Scientific Annual Report 2012 Scientific Annual Report 2012

119 Pages·2013·6.11 MB·English

Contents 2 Introduction 8 Board members
Director of Research
12 Group leaders 118 Division of 130 Division of
Diagnostic Oncology Medical Oncology
12 Neil Aaronson
14 Reuven Agami
16 Roderick Beijersbergen
18 Andre Bergman
20 Rene Bernards
22 Anton Berns
S 24 Christian Blank
26 Eveline Bleiker
c 144 Division of 158 Division of
i 28 Jannie Borst
e Surgical Oncology Radiotherapy
30 Piet Borst
n
32 Thijn Brummelkamp
t
i 34 Jan-Hermen Dannenberg
f
i 36 Karin de Visser
c
38 John Haanen

A 40 Michael Hauptmann
n 42 John Hilkens
n
44 Metello Innocenti
u
a 46 Heinz Jacobs 178 Biometrics 184 Research
48 Jacqueline Jacobs
l Department facilities
R 50 Kees Jalink
e 52 Jos Jonkers
p 54 Sabine Linn
o 56 Rene Medema
r 58 Wouter Moolenaar
t 60 Sach Mukherjee

2 62 Jacques Neefjes
0 64 Huib Ovaa
1
2 66 Daniel Peeper 186 Education in 190 Clinical
68 Anastassis Perrakis
oncology trials
70 Peter Peters
72 Sven Rottenberg
74 Sanne Schagen
76 Jan Schellens
80 Alfred Schinkel
82 Marjanka Schmidt
84 Ton Schumacher
86 Titia Sixma
88 Arnoud Sonnenberg 206 Invited 208 Research
90 Fiona Stewart
speakers projects
92 Hein Te Riele
94 Wim Van Harten
96 Flora Van Leeuwen &
Matti Rookus
100 Fred Van Leeuwen
102 Maarten Van Lohuizen
104 Bas Van Steensel
106 Marcel Verheij
108 Jelle Wesseling 226 Personnel
110 Lodewyk Wessels
index
Scientific Annual Report 2012 112 Rob Wolthuis
114 Wilbert Zwart
nl |
NP1Twh0lewee6tswh 6Nme. neCraktlXnahi .lne naAdrlamslna snC1tda2esn1rcdearm Institute Suzanne CorsettoREDACTIE Netherlands Cancer Institute, AmsterdamCOPyRIGhT Room for ID’s, Nieuwegein | www.roomforids.nl |ONTwERP Martin hogeboom, Epe | www.martinhogeboom.fOTOGRAfIE True Colours, utrecht | www.truecolours.nl |DRukkER
Scientific Annual Report 2012
Introduction 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 to arise in the near future. The cuts we are facing now in fundamental cancer
research will inevitably become rate-limiting for further innovation and progress in
a few years from now. In recent years, several of our principle investigators have
I am pleased to present our Scientific Annual Report. It showcases the scientific been able to compensate the reductions in national funding of fundamental research
Director of Research
achievements of the Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital by obtaining funding from the European Research Council. It is unclear how the Eu
René Medema
(NkI-AVL) in 2012. More background information on our research programs and research budget will develop in the next years, but the current economic situation
principle investigators can be found on our website (www.nki.nl) or in our Scientific makes it likely that this funding source will either also face reductions or not be able to
Brochure that is available for download on our website. compensate reductions elsewhere.
The Antoni van Leeuwenhoek is a Comprehensive Cancer Center, combining a dedicated
cancer hospital and cancer research institute in a single organization. The hospital TABLE 1
has 180 beds, an outpatient clinic, a large radiotherapy department and an extensive CORE RESEARCH FuNDINg THE NETHERLANDS CANCER INSTITuTE - ANTONI VAN LEEuWENHOEK HOSPITAL
infrastructure for clinical research that includes clinical data management, a large By THE DuTCH CANCER SOCIETy AND THE MINISTRy OF HEALTH, WELFARE AND SPORT IN THE PERIOD
array of diagnostic facilities, and a pharmacy with a production unit for experimental 2003 – 2012 IN MILLION EuROS.
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, 25 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
pharmacology, epidemiology and psychosocial oncology and research into cost
20
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
15
growth of 7%. This growth is part of a planned expansion that projects a growth of
our clinical production by 70% in 2020 (compared to 2010). To facilitate this growth,
10
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
5
room to 4 additional operating rooms and the necessary expansion of our intensive care
unit. In 2012, building activities for the radiotherapy satellite in hoofddorp (Spaarne
Ziekenhuis) reached completion, and this site will open its doors early in 2013. we 0
have also continued our discussions with the university Medical Center utrecht (uMC
DuTCH CANCER SOCIETy
utrecht) to establish a joint cancer hospital next to the uMC utrecht, and aim to start
MINISTRy OF HEALTH, WELFARE & SPORT (ExCLuDED
reorganizing oncological activities in utrecht in 2013. The joint activity aims to improve
ARE THE REIMBuRSEMENT FOR INTEREST
the quality of cancer care, and will bring together a large critical mass in areas such as
AND DEPRECIATION OF BuILDINgS)
radiology, radiotherapy and personalized cancer treatment. This will facilitate further
TOTAL
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.
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 fortunately, the Dutch Cancer Society has increased their financial support for our
Centre and supported in a collaborative effort with the uMC utrecht and the Princess research by allowing a gradual increase of the core grant given by the Dutch Cancer
Máxima Center for Pediatric Oncology (PMC). The proton therapy center is expected Society to the Netherlands Cancer Institute. This funding becomes ever more important
to be operational in 2016 and will treat the patients of the PMC requiring moderate to for our success, because the continuity of our research activities critically depends
high irradiation, as well as a range of inoperable tumors in adult patients surrounded by on a healthy ratio between core funding and external funding. That ratio has steadily
radiation-sensitive healthy tissue. shifted towards external grants, donations and short-term research agreements with
third parties. Currently 65% of our total research budget comes from such sources,
we concluded 2012 again with a modest profit for the hospital, but the growth in making it difficult to maintain sufficient manpower in the underlying infrastructure that
numbers of patients has resulted in a significant increase in the workload per employee is increasingly important to deal with the complexity of present-day cancer research.
and per square meter. An important challenge for our institute is to accommodate this The dependence of our research activities on high-throughput screening facilities, next
growth in order to provide the required clinical care for the growing numbers of cancer generation sequencing, proteomics, a state of the art animal facility, bio-informatics,
patients. yet, this growth must not compromise the high level of quality care that we analysis and maintenance of large datasets requires steady investments that cannot
strive to provide. be easily accommodated by external grants. In an attempt to deal with this problem, we
have, together with the Dutch Cancer Society, established a foundation (NkI-AVL fund)
unfortunately, the sizeable increase of our clinical activities cannot be matched by that will raise additional funds for the Netherlands Cancer Institute. In its first full year,
a comparable growth in our research program. Due to the dire national economic this fund managed to raise a little over 1 million euros. Nonetheless, the large majority
situation, our research budget from the Ministry of health, welfare and Sport will face of those funds were earmarked for specific projects, leaving us with the continued
an annual reduction up to a total of 6% by the end of 2014. In addition, funding options problem of limited core funding.
at the Netherlands Organization for Scientific Research have seen a steady reduction
2 3
HIgHLIgHTS Jonathan Coquet and coworkers in the group of Jannie Borst identified novel signaling
pathways that suppress the function of pathogenic T-helper 17 cells, a class of T cells
It is impossible to provide a complete overview of the total impact generated by our that promotes inflammation and auto-immunity. Nienke van Rooij and Marit van Buuren
Institute in 2012 in this introduction. Many of the highlights can be found in the reports in the Schumacher lab provided the first evidence that information on the mutations
of the individual group leaders further on in this annual report or on our website. I present within individual tumors can be used to successfully predict mutant T cell
have chosen to mention just a few highlights here. Let me begin with an unprecedented epitopes that are recognized by cytotoxic T cells. This approach may in future studies
success of clinical translation. be utilized for the development of personalized immunotherapies. Metamia Ciampricotti
from the group of karin de Visser demonstrated that -against the prevailing dogma-
In March of 2012, the Bernards group published a manuscript explaining how colon adaptive immune cells do not affect the outcome of chemotherapy treatment of
carcinomas carrying a B-Raf mutation fail to respond to B-Raf inhibitory drugs that established spontaneous mammary tumors.  
are successfully used in the treatment of melanomas carrying the same mutations.
They subsequently showed how the resistance to B-Raf inhibitors could be overcome in The division of Radiotherapy reported the long-term results of the EORTC 10801 breast
colon cancer in tissue culture and in mice. In November 2012, the first colon carcinoma cancer trial. This multi-centric trial was the first to investigate the efficacy of breast-
patient entered a clinical trial in our hospital to validate this conceptual advance, an conserving therapy in early breast cancer up to 5 cm. Importantly, the study concluded
unprecedented timeline between discovery and clinical trial. This example very nicely that survival outcomes are similar in patients treated with breast-conserving therapy or
demonstrates how crosstalk between research and clinic can lead to rapid translation modified radical mastectomy, confirming that breast-conserving therapy can be safely
at The Netherlands Cancer Institute. The Bernards group recently identified another applied in patients with early breast cancer up to 5 cm. The group also showed that local
mechanism of resistance that might soon lead to new clinical trials. They identified recurrence in prostate cancer is significantly lower when patients are irradiated with a
MED12, a component of the transcriptional MEDIATOR complex, as a determinant of higher local dose.
response to ALk and EGfR inhibitor drugs in lung cancer. Inhibition of TGfβR signaling
can restore drug responsiveness, suggesting a strategy to treat tumors that have The Epidemiology Group showed that diagnostic radiation exposure of BRCA1/2 mutation
acquired drug resistance as a result of activated TGfβ signaling. Liesbeth Vredeveld carriers is associated with an increased breast cancer risk. Any exposure to diagnostic
and Patricia Possik in the group of Daniel Peeper showed that targeted inhibition of PI(3) radiation before the age of 30 was associated with a 1.9-fold increased risk of breast
kinase restores senescence features in melanoma cells, providing another concept that cancer, with a dose-response pattern. The results of this study support the use of non-
can be tested for clinical applicability. Janneke Jaspers in the groups of Jos Jonkers ionizing radiation imaging techniques (such as magnetic resonance imaging) as the main
and Sven Rottenberg, found that Brca1-mutated mouse mammary tumors acquire tool for surveillance in young women with BRCA1/2 mutations.
resistance to PARP inhibitors through inactivation of 53BP1, suggesting that 53BP1 The psychosocial research group of Neil Aaronson demonstrated the efficacy of
may play an important role in therapy response and resistance of BRCA1-mutated and cognitive behavioral therapy and physical exercise in helping to alleviate endocrine
BRCA1-like cancers. symptom burden in young women with breast cancer who experience chemotherapy-
induced menopause. Such behavioral approaches to treating menopausal symptoms
Piet Borst and henri van Luenen elucidated the long sought-after function of a modified are important, as available medicines are either contraindicated for women with breast
base in the DNA (called base J). with the help of our deep sequencing facility and the cancer or have significant side effects.
group of Peter Myler in Seattle, they showed that Base J is clustered at chromosome-
internal RNA polymerase II termination sites. These findings have broad implications for
our understanding of the formation of repressive chromatin and how chromatin marks
can define transcriptional boundaries. QuALITy OF RESEARCH
Mathias Jenal, Ran Elkon and fabricio Loayza-Puch in the group of Reuven Agami The quality of our research can be monitored in several ways. first of all, objective
identified the PABPN1 gene as a regulator of alternative cleavage and poly-adenylation bibliometric parameters (citations and impact of scientific articles published by NkI
of messenger RNAs (mRNAs), a process linked to proliferation and cancer. Intriguingly, staff) demonstrate that our scientific productivity continues to be outstanding (see
PABPN1 is causal of oculopharyngeal muscular dystrophy (OPMD), and cellular and table 2). The year 2012 is no exception to this trend and it is gratifying to note, that
mouse model systems showed induction of alternative polyadenylation by mutant PABP1, despite the difficulties to obtain sufficient funds for our research, we manage to
linking this for the first time with a genetic disease. maintain our position at the international forefront of cancer research. Secondly, our
In the group of Arnoud Sonnenberg, Coert Margadant identified a novel missense prominent international standing in cancer research is reflected by the frequency
mutation in the gene encoding the integrin a3 subunit that causes interstitial lung with which our staff members are invited to present at international meetings and
disease and nephrotic syndrome. in the awards and grants that they obtain. we score high on all of these accounts.
Several NkI-postdocs have received competitive grants from national and international
francesca Mattiroli in the group of Titia Sixma studied the role of ubiquitination in the organizations. In addition, a number of our principle investigators received prestigious
DNA damage response, showing that RNf168, not RNf8 ubiquitinates h2A after ionizing (inter)national research grants. Jacqueline Jacobs and Thijn Brummelkamp were
radiation. her studies revealed that this mark is positioned at a novel site on the histone awarded an ERC Starting Grant, Reuven Agami received an ERC Advanced Grant. fred
protein, and that this modification, rather than the RNf168-dependent chain formation, van Leeuwen received a prestigious VICI grant and Rene Bernards received the Queen
is essential for recruitment of downstream effectors such as Brca1 and 53BP1. wilhelmina Research Award. Anton Berns coordinated the Mouse Clinic for Cancer and
karim Nacerddine and colleagues in the group of Maarten van Lohuizen showed that Ageing, together with the European Institute for the Biology of Ageing (ERIBA). They
the key Polycomb E3 ubiquitin ligase Bmi/Ring1B is regulated by phosphorylation, received 18 million euros from the National Roadmap to build a national research facility
coupling Pi3k/AkT signaling to epigenetic gene regulation. Phosphorylation of Bmi1 for the generation of mouse models for cancer and ageing. The ERC Synergy proposal
correlates with PTEN-loss and PI3k activation in prostate cancer with high grade and of Anton Berns, Daniel Peeper, Lodewyk wessels and groups of the Sanger Institute was
poor prognosis, whereas mutation of the phosphorylation sites diminishes the oncogenic selected out of over 700 proposals and was awarded with 15 million euros for the next 5
effects of Bmi1 in prostate cancer cells. years. This project, entitled COMBATCANCER, will seek to optimize personalized medicine
for lung and melanoma cancer. finally, Rene Bernards coordinated a Zwaartekracht
proposal that was awarded 30 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
4 5
work together to study (targeted) drug responses and optimize targeted therapies. There were several changes in our staff. karin de Visser was appointed as junior group
The quality of research within each division is assessed every 5 years by external leader, Sven Rottenberg was appointed as staff member and head of the intervention
site visit teams. In 2012 we have organized several site visits. On March 5th and 6th, unit of our mouse cancer clinic, and Jacqueline Jacobs was appointed as tenured staff
a site visit team composed of hidde Ploegh (MIT, Boston), Reinhard faessler (Max- member. with my appointment as Scientific Director, my research group also took up
Planck Institute, Martinsried), Vivek Malhotra (CRG, Barcelona), Rienk Offringa (DkfZ, base at the The Netherlands Cancer Institute, in the division of Cell Biology I.
heidelberg) and Benjamin Geiger (weizmann Institute, Rehovot) evaluated the divisions Staff of the NkI-AVL fulfilled numerous functions in national and international
of Cell Biology I, Cell Biology II and Immunology. On May 14th, a site visit committee organizations, on boards of scientific journals, as members of study sections, site visit
formed by Johann De Bono (ICR, London), Antoni Ribas (Jonsson Comprehensive Cancer committees and as organizers or co-organizers of scientific meetings, workshops and
Center, uCLA), Rolf Stahel (uZh, Zurich) and Ian Tannock (The Princess Margeret, conferences. Jannie Borst and Jos Jonkers were elected as members of the European
Toronto) evaluated the research program of the division of Medical Oncology. finally, Molecular Biology Organization (EMBO).
on December 18th and 19th, a site visit team formed by Roel Nusse (Stanford, CA),
kristian helin (BRIC, Copenhagen), David Livingston (DfCI, Boston), Simon Boulton (Clare
hall Laboratories, London) and Michael Gottesman (NCI, Center for Cancer Research,
Bethesda) evaluated the research of the divisions of Molecular Pathology, Molecular OuTLOOK AND ACKNOWLEDgEMENTS
Oncology, Molecular Genetics and Biological Stress Response. The overall impression
of each of these committees was very positive and the ranking of the majority of for the last decennia our Institute has been at the international forefront in cancer
the evaluated principle investigators was outstanding. All committee members were research and innovative cancer treatments. It has demonstrated to be able to maintain
impressed with the international standing of our research programs, considering the that position, despite the difficult economic situation of the last few years. we have
relatively small size of our institute. Several valuable suggestions were made; how to been very successful in obtaining external grants for our research and I am convinced
further strengthen the ties between fundamental and clinical research, how to provide that we will continue to do so. Provided that we can match this with a healthy ratio
more support for our junior investigators. we will implement these suggestions where of core funding, I foresee that the Netherlands Cancer Institute can continue to
possible in the next years. 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
HONORS AND APPOINTMENTS 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
The NkI-AVL cannot award university degrees, but many of our staff members hold patient. Success in this area will critically depend on a close collaboration between
special part-time chairs at Dutch universities. This allows them to award PhD degrees basic and clinical research; where basic research can provide the concepts for new
to graduate students who receive their training at the Netherlands Cancer Institute. drug combinations that can be taken to the clinic, and vice-versa, where response
Currently, 33 staff members have professorships at one of the Dutch universities. In failure of a genetically and immunologically defined tumor in the clinic can be taken
2012, huib Ovaa was appointed Professor of Chemical Biology at Leiden university, to the lab to identify alternative strategies. The integration of research and clinic in
Lodewyk wessels as Professor of Bioinformatics at the Technical university in Delft and a single Comprehensive Cancer Center provides us with the ideal setting to facilitate
Sabine Linn as Professor of Translational Oncology at the university Medical Center in this collaboration, and our first concrete steps in this area hold great promise for the
utrecht. 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. Our newly established NkI-AVL fund and our upcoming anniversary provide us
TABLE 2 with great opportunities to obtain such funds.
SHORT TERM CITATIONS AND IMPACT OF SCIENTIFIC ARTICLES PuBLISHED By THE NETHERLANDS In 2013, The Netherlands Cancer Institute will celebrate its 100th year anniversary.
CANCER INSTITuTE RESEARCH STAFF 2000 – 2010/2012 we will use this year to bring our new ambitions to the attention of a large audience,
ranging from individuals to large organizations. By showcasing our past performance
and by providing a clear explanation of the opportunities that lie within our grasp,
PuBLICATION PuBLICATIONS CITATIONS CITATIONS/ IMPACT combined with the drive and enthusiasm of our employees, we should be able to convince
yEAR PuBLICATIONS a wide audience to support our cause.
2000 270 4314 16,0 1699
2001 305 4944 16,2 1554 I want to end by thanking all of our employees and everyone that supported us; the Dutch
2002 349 7436 21,3 2324 Cancer Society that has been a very significant sponsor of our research for many years;
2003 330 5084 15,4 1963 the Ministry of health welfare and Sport that provides a substantial core grant to our
2004 324 5254 16,2 2018 Institute and has provided the funds to renovate our research facilities; and all of those
2005 362 6261 17,3 2442 individuals that provided us with financial, moral and practical support. Their support
2006 390 6302 16,2 2584 is making it possible for us to continue to strive for better treatments to improve the
2007 400 5515 13,8 2590 outlook of cancer patients. And last but not least, I would like to extend my sincere
2008 408 5671 13,9 2553 gratitude to all of our patients willing to participate in our clinical studies; they are vital
2009 472 7405 15,7 3122 to the progress that we can make.
2010 467 8784 18,8 2847
2011 444 3110 René Medema
2012 412 2527 Director of Research
6 7
Board members
Chairman of Board Scientific International scientific National scientific
Board of governors of Directors Advisory Council advisory board advisory board
T de Swaan
RH Medema RH Medema T De Lange DD Breimer
Chairman and Director of Research Chairman Leon hess Professor, The Rockefeller university, Professor of Pharmacology, Leiden
New york, uSA university
S Rodenhuis TNM Schumacher
Director Clinical Research and Secretary RA Flavell JL Bos
Development Professor of Immunobiology, yale university Professor of Physiological Chemistry,
S Rodenhuis School of Medicine, New haven, uSA university of utrecht
WH Van Harten
Director Organization and Management B Van Steensel (until October 1, 2012) WgJ Ho EgE De Vries
Professor of Biochemistry and Biological Structure, Professor of Medical Oncology,
T Ruers university of washington, Seattle, uSA university of Groningen
J Jonkers J Mendelsohn JHF Falkenburg
President MD Anderson Cancer Center, Professor of Experimental hematology,
ML Van Lohuizen university of Texas, houston, uSA Leiden university
P Nurse Cg Figdor
Board Professor of Microbiology, President of Professor of Experimental Immunology,
of governors The Rockefeller university, New york, uSA Radboud university Nijmegen
R Nusse JHJ Hoeijmakers
Professor of Developmental Biology, Professor of Molecular Genetics,
T De Swaan Stanford university, Stanford, uSA Erasmus university Rotterdam
President
HL Ploegh P Lambin
EH Swaab Professor of Biology, whitehead Institute Professor of Radiation Oncology,
Vice-president for Biomedical Research, Cambridge, uSA Maastricht university
JP Balkenende S Powell CJH Van de Velde
Chairman, Department of Radiation Oncology, Memorial Professor of Surgical Oncology, Leiden
gH Blijham Sloan-kettering Cancer Center, New york, uSA university
FH Schröder IF Tannock
Daniel E. Bergsagel Professor of Medical
MC Smeets Oncology, Princess Margaret hospital and university of
Toronto, Toronto, Ontario, Canada (from June 1, 2012).
F Sijbesma (from October 1, 2012)
K Vousden
PC Van der Vliet Director, Beatson Institute for Cancer Research,
Glasgow, uk
MJ Van Mourik
RA Weinberg
Professor of Biology, Massachusetts Institute of
Technology, whitehead Institute for Biomedical Research,
Cambridge, uSA
8 9
10 11
A A
Holzner B, Efficace F, Basso u, Health-related quality of findings support the tenability of generating both subscale and Wolf SL, Barton DL, Qin R, Wos EJ, Smith EML, Barton DL, Qin R, Steen
Incrocci L, Johnson C, Aaronson overall scores for the fACT-ES. This will allow a more detailed Sloan JA, Liu H, Aaronson NK, Satele PD, Aaronson NK, Loprinzi CL.
N, Arraras J, King M, Chow E, life assessment and assessment and reporting of endocrine symptoms. DV, Mattar BI, green Nb, Loprinzi CL. Assessing patient-reported peripheral
Oberguggenberger A, Bottomley A, The relationship between numbness, neuropathy: The reliability and validity
Steiner H, giesinger J. Cross-cultural tingling and shooting/burning pain in of the European Organization for
development of an EORTC questionnaire behavioral interventions Physical exercise during chemotherapy to improve patients with chemotherapy induced Research and Treatment of Cancer
to assess health-related quality of life physical fitness and reduce fatigue (PACES) peripheral neuropathy (CIPN) as QLQ-CIPN20 Questionnaire. Qual Life
in patients with testicular cancer: The in clinical oncology In this multicenter RCT we are evaluating the effectiveness of measured by the EORTC QLQ-CIPN20 Res (in press)
EORTC TC26. Qual Life Res, 2012 instrument. Support Care Cancer
two physical exercise interventions in maintaining or enhancing
2012;20:625-32
physical fitness and minimizing fatigue in patients undergoing
Khoshnevisan A, yekaninejad MS,
Ardakani SK, Pakpour AH, Mardani A, This research line has two primary foci: (1) development of adjuvant chemotherapy for breast or colon cancer: (1) a low Petersen MA, Aaronson NK, Arraras
Aaronson NK Translation and validation methods and applications of health-related quality of life (hRQL) intensity, home-based, self-management program; and (2) a JI, Chie W-C, Conroy T, Costantini A,
group leader of the EORTC brain cancer module assessment in clinical research and clinical practice; and (2) moderate intensity, structured, supervised program. All partici- giesinger JM, Holzner B, King MT,
Neil Aaronson (EORTC QLQ-BN20) for use in Iran. Singer S, Velikova g, Verdonck-de
development and testing of behavioral and psychosocial inter- pants undergo physical performance tests and complete self-
health Qual Life Outcomes 2012;10:54 Leeuw IM, young T, groenvold M.
ventions to reduce symptom burden and improve the hRQL of report questionnaires at baseline, at the completion of chemo-
The EORTC computer-adaptive tests
Lagerwaard FJ, Aaronson NK, gundy patients with cancer. therapy, and at 6 month follow-up. we completed patient recruit- (CATs) measuring physical functioning
Neil Aaronson PhD Group leader CM, Cornelis JA, Slotman BJ, Senan ment in December 2012. In total, we have entered 253 patients and fatigue exhibited high levels of
Marieke Van Leeuwen PhD Post-doc S. Patient-reported quality of life after Methods and measures for assessing the HRQL of (230 and 23 with breast and colon cancer, respectively), of whom measurement precision and efficiency J
Chantal Lammens PhD Post-doc stereotactic ablative radiotherapy for Clin Epidemiol (in press)
long-term survivors of testicular and prostate cancer 190 have completed the first follow-up (T1) and 140 the 6-month
Willem Eijzenga MSc PhD student early stage lung cancer. J Thorac Oncol
This study, a collaboration between the EORTC Quality of Life and follow-up (T2). Data collection will continue until December 2013.
Lisanne Hummel MSc PhD student 2012;7:1148-54 Victorson DE, Brucker PS, Bode RK,
Hanna Van Waart MSc PhD studentt Genitourinary Cancer Groups, has two primary objectives: (1) Eton DT, Talcott JA, Clark JA, Knight
Marijke Wevers MD MSc PhD student Nieuwenhuis MH, Douma KFL, to test the logistics required to conduct long-term survivorship Behavioral and psychosocial effects of rapid SJ, Litwin MS, Moinpour CM, Reeve
Jacobien Kieffer MSc Senior statistical Bleiker EMA, Aaronson NK, Clevers studies within the context of the EORTC; (2) to pilot test genetic counseling and testing (RgCT) in BB, Aaronson NK, Bennett CL, Herr
analyst H, Vasen HFA. Clinical evidence for HW, Mcguire M, Shevrin D, McVary
questionnaires for assessing the hRQL of long-term cancer newly diagnosed breast cancer patients
Marianne Berkhof Research assistant an association between familial K, Cella D. Ensuring Comprehensive
Miranda gerritsma Research assistant adenomatous polyposis (fAP) survivors (> 10 years disease free). we recruited 280 long-term In this multicenter, randomized trial, carried out in collaboration Assessment of urinary Problems in
Marianne Kuenen Research assistant and type II diabetes. Int J Cancer prostate and testicular cancer survivors who had participated in with the university Medical Center utrecht (Dr. Margreet Ausems), Prostate Cancer through Patient-
Jacoline Melis MSc Research assistant 2012;131:1488-9 EORTC phase III clinical trials. Patients were drawn from 3 broad we are investigating the uptake of RGCT when offered routinely Physician Concordance. urol Oncol (in
grace Sidharta Research assistant geographic/cultural regions: (1) Northern Europe; (2) Southern to newly diagnosed breast cancer patients who, prior to receiving press)
Scott NW, Etta JA, Aaronson NK,
Europe; and (3) the united kingdom. hRQL was assessed at 3 primary treatment, are identified as having at least a 10% risk
Bottomley A, Fayers PM, groenvold M, Chinapaw MJM, Buffart LM, van
Publications Koller M, Kuli D, Marais D, Petersen levels: (1) generic (the Sf-36 health Survey); (2) cancer-specific of carrying a mutation in the BRCA1/2 gene, and the impact of Mechelen W, Schep g, Aaronson
MA, Sprangers MA. An evaluation of (the EORTC QLQ-C30 plus condition-specific modules; and (3) RGCT on choice of surgery and psychosocial well-being. women NK, van Harten WH, Stuiver MM,
the response category translations of cancer survivor-specific (the Impact of Cancer). Time required to were recruited from 12 hospitals in the Amsterdam and utrecht Kersten MJ, Nollet F, Kaspers gJK,
the EORTC QLQ-C30 questionnaire. Qual van Dulmen-den Broeder E, Huisman
obtain medical ethical approval for the patient survey ranged from regions of the Netherlands and were randomized to either the
Life Res 2012 J, Takken T, van Tulder M, Brug J.
1.5 to 25 months. we encountered most problems with obtaining RGCT group or a usual care group (2:1 ratio). The study endpoints
Duijts SFA, van Beurden M, Oldenburg Alpe d’huZes Cancer Rehabilitation
HSA, Hunter MS, Kieffer JM, Stuiver Snyder C, Aaronson N, Choucair A, ethical approval in the uk, Italy and Belgium. The average time to include: (1) uptake of RGCT; (2) choice of clinical management (A-CaRe) research: four randomized
MM, gerritsma MA, Menke-Pluymers Elliott T, greenhalgh J, Halyard M, recruit patients and field the survey questionnaire was 3 months. strategy, including direct bilateral mastectomy or delayed controlled exercise trials and
MBE, Plaisier PW, Rijna H, Lopes Hess R, Miller D, Reeve B, Santana Completed questionnaires were received from 242 patients. preventive contralateral mastectomy; (3) cancer risk perception economic evaluations in cancer
Cardozo AMF, Timmers gJ, van der M. Implementing patient-reported patients and survivors. Int J Behav Med
Although many survivors scored at the upper extremes of the and cancer-related distress; (4) knowledge of genetic aspects
Meij S, van der Veen H, Bijker N, de outcomes assessment in clinical 2012;19:143-56
questionnaires, in general, the Sf36, the QLQ-C30 and the IOCv2 of breast cancer; (5) decisional satisfaction; (6) hRQL; and (6)
Widt-Levert LM, geenen MM, Heuff g, practice: A review of the options
van Dulken EJ, Boven E, Aaronson NK. and considerations Qual Life Res exhibited adequate reliability (< 0.70), and known groups validity satisfaction with RGCT. Between 2008 and 2010, 265 women were Reeve BB, Wyrwich KW, Wu AW,
Efficacy of cognitive behavioral therapy 2012;21:1305-14 (e.g., discriminated between subgroups formed on the basis of randomized into the study. Questionnaires were administered Velikova g, Terwee CB, Snyder CF,
and physical exercise in alleviating comorbidity and age). The QLQ-C30 condition-specific modules at study entry, and at 6 month (response 92.5%) and 12 month Schwartz C, Revicki DA, Moinpour
treatment-induced menopausal Snyder CF, Blackford AL, Wolff CM, McLeod LD, Lyons JC, Lenderking
could benefit from modification for cancer survivor populations follow-up (response 90.6%). A subset of women has been
symptoms in patients with breast AC, Carducci MA, Herman JM, Wu WR, Hinds Ps, Hays RD, greenhalgh J,
(e.g., by deleting acute, treatment-related side effects). interviewed to obtain supplementary, qualitative data. follow-up
cancer: Results of a randomized AW, Aaronson N, gotay C, Halyard gershon R, Feeny D, Fayers PM, Cella
controlled multicenter trial. J Clin Oncol M, Hynes D, Jones JB, yount S, was completed in 2012 and data analysis is currently ongoing. D, Brundage M, Ahmed S, Aaronson
2012;30:4124-33 Velikova g. feasibility and value of Identifying symptom clusters in the endocrine NK, Butt Z on behalf of the International
PatientViewpoint: A web system for scale of the Functional Assessment of Cancer Online cognitive behavioral therapy (CBT) for Society for Quality of Life Research
gundy CM, Fayers PM, groenvold M, patient-reported outcomes assessment (ISOQOL). ISOQOL recommends
Therapy Measurement System (The FACT-ES) climacteric symptoms in breast cancer patients
Petersen MA, Scott NW, Sprangers in clinical practice. Qual Life Res, 2012 minimum standards for patient-
The fACT-ES is an 18-item questionnaire assessing treatment- experiencing treatment-induced menopause
MAg, Velikova g, Aaronson NK. reported Outcome Measures used in
Comparing higher order models for Wevers MR, Hahn DE, Verhoef S, induced endocrine symptoms. Currently, the scoring algorithm Menopausal symptoms are common, and may be particularly Patient-Centered Outcomes Research.
the EORTC QLQ-C30. Qual Life Res Bolhaar MD, Ausems Mg, Aaronson for the fACT-ES yields a single, overall score. we carried out a severe in younger women with breast cancer who undergo Qual Life Res 2013
2012;21:1607-17 NK, Bleiker EM. Breast cancer genetic psychometric study to identify a potential subscale structure for treatment-induced menopause. Effective and safe treatment
counseling after diagnosis but before Kuijpers W, groen Wg, Aaronson NK,
the fACT-ES, reflecting symptom clusters. we used questionnaire options for these symptoms in breast cancer patients are needed.
Hilarius DL, Kloeg PH, van der Wall treatment: Treatment consequences van Harten WH. A systematic review
data from 422 breast cancer patients who had experienced In a recently completed RCT, we demonstrated the efficacy of
E, van den Heuvel JJg, gundy CM, and psychological impact. Pat Educ of web-based interventions for patient
Aaronson NK. Chemotherapy-induced Counsel 2012;89:89-95 chemotherapy-induced menopause. using exploratory factor a group-based, CBT program that included psychoeducation, empowerment and physical activity in
nausea and vomiting in daily clinical analysis, we identified 6 symptom clusters: vasomotor symptoms, cognitive restructuring, behavioral strategies and relaxation chronic diseases: Relevance for cancer
practice: A community hospital- gynaecological symptoms, sexual symptoms, mood, weight, training. however, compliance with the program was problematic. survivors. J Med Internet Res (in press)
based study. J Support Care Cancer
and other endocrine symptoms. Confirmatory factor analysis In attempt to increase the accessibility to and compliance with
2012;20:107-117
confirmed this subscale structure in a second sample of 141 this CBT program, we are developing a web-based version in
women who had undergone prophylactic oophorectomy due collaboration with MindDistrict and king’s College, London. The
to a heightened risk of familial breast/ovarian cancer, and program is currently under development and will be tested
who had experienced treatment-induced menopause. These iteratively for feasibility and effectiveness.
12 13
A A
Jenal M, Elkon R, Loayza-Puch F, Identifying and Research line 4: Regulation of alternative
van Haaften g, Kuhn u, Menzies FM, cleavage and polyadenylation of mRNAs
Oude Vrielink JA, Bos AJ, Drost J, characterizing novel The 3’-end of most message RNAs (mRNAs) is cleaved and
Rooijers, K, Rubinsztein DC, Agami
polyadenylated, a process that is required for mRNA function.
R. The poly(A)-binding protein nuclear
1 suppresses alternative cleavage cancerous processes Recent discoveries revealed that a large proportion of human
and polyadenylation sites. Cell genes contain more than one polyadenylation site. Therefore,
2012;149:538-553 alternative cleavage and polyadenylation (APA) is a widespread
phenomenon that generates mRNAs with alternative 3’ends.
Wilting SM, Snijders PJ, Verlaat
Potentially, APA generates isoforms differing in their coding
W, Jaspers A, van de Wiel MA, van
Wieringen WN, Meijer gA, Kenter Our main research objective is to understand the cancerous and non-coding regions, thereby affecting gene function and
gg, yi y, le Sage C, Agami R, Meijer process in humans – with the focus on RNA-directed gene its regulation by miRNAs and RBPs. Thus, APA provides an
Division head, CJ, Steenbergen RD. Altered regulation. we either use RNA as a tool to interfere with important regulatory layer of gene expression. Interestingly, figure 1: A model for PABPN1’s Mode of
group leader microRNA expression associated with Action in Regultion of APA. Schematic
cellular gene expression or study various cellular RNA types to very strong genome-wide switches in APA are observed when
Reuven Agami chromosomal changes contributes model for PABPN1’s role in suppressing
uncover novel cancer causing or inhibiting genetic programs. cells are stimulated to proliferate, differentiate, and during
to cervical carcinogenesis. Oncogene APA (upper and middele panels).
2012;3;32:106-16 The knowledge we gather is used to design novel therapeutic cancer progression. however, how APA is regulated and what is Normally, PABPN1 binds APA sites and
Reuven Agami Group leader approaches. its function, are largely unknown. competes with the 3’-end cleavage
Rani Elkon PhD Post-doc Wilting SM, Verlaat W, Jaspers To identify regulators of APA we developed a reporter-based and polyadenylation machinery (CPSf).
Nicolas Léveillé PhD Post-doc A, Makazaji NA, Agami R, Meijer Expression of an OPMD mutant PABPN1
Research line 1: Functional screens RNAi screen and devised a genome-wide approach to detect
Mathias Jenal PhD Post-doc CJ, Snijders PJ, Steenbergen RD. (trePABPN1) sequesters wild type
using RNA interference (RNAi) 3’ends of mRNAs (named 3’Seq). with these tools we identified
Fabricio Loayza Puch PhD Post-doc Methylation-mediated transcriptional PABPN1 in aggregates causing 3’uTR
Pieter Van Breugel PhD Post-doc repression of microRNAs during All human tumors harbor multiple genetic alterations that the gene PABPN1 as a regulator of APA. Loss-of PABPN1 shortening.
Boris Slobodin PhD Post-doc cervical carcinogenesis. Epigenetics. activate oncogenes, inhibit tumor suppressors and induce resulted in extensive 3’uTR shortening and a compromised
Jarno Drost MSc PhD student 2013;8 genomic instability. As each tumor contains many genetic miRNA-mediated repression. Interestingly mutations in PABPN1
Marieke Van Kouwenhove MSc PhD
alterations, the study of the contribution of each alteration causes the autosomal dominant oculopharyngeal muscular
student Tekirdag KA, Korkmaz g, Ozturk
to the cancerous phenotype was obscured. we developed and dystrophy (OPMD). Intriguingly, the expression of mutant PABPN1
Arnold Bos MSc PhD student Dg, Agami R, gozuacik D. MIR181A
Carlos Melo MSc PhD student regulates starvation- and rapamycin- successfully used an RNA interference (RNAi) approach to in both a mouse model of OPMD and human cells elicited 3’uTR
Koos Rooijers MSc PhD student induced autophagy through targeting of inactivate genes in mammalian cells to identify and characterize shortening, linking for the first time APA with a genetic disease.
Rui Lopes MSc PhD student ATG5. Autophagy. 2013;9:374-85 cancerous genes. As an example, we lately identified and we conclude that PABPN1 is a suppressor of APA (figure 1).
Mariëtte Schrier PhD Technical staff
characterized the role of the gene BRD7 (bromodomain- Additionally, we explored, on a transcriptome-wide scale,
Joachim Oude Vrielink Technical staff
containing 7) as a protein whose inhibition allows full neoplastic APA events that are associated with cancer. first, we
transformation in the presence of the tumor suppressor p53. comprehensively mapped APA events associated with cellular
Publications
Our results proposed a tumor suppressive role in breast cancer. proliferation and transformation, and cancer. Second, we
Now, we generate a mouse model system for BRD7 to study in demonstrated that E2f-mediated transcriptional regulation of
figure 2: E2f controls alternative
detail its in vivo role as a tumor suppressor, and to assess novel 3’-end processing genes is one of the key mechanisms that links
cleavage and polyadenylation of mRNAs.
therapeutic strategies. APA to proliferation. Increase in E2f activity enhances 3’-end Many 3’-end enzymes are under the
Melo CA, Drost J, Wijchers, PJ, van de processing expression that results in more potent usage of control of the E2f transcription factor.
Werken H, de Wit E, Oude Vrielink JA, Research line 2: Functional screens alternative polyadenylation sites (figure 2). when cell enter proliferation, E2f level
Elkon R, Melo SA, Leveille N, Kalluri and activity increase, resulting in more
to identify cancerous miRNAs
R, de Laat W and Agami R. eRNAs Are 3’-end cleavage activity and induction
In the past years we initiated studies to identify cancerous Research line 5: Role of enhancer RNAs in
Required for p53-Dependent Enhancer of broad mRNA shortening.
Activity and Gene Transcription. Mol microRNAs (miRNAs), a newly emerging gene family encoding controlling gene expression and in cancer
Cell. 2012 for endogenous small RNAs. we developed novel and unique It is well known that the p53 tumor suppressor gene regulates
genetic approaches to screen for cancer-causing and cancer- transcription and cell cycle progression by binding within or
Elkon R, Drost J, van Haaften g,
preventing miRNAs. with these tools we discovered and nearby target genes controlling cell proliferation and survival.
Jenal M, Schrier M, Oude Vrielink
characterized the role of the microRNAs in autophagy, tumor we found that p53 binds genomic regions located distantly from
JA, and Agami R. E2f mediates
enhanced alternative polyadenylation in growth, cancer and metastasis. any known p53 target gene. Interestingly, many of these regions
proliferation. Genome Biol 2012;13:R59 possess conserved p53-binding sites and all known hallmarks
Research line 3: Interplay between miRNAs of enhancer regions. we demonstrate that these p53-bound
Morris AR, Bos A, Diosdado B, Rooijers
and RNA binding proteins in cancer regions are indeed enhancers. Moreover, these p53-binding
K, Elkon R, Bolijn AS, Carvalho B,
we recently noticed that the regions surrounding some sites produce enhancer RNAs (eRNAs) that are required for
Meijer gA and Agami R. Alternative
Cleavage and Polyadenylation during functional miRNA targets are highly conserved throughout enhancer activity. The production of eRNAs is interesting, as
Colorectal Cancer Development. Clin evolution. we hypothesized that these regions recruit RNA they can be used to control enhancer activity and phenotype
Cancer Res. 2012;18:5256-66 binding proteins (RBPs) to control miRNA function during (figure 3). figure 3: p53-induced eRNAs are
required for p53 function. The
induction of various stress responses. we performed genetic
Korkmaz g, le Sage C, Tekirdag p53 tumor suppressor gene binds
screens and identified and characterized RBPs that can inhibit
KA, Agami R and gozuacik D. miR- enhancers to generate eRNAs and
376b controls starvation and mTOR or potentiate the accessibility of miRNAs to their target mRNAs. activate distal genes. knocking down
inhibition-related autophagy by we suggest that the genetic interaction between miRNAs and eRNAs results in reduced enhancer
targeting ATG4C and BECN1. Autophagy RBPs influence developmental processes, cellular proliferation, activity.
2012;8:165-176
and cancer.
14 15