15CRI Preoperative chemo vs Resectable gastric cancer
chemoradiotherapy vs chemo
+ chemoradiotherapy
38 M15PAP Pre- vs postoperative Early stage breast cancer
accelerated partial breast
irradiation
39 M16HFL Hypofractionated focal Prostate cancer
ablative radiotherapy
* THERAPEUTIC CONCEPT NOT SOLELY, BUT PRIMARILY DEVELOPED AT THE NETHERLANDS CANCER INSTITUTE
** SEE REFERENCE ON THE NEXT PAGE
4
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5
The group of Heinz Jacobs demonstrated that open chromatin configuration is a
primary risk-determinant for chromosome translocations. Thomas van Ravesteyn,
Marleen Dekker and Hellen Houlleberghs from the Te Riele group developed a method
for high-throughput oligonucleotide-directed mutation screening (ODMS) which will be
very useful to distinguish mutants of DNA mismatch repair genes that are of clinical
significance versus others that are not.
Michela Serresi and colleagues (Van Lohuizen group) demonstrated that loss of the
Polycomb repressor complex2 (PRC2) can promote inflammation and reduce tumor
growth in KRAS-driven non-small cell lung cancer that have retained wildtype p53, while
it promotes a switch to a highly aggressive mutinous adenocarcinoma via an epithelial-
mesenchymal transition (EMT) in this tumor type when p53 is mutated.
Willem-Jan Keune from the lab of Anastassis Perrakis has discovered the function of
the elusive ‘tunnel’ structure in autotaxin, an enzyme that is involved in numerous cell
signaling processes, including cell proliferation and cell migration. It turns out that
certain natural steroids can bind inside this tunnel and thus inhibit the function of
the enzyme. It was the first time a natural regulator for the activity of autotaxin was
discovered. The discovery provides a molecular explanation for the therapeutic effect
of bile salt based drugs, but also has several other potential clinical implications.
Jacqueline Staring, a member of the laboratory of Thijn Brummelkamp, has discovered
that once picornaviruses are attached to the cell a single human host cell protein
assists their further entry. The discovery of this common host factor, the lipid-modifying
enzyme PLA2G16, offers promise for future antiviral therapies against this large
family of viruses, that cause diseases such as polio, infections of the heart, meningitis,
hepatitis and the common cold. Brummelkamp’s lab previously discovered that the Ebola
and Lassa viruses also rely on a two-step mechanism to infect cells, including a receptor
on the cell surface as well as one inside of the cell.
Personalized treatment
In 2016, the final conclusions of the MINDACT study were published. In this large-scale,
long-term European study, the reliability of the 70-gene signature test for breast
cancer patients (also known as the MammaPrint) was evaluated. The MammaPrint was
invented around a decade ago by NKI researchers Laura van ‘t Veer and René Bernards.
It can classify hormone-sensitive early stage breast tumors as ‘low risk’ or ‘high risk’
when it comes to the possibility of developing metastases. MINDACT has provided
the highest level of clinical evidence of the test’s reliability. This means it can safely
and reliably be used in the clinic to determine which women with breast cancer need
additional chemotherapy and which do not, an issue that is relevant for as much as 2000
women per year in the Netherlands alone.
Loredana Vecchione and Valentina Gambino from the group of René Bernards showed
that a subset of colon cancers is exquisitely sensitive to the microtubule poison
vinorelbin. They showed that this subset has a characteristic gene signature, also
known as “B-Raf”-like tumors, implying that vinorelbin is a potential tailored treatment
for B-Raf-like colon cancers.
The lab of Jan Schellens published the results of a clinical trial that shows how a new
type of anti-cancer drug, currently known by the name AZD1775, can enhance the effect
of existing chemotherapeutic drugs. It shuts down the G2 phase of cell division, so DNA
damage that is induced by the chemotherapeutics cannot be repaired. Of 23 women with
advanced ovarian cancer who at first did not respond to classic chemotherapeutics
and whose tumors harbored a p53 mutation, 43% had benefit from the combination of
chemotherapy with AZD1775. They lived much longer than they would have without the
drugs, and two of the patients have survived for six years now. Also, Maarten Deenen
in the group of Jan Schellens obtained evidence that upfront genotyping of patients
for dihydropyrimidine dehydrogenase (DPD) activity and dose-adaptation significantly
improves safety of fluoropyrimidine therapy and is cost-effective.
Suzan Stelloo from the labs of Wilbert Zwart and André Bergman revealed a surprising
favorable prognosis in primary prostate cancer patients with activated mTOR pathway,
providing a clinical rationale why neoadjuvant mTOR inhibitor treatment in prostate
cancer is unsuccessful.
Daniel Vis of the lab of Lodewyk Wessels has shown that patient-derived cancer cell lines
harbor most of the same genetic changes found in patients’ tumors. This means they
can indeed be used to learn how tumors are likely to respond to new drugs, increasing
6
the success rate for developing new personalized cancer treatments. In his systematic,
large-scale study, Vis combined molecular data from 11.000 tumors and cancer cell
lines with drug sensitivity measurements. Also from the Wessels’ lab, Ewald van Dyk
spearheaded the development of a new algorithm called RUBIC, to detect aberrations
in DNA copy number data sets. RUBIC performs better than two of the existing state-
of-the-art approaches to detect these aberrations, that can be used for cancer driver
gene discovery.
The Jonkers lab managed to develop a technique to create mouse models for invasive
lobular carcinoma that doesn’t require lengthy breeding of transgenic mice. His lab
also discovered two previously unidentified ways in which breast tumors can harbor
resistance against cisplatin and PARP-inhibitors. In turns out that if the protein that
is produced by BRCA1 lacks a characteristic RING-domain, cancer cells don’t respond
to these two drugs. Next to this they found that certain epigenetic changes in the
regulation of BRCA1 can cause acquired drug resistance.
To broaden the perspectives of melanoma patients, the groups of Peeper, Haanen,
Schumacher and Blank established a large collection of patient-derived xenografts (PDX)
and identified a BRAFV600E kinase domain duplication in drug-resistant tumors. Treatment
with a new RAF dimerization inhibitor reversed drug resistance, illustrating the utility of
this PDX platform and warranting clinical validation of BRAF dimerization inhibitors for
this group of melanoma patients.
Immunotherapy
NKI immunologists Christian Blank, John Haanen and Ton Schumacher proposed a
framework that can be used to determine which type of cancer immunotherapy is best
for an individual patient: The Cancer Immunogram, that was published in the journal
Science. In another paper in Science, Ton Schumacher and his Norwegian colleague
Johanna Olweus showed that it is possible to fight cancer with the help of ‘borrowed’
immune cells. In their proof-of-principle study they found that naïve T cell repertoires of
healthy blood donors provide a source of neoantigen-specific T cells. T cells redirected
with T cell receptors identified from donor-derived T cells efficiently recognized patient-
derived melanoma cells harboring the relevant mutations, providing a rationale for the
use of such “outsourced” immune responses in cancer immunotherapy.
A team led by Inge Verbrugge and Christian Blank compared several combinations of
immunotherapy and radiotherapy in a mouse melanoma model, to see whether these
therapies can enhance each other. Their study suggests that a combination of anti-PD-1,
anti-CD137 and radiotherapy may be superior to other combinations of immunotherapy
and radiotherapy that are currently being tested in human patients.
In his OpACIN study, Christian Blank showed the profound anti-tumor activity, but also
toxicity, of neo-adjuvant immunotherapy with anti-CTLA-4 and anti-PD-1 antibodies
in stage III melanoma patients.  These data underscore the potential value of T cell
checkpoint blockade during earlier disease stage. In addition, these data strongly
suggest systemic immune suppression as an important factor limiting the activity
of T cell checkpoint blockade during later stage disease.
Tomasz Ahrends in the group of Jannie Borst demonstrated how CD4 T cell help alters
many aspects of CD8 T cell function, and also how CD27 ligation can largely compensate
for the lack of T cell help. These data may be used to design strategies to optimally instill
desired activities in tumor reactive CD8 T cells that are induced by vaccination. 
In a collaboration between the Schumacher, Brummelkamp, and Jannie Borst lab,
Riccardo Mezzadra, Chong Sun, and Lucas Jae identified CMTM6 as a protein partner of
PD-L1 that influences the expression of PD-L1 on the surface of both tumor cells and
myeloid cells.  Based on these data, CMTM6 may be pursued as a potential therapeutic
target.
Image-guided interventions
In March the MRI-linac was installed at the department of Radiation Oncology, marking
the beginning of a practice-change in image-guided adaptive radiotherapy. In September
the first images were made with the MR-Linac system, while simultaneously irradiating
the object. The group of Uulke van der Heide developed and validated a method to
generate ‘CT-like’ images from MRI scans of the prostate. This will avoid the need to
acquire a planning CT scan for patients who already received an MRI exam for target
delineation. This method is currently implemented clinically.
7