André Bergman René Bernards Christian Blank Eveline Bleiker
Wim van Harten
Flora van Leeuwen and Matti Rookus
Karin de Visser
Fred van Leeuwen
Elzo de Wit
Benjamin Rowland Sanne Schagen Alfred Schinkel Marjanka Schmidt Ton Schumacher
Maarten van Lohuizen Jacco van Rheenen
William Faller John Haanen Hugo Horlings Heinz Jacobs Kees Jalink Jos Jonkers Marleen Kok Jacqueline Jacobs
Bas van Steensel Olaf van Tellingen
Jelle Wesseling Lodewyk Wessels
Jan-Jakob Sonke Arnoud Sonnenberg
Hein te Riele
Division of Diagnostic Translational Oncology
Division of Medical Oncology
Division of Surgical Oncology
Division of Radiation Oncology
Division of Pharmacology and Biometrics
Technology Transfer Office
Education in Oncology
Netherlands Cancer Institute Plesmanlaan 121 1066 CX Amsterdam The Netherlands www.nki.nl
Scientific Annual Report 2020
The year 2020 has been a difficult year for all of us, and first of all I want to emphasize that I am extremely proud of all our employees for their unremitting flexibility, creativity, and stamina. Defending your PhD thesis at your kitchen table, arriving in the Netherlands for your PhD project and not being allowed to start, worrying about your relatives, working from home with your children, waiting your turn to use a microscope - it has all been far from easy, but so far you have managed very well. Although we have had to put on hold the majority of our clinical trials and lab experiments for several months, we have been able to ward off a complete lockdown in our research labs and most critical experiments could be continued. The COVID-19 pandemic has been dealing a serious blow to cancer research, the extent of which we cannot yet foresee, but at the same time it has been an invaluable wake-up call, because it dramatically highlights how vulnerable our world is regarding health safety. With our partner institutes in EU-LIFE, we have argued that the health and wellbeing of European citizens requires a long-term vision and better coordination among European countries in order to respond more effectively to current global health crises. Understandably, policy makers are now focused on tackling infectious diseases, but let us not forget that the common ground underlying knowledge of infectious diseases and cancer alike is fundamental research: research into the immune system, research into mRNA, research into genetic vulnerability to diseases. This is one of the reasons, sheer pride aside, that I am so happy that our senior group leader Ton Schumacher, a world-renowned fundamental scientist who unraveled one of the cellular prerequisites for cancer immunotherapy, was awarded the Stevin Prize 2020, which goes to scientists whose research has major technological and practical impact. With the Spinoza Prize, the Stevin Prize is the highest academic prize in the Netherlands. Despite the COVID crisis, which affects all people worldwide, we can look back on a productive and future-oriented year at the NKI. We formulated our new institutional strategy for 2030, in which we have set ourselves a bold goal: a cure for every cancer. We are fully aware that we can neither reach this goal overnight nor on our own. However, we will steadily work our way towards it, implementing our tried and trusted formula of combining innovative fundamental, translational, and clinical research with dedicated patient care, teaching, and collaboration. The year 2020 also saw our in-house pharmacy going operational, after several years of thinking, planning and building. It is equipped with a number of innovative facilities, including clean rooms for developing next generation cellular immunotherapy. In the past years, we have designated five overarching research themes: fundamental science, image-guided therapy, immunotherapy, precision oncology, and survivorship. In 2020, all five theme leaders delivered their visionary and ambitious plans for the coming five years, in which they focus on the major challenges and opportunities in their fields. I am looking forward to many exciting new developments in our labs and our hospital. In 2020, we also generated important new knowledge, published new findings, and implemented new knowledge in the clinic. For example, we showed that neo-adjuvant immunotherapy can be effective in colorectal cancer and urothelial carcinoma and we shed new light on the link between DNA folding and gene expression. We are implementing patient reported outcome measures in our own hospital, building on
Director of Research René Medema
the seminal research that we started over 25 years ago. We showed that whole genome sequencing of tumour DNA can be implemented in routine diagnostics, and we embarked on some beautiful new collaborations in artificial intelligence. In January 2020, the Dutch Cancer Society and the NKI announced their renewed cooperation agreement covering the next five years. Together, we decided to focus on patient impact, quality of life for cancer patients, and better access to medicines. In November, the Dutch Cancer Society launched a European collaboration collective that advocates transparent pricing of cancer drugs, in which researchers from our Health Technology Assessment group are involved to do the research that will enable us to turn the right knobs. Below, you will find some of our highlights from 2020. However, I would also like to stress that cutting-edge research includes failure. A very important ingredient for our success throughout the years is that we dare to undertake risky research that might fail. In fact, we would really fail in fulfilling our mission if we would not allow ourselves to fail. But this takes courage, and I want to thank our employees for showing this courage. I want to end by thanking everyone who supported us and collaborated with us in 2020, including the Dutch Cancer Society for their institutional support and the Ministry of Health, Welfare and Sport for their core funding. I also want to thank Emile Voest, who stepped down as Medical Director per 1 January 2021, for all his work, and particularly for his highly successful efforts to further improve our clinical research programme. We are all very glad that he has decided to continue his important research within the NKI. Above all, I would like to express my sincere gratitude to all our patients for their patience and trust in our research and care. The COVID crisis has been far from easy for them. We shall do our utmost to continue earning their trust.
René Medema Director of Research
FIGURE 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 2009-2020 IN MILLION EUROS.
DUTCH CANCER SOCIETY MINISTRY OF HEALTH, WELFARE & SPORT* TOTAL
* EXCLUDED ARE THE REIMBURSEMENTS FOR INTEREST AND DEPRECIATION OF BUILDINGS
A SELECTION OF HONOURS AND APPOINTMENTS
— Immunologist Ton Schumacher has been awarded the Stevin Prize. With the Spinoza Prize, this is the highest academic prize in the Netherlands. The Stevin Prize is awarded to researchers whose research has major social impact. — Senior group leader Rene Bernards has been elected member of the prestigious US National Academy of Sciences (NAS). He was elected because of his extraordinary contributions to the study of cancer genetics. — Molecular biologist Tineke Lenstra was awarded the Early Career Award by the Royal Netherlands Academy of Arts and Sciences. She studies the mechanisms of transcription variation and dynamics in single cells. — Pathologist Mathilde Almekinders has been awarded the PALGA 2020 Award for her research on DCIS. PALGA is the national network and registry of pathology in the Netherlands. — Colinda Scheele, who defended her PhD thesis cum laude in 2020, has won the Antoni van Leeuwenhoek Award 2020 for her extraordinary research into stem cells and the development of breast cancer. The Netherlands Cancer Institute awards the Antoni van Leeuwenhoek award every year to its most talented young researcher. — The nation-wide Advisory Board on Cancer in Pregnancy, founded and chaired by NKI gynecological oncologist Christianne Lok, has been awarded the NKI Patient Impact Award 2020. This multidisciplinary board helps physicians in the Netherlands to reach the best possible treatment decisions for pregnant cancer patients. — Renowned life sciences organization EMBO has selected group leader Leila Akkari for their Young Investigator Programme. She investigates how we can use immune cells called macrophages to combat cancer. — Medical oncologist Christian Blank has been appointed professor in internal medicine at Leiden University, with a focus on clinical research into immunotherapy against cancer. — Radiation oncologist Rick Haas has also been appointed professor at Leiden University, with a focus on bone and soft tissue tumours. Also, he has been elected 2021 President of the Connective Tissue Oncology Society (CTOS). — The Dutch Research Council has granted researcher Hendrik Messal a Veni grant. Using 3D whole organ microscopy, he intends to elucidate how breast cancer precursors develop into malignant tumors.
In all five of our research themes, and very often in a multidisciplinary setting, our researchers and clinicians have made progress in understanding cancer and bringing new knowledge to the clinic. Here, we present some of our 2020 research highlights. We also show how cancer research can be of help in the current COVID crisis.
New insights into genome organization and gene regulation Our DNA in the cell nucleus is organized in loops, which look like shoelaces. How are these loops formed and what is the link with gene regulation? Several NKI groups are working on this basic biological problem. In January 2020, the groups of Benjamin Rowland and Elzo de Wit, with colleagues from Leicester, unraveled the interaction between cohesin protein rings, which entrap DNA and act as a motor that increases the loops in size, and CTCF proteins, the roadblocks keeping the loops in place. They discovered how CTCF binds with cohesin and fixes it onto the DNA, which allows cohesin to build loops connecting one CTCF to another one that may be millions of nucleotides further along the DNA (Li et al., Nature 2020). In a November 2020 Nature Genetics paper , the Elzo de Wit group provided new insight into the link between loop formation and gene regulation. They showed the importance of cohesin turnover in controlling transcription, and propose that a dynamic cycle of cohesin loading and off-loading, instead of static cohesin binding, mediates promoter and enhancer interactions critical for gene regulation (Liu et al., Nature Genetics 2020). Cellular plasticity is crucial for outgrowth of metastases Which cancer cells are responsible for metastasis in colorectal cancer? This depends on the stage of metastasis we are talking about, the Jacco van Rheenen group discovered. Using intravital microscopy (filming fluorescently labeled cells and their offspring) in mouse models, they saw that most colorectal cancer metastases are seeded by differentiated (‘adult’) cancer cells, which, however, turn back into cancer stem cells when they grow out into a metastatic lesion. Surprisingly, this cellular plasticity occurred independently of stemness-inducing microenvironmental factors (Fumagalli et al., Cell Stem Cell 2020). Skipping letters makes for sloppy proteins Ribosomes are the protein factories of the cell. They read the mRNA code, and then produce proteins. Using ribosome profiling, the Reuven Agami group and colleagues from the Weizmann Institute discovered an interesting unknown vulnerability of melanoma cells. When fighting off T cells, the cancer cells get short of food: they deplete their tryptophan, which is an essential nutrient for cells to survive. For a normal cell, this would be a sign to stop reading the code and stop producing proteins until the tryptophan is replenished. However, the melanoma cells continue reading, simply skipping the first letter of the tryptophan codon, and thus shifting the entire reading frame. As a result, aberrant proteins are produced, based on a faulty mRNA code. Although the cancer cell continues to function, this comes at a cost, for the aberrant proteins duly present their antigens to the immune system. The discovery of this vulnerability may lead to new forms of immunotherapy, based on T cells from healthy donors that are trained to recognize specific aberrant tumor cells (Bartok et al., Nature 2021). Metastasizing tumor cells reactivate a fetal program Metastatic prostate cancer cells reactivate an epigenetic program for fetal prostatic development. Researchers from Wilbert Zwart and Andre Bergman’s hormonal cancer groups and researchers from the Dana-Farber Cancer Institute demonstrated this process in tissue samples taken from hundreds of surgically removed prostate tumors. The team found multiple proteins involved in the programs for organ development that appear to be hijacked by metastatic prostate cancer. By using drugs to inhibit these proteins, they now hope to be able to block tumor metastasis. This reactivation of an
embryonic DNA program during metastasis has never been documented in cancer research. The NEJM highlighted the paper in the section ‘Clinical implications of basic research’, and the Dutch Society for Endocrinology proclaimed it ‘best non clinical research paper of the year’ (Severson et al., Nature Genetics 2020).
Stevin Prize for Ton Schumacher ‘Immunotherapy has been a victory of fundamental research’, Ton Schumacher said when he was awarded the Stevin Prize in 2020. With the Spinoza Prize, this is the highest academic prize in the Netherlands. The Stevin Prize is awarded to researchers whose research has major societal impact. Schumacher himself started his academic career asking highly fundamental questions, such as ‘How does a T cell recognize a tumor cell?’. The key turned out to be mutations: the more mutations, the better the immune response. Schumacher and his group are now developing technology to measure patients’ immune responses. He will use the prize worth 2,5 million euros to build an algorithm which can predict whether T-cells from a specific patient are able to recognize a cancer cell. T cells and immune cells wage war at a distance In March 2020, researchers from the Schumacher group and the Van Rheenen group showed in ovarian cancer that T cells and tumor cells wage war at a distance: a T cell, as soon as it recognizes a tumor cell, not only disables the target cell itself, but also affects more distant parts of the tumor, up to 30-40 cell layers removed, by secreting the signaling molecule interferon gamma. This even kills tumor cells that were no longer recognized by the T cells themselves. The downside is that interferon gamma also warns the tumor cells that a T cell is tracing them, so a lot more research is needed before this finding can be clinically exploited (Hoekstra et al., Nature Cancer 2020).
TABLE 1 SHORT TERM CITATIONS AND IMPACT OF SCIENTIFIC ARTICLES PUBLISHED BY THE NETHERLANDS CANCER INSTITUTE RESEARCH STAFF 2006-2020
* SINCE 2014 A NEW STANDARD WAS USED TO PERFORM THE CITATION AND IMPACT FACTOR ANALYSES. CONSEQUENTLY, THE NUMBERS CAN DIFFER FROM THE PREVIOUS YEARS. ** ANALYSIS WAS PERFORMED IN MARCH 2021. DATA CAN BE SUBJECT TO CHANGE.
Pre-existing immune-resistant tumor cells identified in melanoma Immunotherapy has improved the prospect of patients with late stage melanoma. However, many tumors display some form of intrinsic or acquired resistance to immunotherapy. This is why researchers are searching for clues to combine immunotherapy with other drugs that will hopefully tackle resistance. In 2020, researchers from the Daniel Peeper group managed to identify a population of melanoma cells that show resistance to cytotoxic T cells from the start. They also saw that these (cultured) cells express high amounts of the Nerve Growth Factor Receptor (NGFR), and that inhibiting NFGR re-sensitized the melanoma cells to T cells. In addition, melanoma-bearing mice survived longer when NGFR was inhibited during immunotherapy. This indicates that NGFR may be an attractive therapeutic target used in combination with immunotherapy. Since there are no NGFR precision medicines available yet, an antibody approach may be feasible, provided that this does not cause undesired side effects in normal cells expressing NGFR (Boshuizen et al., Nature Communications 2020). Neo-adjuvant immunotherapy, in which the NKI has been a front-runner, has recently been showing promising results, with lab work and clinical practice becoming more and more integrated. Its main rationale, hypothesized some years ago within the NKI by Ton Schumacher and Christian Blank, is to familiarize the immune system with the entire heterogeneous tumor before this is surgically removed, enabling the immune system to respond better. Over the past years, NKI clinicians have been running a range of clinical trials to investigate the feasibility and the effects of a neo-adjuvant immunotherapy strategy, of which the year 2020 saw new promising results. In April, the results of the NICHE trial, led by Myriam Chalabi, were published. This is a unique investor-initiated study investigating the use of neo-adjuvant immunotherapy in colorectal cancer. In the patients enrolled who had an MSI subtype of colon cancer, the response rate was an unprecedented 100%. In MSS patients, who are known not to respond well to immunotherapy, this was 25%. Given that 85% of all patients with non- metastasized colon cancer have this type, this too is a hopeful outcome (Chalabi et al., Nature Medicine 2020). In November, Michiel van der Heijden published the results of the NABUCCO study, which is also an investigator-initiated study. The team showed that neoadjuvant immunotherapy, using a combination of nivolumab and ipilimumab, is a feasible treatment for locally invasive bladder cancer, without harming the scheduled resection and showing promising results for patients who have a high risk of relapse but not many good treatment options (Van Dijk et al., Nature Medicine 2020). New junior group leader Daniela Thommen exploits tumor avatars In 2020, the NKI welcomed Daniela Thommen as a new junior group leader. Exploiting her unique patient-specific tumor fragment platform, nicknamed ‘tumor avatars’, she aims to personalize immunotherapy by identifying new biomarkers and treatment strategies. Support from the AVL Foundation already allowed her to book positive results with her platform. Daniela works in close collaboration with clinical researchers. Neo-adjuvant immunotherapy is effective in colon cancer and bladder cancer
Tackling therapy resistance with multiple low dose therapy In cancers with targetable mutations, such as EGFR-mutant lung cancer, patients are treated with precision drugs that block the altered proteins. Unfortunately, the cancer cells eventually become resistant. To overcome this problem, rational combination therapies have been developed. The downside of this is that administering more drugs results in more toxicity. The Rene Bernards group has found a solution to this dilemma: Multiple Low Dose Therapy. In this approach, multiple drugs that act in the same oncogenic signaling pathway are combined at low concentration. The team showed that as little as 20% of the individual effective drug doses, used in a combination therapy, can
completely block MAPK signaling and proliferation without inducing resistance. In animal models, they found durable responses to MLD therapy without associated toxicity. The next step will be a clinical trial (Fernandes Neto et al., Nature Communications 2020). Predicting the risk of developing contralateral breast cancer Approximately 4% of all breast cancer patients develop a second tumor in the other breast within 10 years after their first diagnosis. In 2020, the Marjanka Schmidt group showed that a so-called polygenic risk score (PRS) of 313 common genetic variants is an independent risk factor for the development of contralateral breast cancer. The researchers tested their PRS 313 against a dataset of more than 56,000 European breast cancer patients, made available by the Breast Cancer Association Consortium. Patients were tracked for more than eight years. This new information will be included in the group’s prediction model for contralateral breast cancer, which is under development. The ultimate aim is to develop a personalized plan for each breast cancer patient (Kramer et al., American Journal of Human Genetics 2020). Compound library makes over 6000 drug available for repurposing Drug repurposing is an effective approach to rapidly identify novel indications for known drugs and compounds. Also, it can make healthcare more affordable. The Dutch virtual cancer institute Oncode has acquired the next generation Drug Repurposing Library, based on the Broad Repurposing Library, which contains more than 6000 drugs in various stages of clinical development, including drugs that are on the market as well as abandoned and off-patent drugs. Together with the NKI and LUMC, Oncode has made this library available for screening by research groups within and outside their institutes. Head of the NKI Robotics and Screening Center Roderick Beijersbergen was closely involved in the generation of this library, which is now available for researchers within and outside Oncode Institute and the NKI. US grant for clinical study of pancreatic cancer Pancreatic cancer, often triggered by a mutation in the KRAS gene, is still one of the deadliest forms of cancer. In 2018, the Rene Bernards group discovered an unknown weakness of pancreatic cancers. In a preclinical study, funded by the new US Pancreatic Cancer Collective (SU2C and Lustgarten Foundation), the Bernards’ team tested a combination therapy based on this lab finding. In 2020, the same Pancreatic Cancer Collective awarded the NKI team a research grant of 3.8 million dollars, allowing them to start working towards a clinical trial, which will be led by medical oncologist Emile Voest. NKI researchers discover new salivary gland Radiation oncologist Wouter Vogel and oral surgeon Matthijs Valstar have discovered a new salivary gland. The presence of this previously unnoticed macroscopic salivary gland in the human nasopharynx was suspected after visualization by positron emission tomography/computed tomography with prostate-specific membrane antigen ligands. In October 2020, they published their findings, together with colleagues from Amsterdam UMC, UMCG and UMC Utrecht. This fortunate stroke of serendipity, which generated worldwide media attention, may be good news for patients with head and neck tumors: radiation oncologists will now be able to circumvent this area to avoid potential complications (Valstar et al., Radiotherapy and Oncology 2020). Navigation becomes standard technology for complex colorectal surgery The division of Surgical Oncology, led by Theo Ruers, aims to improve the balance between radical surgery and tissue sparing, by bringing innovative navigation technology to the OR. Over the past years, they have introduced the first in world electromagnetic navigation system for abdominal, pelvic and liver surgery. Over 200 patients have now been operated, and in the spring of 2020 the surgeons in our hospital decided to use navigation as standard technology for complex colorectal pelvic surgery. IMAGE-GUIDED THERAPY
New collaborations in Artificial Intelligence Artificial intelligence is becoming more and more important for cancer research, diagnostics, and treatment, and AI-driven image analysis is rapidly developing. In September 2020, the University of Amsterdam and the Netherlands Cancer Institute joined forces in the development of AI algorithms that can improve cancer treatment. The lab, which will be launched in 2021, will be part of the Innovation Center for Artificial Intelligence (ICAI). Junior group leader Jonas Teuwen develops algorithms for image analysis In 2020, the NKI welcomed Jonas Teuwen as a new junior group leader, to start his own ‘AI for Oncology’ group. Teuwen and his group develop algorithms for image recognition that can aid early detection and treatment of cancer. Teuwen works in close collaboration with clinicians. His new lab also closely collaborates with scientists at the University of Amsterdam and is part of the Innovation Center for Artificial Intelligence (ICAI). Implementing quality of life assessment in daily clinical practice In 2020, Lonneke van de Poll’s Survivorship group started implementing and evaluating Patient Reported Outcomes (PRO) assessment in daily clinical practice in our hospital. The ultimate aim is integrating Quality of Life risk factors into the treatment plan for each patient. The pilot work started in breast cancer and melanoma patients. For melanoma, the Survivorship group collaborates with the Blank group, evaluating the impact of neo-adjuvant immunotherapies on the quality of life of melanoma patients participating in trials. complications of cancer treatment affect their long-term survival and mortality. In 2020, the Floor van Leeuwen group and others published two large multicentre studies on long-term cause-specific mortality after Hodgkin lymphoma and testicular cancer (In the Journal of the National Cancer Institute , and Cancer , respectively). They concluded that Hodgkin lymphoma survivors have a substantially reduced life expectancy compared to the general population. Optimal selection of patients for primary chemotherapy is therefore crucial, weighing risks of relapse and long-term toxicity. In a large cohort of patients treated with platinum-based combination chemotherapy for testicular cancer before age 50, the researchers showed that mortality due to subsequent cancers increases with higher platinum doses, suggesting that platinum exposure should be kept as low as possible when treating metastatic testicular cancer (De Vries et al., Journal of the National Cancer Institute 2020 and Groot et al., Cancer 2020). Cause-specific mortality after Hodgkin’s disease and testicular cancer Now that more patients survive cancer, it is important to evaluate how late SURVIVORSHIP AND EPIDEMIOLOGY
COVID-19 AND CANCER RESEARCH
Our mission is researching and treating cancer. However, besides collaborating closely with other hospitals in our region to tackle the COVID crisis and taking good care of Dutch cancer patients, we have also applied our basic and cancer-related knowledge and toolboxes to gain more insight into the virus and its consequences, and to take lessons from this crisis for the future. Here, we present some highlights. Fighting COVID together In just a few weeks in the spring of 2020, all European cancer centres had to drastically revise and reorganise their patient care and scientific research due to the coronavirus crisis. In April 2020, in a Nature Medicine publication, the seven comprehensive cancer centres of Cancer Core Europe, chaired by NKI’s medical director Emile Voest, shared how they had rapidly reorganised their oncological healthcare systems during the COVID-19 pandemic. In this publication, the centres offer guidance to institutions globally by outlining their general consensus measures and organisational strategies adopted to make their operations ‘pandemic proof’ (Van de Haar et al., Nature Medicine 2020). Measuring care and well-being during the COVID-19 crisis How do Dutch cancer patients perceive care and well-being during the COVID-19 crisis, compared to a matched norm population? Group leader Lonneke van de Poll, who specializes in patient-reported outcomes (PRO) assessment, and colleagues from other Dutch centres, used their nation-wide PROFILES registry to study this empirically. Their findings confirm anecdotal reports of cancer patients being afraid, with 23% reporting to be worried about getting COVID-19. However, almost similar anxiety and depression levels in the norm population were seen, as well as an even higher prevalence of loneliness (albeit the difference was not clinically relevant), suggesting that the impact of the crisis may be larger in the norm population than in patients with cancer. The authors conclude that long- term monitoring will be needed (Van de Poll-Franse et al., JAMA Oncology 2021). Cancer immunologist goes corona Group leader Pia Kvistborg normally investigates the interplay between cancer and the immune system, focusing on how the tumor-reactive T cell response, often rendered dysfunctional in cancer, can be improved. In the spring of 2020, she decided to temporarily focus her techniques towards understanding how our immune cells can recognize a coronavirus. Her aim was to unravel which part of the SARS-CoV-2 coronavirus is recognized by our immune system. This will render important knowledge for successful vaccine design. In her corona project, she collaborates with the LUMC, Sanquin, and other partners in Europe and the US. Imaging COVID using AI NKI radiologist Laurens Topff is among the initiators of the ‘Imaging COVID-19 AI’ initiative. This is a European multicenter project to enhance computed tomography (CT) in the diagnosis of COVID-19 by using artificial intelligence. The project group will create a deep-learning model for automated detection and classification of COVID-19 on CT scans, and for assessing disease severity in patients by quantification of lung involvement. VOICE study: Vaccination against cOvid In CancEr Researchers from the NKI, led by medical oncologist John Haanen, the UMCG, LUMC, Erasmus Medical Center and the RIVM, have been awarded 3,3 million euros by national funding agency ZonMW to run a clinical study to investigate how COVID-19 vaccines affect patients with cancer who are treated with chemotherapy, immunotherapy, or both. The study was launched in February 2021.
Chairman of Board of Governors
Her Royal Highness Princess Beatrix of the Netherlands
LJ Hijmans van den Bergh
Board of Governors
Board of Directors
Internal Scientific Advisory Council
LJ Hijmans van den Bergh
RH Medema Chairman and Director of Research
EE Voest Medical Director
ACJ van Akkooi
M van der Meer Director of Organisation, Operations and Management
HGAM van Luenen
JMJM van Krieken
MP Lap From February 2020
Scientific Advisory Board
A Ashworth Director of the UCSF Helen Diller Family Comprehensive Cancer Center, at the University of California, San Francisco T de Lange Leon Hess Professor, The Rockefeller University, New York, USA
SP Jackson Head of Cancer Research UK Laboratories, The Gurdon Institute, University of Cambridge, United Kingdom A Musacchio Honorary Professor, Max- Planck Institute of Molecular Physiology, Dortmund, Germany
R Nusse Professor of Developmental Biology, Stanford University, Stanford, USA HL Ploegh Professor of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Uncovering novel vulnerabilities of cancer
Our main research objective is to identify novel cellular vulnerabilities that can be exploited for cancer therapies. For this purpose, we have developed and are still developing, innovative genomic and genetic tools. In the past, we interrogated diverse targets, such as microRNAs, RNA-binding proteins, regulatory DNA elements (e.g. enhancers and chromatin domains), and non-coding RNAs. Currently we focus on the impact that amino acid shortages have on the proteome. To establish uncontrolled proliferation and aggressive behaviour, cancer cells enhance protein production by deregulating mRNA translation. We hypothesize that this comes at the expense of the quality by which proteins are produced. Indeed, prolonged amino acid deprivation induces the production of aberrant proteins, for example by ribosomal frameshifting. The generation of aberrant proteins can impact protein function, but also can trigger the immune system, as they can be processed and presented on the cell membrane. The generation of aberrant proteins in cancer cells suggests a compromised quality control mechanisms of protein production under stress conditions. We coin this phenomenon sloppiness . In the coming years we intend to investigate the underling mechanisms leading to sloppiness in mRNA translation in cancer cells, and exploit this exciting new field for cancer therapy. Anti-tumour immunity induces aberrant peptide presentation in melanoma Extensive tumour inflammation, which is reflected by high levels of infiltrating T cells and interferon- γ (IFN γ ) signalling, improves the response of patients to checkpoint immunotherapy. Many tumours, however, escape by activating cellular pathways that lead to immunosuppression. One such mechanism is the production of tryptophan metabolites along the kynurenine pathway by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1), which is induced by IFN γ . However, clinical trials using inhibition of IDO1 in combination with blockade of the PD1 pathway in patients with melanoma failed to improve the efficacy of treatment. The role of IDO1 and the consequent degradation of tryptophan in mRNA translation and cancer progression therefore remains unclear. Here we used ribosome profiling in melanoma cells to investigate the effects of prolonged IFN γ treatment on mRNA translation. Notably, we show that ribosomal frameshifting events allow ribosomes to bypass tryptophan codons in the absence of tryptophan. Consistently, reporter assays combined with proteomic and consequent presentation of aberrant peptides at the cell surface after treatment with IFN γ . Priming of naive T cells from healthy donors with aberrant peptides induced peptide- specific T cells. Together, our results suggest that IDO1-mediated depletion of tryptophan, which is induced by IFN γ , has a role in the immune recognition of melanoma cells by contributing to diversification of the peptidome landscape. Frequent activation of the co-transcriptional factor YAP is observed in a large number of solid tumors. Activated-YAP associates with enhancer loci via TEAD4-DNA-binding protein, and stimulates cancer aggressiveness. Although thousands of YAP/TEAD4 binding-sites were annotated, their functional importance is unknown. In this study, we aimed to explore our functional genetic enhancer screening approach (Korkmaz et al., Nat Biotechnol. 2016) to identify regulatory enhancer elements that are required for YAP function. First, we used genome-wide CHIP profiling of YAP to systematically identify enhancers that are bound by YAP/TEAD4. Then, we implemented a genetic approach to uncover functions of YAP/TEAD4-associated enhancers, demonstrated its robustness, and used it to uncover a network of enhancers required for YAP-mediated proliferation. We focused on Enhancer TRAM2 , as its target gene TRAM2 showed the strongest expression-correlation with YAP activity in nearly all tumor types. Interestingly, TRAM2 phenocopied the YAP-induced cell proliferation, migration and invasion phenotypes, and correlated with poor patient survival. Thus, TRAM2 is a key novel mediator of YAP-induced oncogenic proliferation and cellular invasiveness. Our findings elucidate how YAP induces cancer aggressiveness, and may assist diagnosis of cancer metastasis. A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis
Division head, group leader Division Oncogenomics
Reuven Agami PhD Group leader Daniela Annibali PhD Post-doc Julien Champagne PhD Post-doc Li Li PhD Post-doc
Bartok O, Pataskar A, Nagel R, Laos M, Goldfarb E, Hayoun D, Levy R, Körner PR, Kreuger IZM, Champagne J, Zaal E, Bleijerveld OB, Huang X, Kenski J, Wargo J, Brandis A, Levin Y, Mizrahi O, Alon M, Lebon S, Yang W, Nielsen MN, Stern-Ginossar N, Altelaar M, Berkers CR, Geiger T, Peeper DS, Olweus J, Samuels Y, Agami R. Anti-tumor immunity induces the presentation of aberrant peptides in melanoma. Nature 2020 Li L, Ugalde AP, Scheele C, Dieter SM, Nagel R, Ma J, Pataskar A, Korkmaz G, Elkon R, Chien MP, You L, Su PR, Bleijerveld OB, Altelaar M, Momchev L, Manber Z, Han R, van Breugel PC, Lopes R, ten Dijke P, van Rheenen J, Agami R. A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis. Genome Biol 2020 (in press) Slobodin B, Bahat A, Sehrawat U, Becker-Herman S, Zuckerman B, Weiss AN, Han R, Elkon R, Agami R, Ulitsky I, Shachar I, Dikstein R. Transcription Dynamics Regulate Poly(A) Tails and Expression of the RNA Degradation Machinery to Balance mRNA Levels. Mol Cell. 2020;78(3):434-444
Macrophage dynamics in cancer progression and response to treatment
The overall goal of our research group is to determine the mechanisms utilized by tumors to shape myeloid cell subset content and education to their advantage, and how the evolution of these cells’ programming influences response to therapy. Through mechanistic understanding of the crosstalk between macrophage subpopulations and cancer cells, we aim to contribute to the design of novel immunomodulatory strategies that can potentiate anti-cancer therapy response. Uncovering glioma macrophage populations’ dynamic changes after radiotherapy In murine and human glioblastoma (GBM), the dominant non-cancerous cell populations are the innate immune tumor-associated macrophages (TAMs). However, the relative abundance and contribution of each macrophage subsets, namely the brain resident microglia (MG) and tumor-recruited monocyte derived macrophages (MDMs) in GBM progression and response to radiotherapy was previously unknown. In light of the ontogenical differences between these two subset of TAMs, we identified radiation-specific, stage-dependent MG and MDM phenotype in murine gliomas, and confirmed these findings in recurrent human glioblastoma. Therapeutically, hindering the adapted education that these cells acquire post-radiotherapy delayed the emergence of GBM recurrence. Our findings revealed the dynamics and plasticity of distinct macrophage subset, which has translational relevance for enhancing the efficacy of combination therapy in GBM. Optimizing the combination between radio- and immunotherapy in glioblastoma Incorporating anti-PD1 T-cell immunotherapy (IT) to the current standard of care treatment in GBM has failed to provide therapeutic results. In collaboration with Dr Gerben Borst, we are investigating the efficacy of concurrent as opposed to an adjuvant IT to radiotherapy (IR). We found that the numbers of CD4 + T cells was acutely increased immediately at cessation of radiation treatment in GBM-bearing mice. Anti-PD-1 administration as concurrent (initiated 1 day prior to IR) or adjuvant therapy (initiated 6 hours following the last IR dose) had strikingly different outcomes, with only adjuvant anti-PD-1 treatment resulting in increased animal survival, despite fewer anti-PD-1 doses administered. No differences in CD8 + T cell content or activation were found, and our results suggest that resistant to concurrent IT is orchestrated by myeloid cells in the IR-treated GBM TME. These findings support the timely combination of IT with myeloid-centric targeting to harness anti- tumor immunity in IR-treated GBM. We have developed multiple hepatocellular carcinoma (HCC) murine models using the relevant oncogenic drivers of this disease, by taking advantage of hydrodynamic gene delivery and the Sleeping Beauty-mediated somatic integration in mouse hepatocytes in vivo . We found that different oncogenic drivers distinctively shape the HCC tumor microenvironment. We generated aggressive or slow-growing HCC which contained different amounts of myeloid cells, including tissue-resident or infiltrating macrophages. Our results support the hypothesis that IL-1 pathway activity correlates with chronic inflammation, tumor growth and overall survival through increased infiltration of IL-1 cytokine producing myeloid cells in myeloid-dominant HCC and that the underlying genetic background of liver cancer cells regulates the responsiveness of this pathway activity. Unraveling the cancer cell genetics’ regulation of the HCC immune tumor microenvironment.
Group leader Division Tumor Biology & Immunology
Leila Akkari PhD Group leader Luuk van Hooren PhD Post-doc Serena Vegna PhD Post-doc Johanna Erbani PhD Post-doc Awa Gassama MSc PhD student Daan Kloosterman MSc PhD student Christel Ramirez MSc PhD student Daniel Taranto MSc PhD student Jeremy Tessier MSc PhD student Marnix de Groot MSc Technical staff Shanna Handgraaf MSc Technical staff
Akkari L, Bakhoum SF. The Future of Cancer Research. Trends Cancer. 2020;6:724-729 Akkari L*, Bowman RL, Tessier J, Klemm F, Handgraaf SM, de Groot M, Quail DF, Tillard L, Gadiot J, Huse JT, Brandsma D, Westerga J, Watts C, Joyce JA*. Sci Transl Med. 2020;12(552). *co-corresponding authors Kloosterman DJ, Akkari L. Mapping the Uncharted Territories of Human Brain Malignancies. Cell 2020;181(7):1454- 1457
Oncologic Imaging Research
The research brings together physicians, computer scientists, engineers to work in synergy on the development of imaging technologies to improve personalised treatment.
Imaging for Organ preservation The group has a longstanding track record in MRI for organ preserving treatment of rectal cancer. This rectal cancer imaging research is expanded with an EU funded study aiming at developing AI models to predict outcome using data from MRI, endoscopy and biopsy. A nationwide study generates real life evidence using imaging and clinical data from over 10 Dutch medical centers. A spin off research is the creation of a (webbased) infrastructure aiming to exchange data for implementation studies and training of organ preserving diagnostics and treatment. The organ- preservation research is extended to oesophageal cancer and together with Erasmus MC we investigate the value of a multimodal stratification tool using endoscopy and MRI. In colorectal cancer multicenter studies aim to build models linking multiple MR and CT parameters to clinical data to predict treatment response and outcome. This is also the focus of research in Head and Neck cancer. In prostate cancer, our studies aim to develop MR- based risk models that can accurately stratify patients for individualized treatment. In Neuro imaging the role of metabolic 7T-MRI and 19F-MRI is being investigated to visualize tumor microenvironment. Breast MRI research focuses on establishing the value of MRI for prediction of response to neoadjuvant systemic treatment. Research in peritoneal carcinomatosis investigates whether MRI can be used to select colorectal and ovarian cancer patients for cytoreductive surgery. In all research lines AI-based solutions are developed and validated. Interventional Oncology Research focuses on evaluating the efficacy and safety of new procedures such as ablation, radioembolization, vertebroplasty etc and on imaging methods, incl AI, to accurately detect local recurrence after treatment. Artificial Intelligence in Immunotherapy and Radiogenomics AI research leverages AI methodologies to develop non-invasive AI-biomarkers and bring clinically- usable algorithms into the clinic. The research focuses on exploring predictive AI signatures of response to immunotherapy in several cancer types. A radio-genomics research aims to link radiomics signatures with clinically relevant genetic mutations using imaging and genomic data from ~ 2000 patients, creating the largest Pancancer radiogenomics cohort in literature. This will allow for the exploration of novel AI radiogenomics signatures. Additionally, with these large and heterogeneous data, we will be able to explore tumour heterogeneity in imaging as well the global impact of the genotype on radiological phenotype, independent of the tumour type. Multiparametric imaging Research in multiparametric CT and MR run with several cancer types.
Group leader Division Diagnostic Oncology
Regina Beets-Tan MD PhD Head Dept Radiology Sean Benson MSc PhD Post-doc Brigit Aarts MD PhD Post-doc Daphne van de Velden MD PhD Post- doc Stefano Trebeschi MSc PhD Post-doc Selam Waktola MSc PhD Post-doc Zuhir Elkarghali MD MSc PhD student Maurits Engbersen MSc PhD student Joost van Griethuysen MD PhD student Kevin Groot Lipman MSc PhD student Kay van der Hoogt MD PhD student Hedda van der Hulst MD PhD student Najim el Khababi MSc PhD student Denise van der Reijd MD PhD student Charlotte Rijsemus MD PhD student Niels Schurink MSc PhD student Femke Staal MD PhD student Marjanneh Taghavirazavizadeh MSc PhD student Teresa Tareco Bucho MD PhD student Melda Yeghaian MD PhD student Engbersen MP, Aalbers AGJ, Van’t Sant-Jansen I, Velsing JDR, Lambregts DMJ, Beets-Tan RGH, Kok NFM, Lahaye MJ. Extent of peritoneal metastases on preoperative DW-MRI is predictive of disease-free and overall survival for CRS/HIPEC candidates with colorectal cancer. Ann Surg Oncol. 2020;27(9):3516-3524 Haak HE, Maas M, Trebeschi S, Beets-Tan RGH. Modern MR Imaging Technology in rectal cancer; there is more than meets the eye. Front Oncol. 2020;10:537532 Vollenbrock SE, et al. Added value of MRI to endoscopic and endosono graphic response assessment after neoadjuvant chemoradiotherapy in oesophageal cancer. Eur Radiol. 2020;30(5):2425-2434 Key publications
Cancer specific dependencies
Our research continues to evolve around the development and use of functional genomic screening technologies for the discovery of regulators of crucial pathways deregulated in cancer, genotype specific dependencies and synthetic lethal interactions that can be explored as drug targets in precision therapy. To achieve these goals, we have used our pooled screening platforms based on shRNA or CRISPR/CAS9. Besides CRISPR-based gene-editing, we also use CRISPR-based transcriptional activation and -repression screening technologies. Although many of our screening technologies are based on pooled screening, we have also established a platform for single well CRISPR screens using synthetic guide RNAs This technology allows for screening with read- outs based on more complex phenotypes and includes the ability of identifying genes that upon inactivation affect the levels of (allele) specific gene transcription. In October 2020, the KWF sponsored ScreeninC national infrastructure, consisting of three research sites (LACDR, Leiden, ERIBA Groningen and NKI Amsterdam) was started. ScreeninC gives clinical and basic research groups in the Netherlands access to expertise, tools and infrastructure to apply functional genomic technologies from advanced model generation to large-scale screening. As part of the ScreeninC infrastructure, we have optimized our screening protocols, set-up large- scale high titer lentivirus production, generated custom sgRNA libraries for specific projects and optimized drug treatment strategies for the identification of response modifiers upon long-term drug exposure. In addition, we expanded our cell line panel with dox-inducible CAS9, dCAS9-VP64 and dCAS9-KRAB expressing clones. Previously, we have shown that the use of stable cell lines with induction of high levels of CAS9, increased the efficiency to identify essential genes. We have now also demonstrated that the ability to identify genes that upon knockout trigger resistance can be increased by not only using high levels of CAS9 but in addition allowing editing time before the first drug exposure. Functional genomic screens based on cell proliferation and survival are key for the identification of genes that determine drug response and treatment resistance. However, many biological phenotypes are only captured by the specific activation of sets of target genes. We have therefore developed a single well CRISPR screening platform with the use of synthetic sgRNAs followed by automated high throughput, mRNA isolation, cDNA production, multiplex PCR and deep sequencing. With this pipeline, we can study the role of subsets of genes, for example epigenetic modifiers, in the control of the (low) expression of specific gene sets. In addition, this platform also allows for the study of the control of mono-allelic expressed genes. We are currently validating the results of an epigenetic modifier genes screen on a panel of mono-allelic expressed genes. These approaches allow for the identification of specific dependencies in the context of tumor- and patient-specific alterations that can be further explored for pathway-targeted therapeutics in cancer.
Roderick Beijersbergen Group leader Division Molecular Carcinogenesis
Roderick Beijersbergen PhD Group leader Lorenzo Bombardelli PhD Post-doc Johan Kuiken PhD Senior post-doc Cor Lieftink MSc Bioinformatician Elke Malzer PhD Technical staff Ben Morris Technical staff Wouter Nijkamp Technical staff
Benedict B, van Bueren MA, van Gemert FP, Lieftink C, Guerrero Llobet S, van Vugt MA, Beijersbergen RL, Te Riele H. The RECQL helicase prevents replication fork collapse during replication stress. Life Sci Alliance. 2020;3(10) Jin H, Wang S, Zaal EA, Wang C, Wu H, Bosma A, Jochems F, Isima N, Jin G, Lieftink C, Beijersbergen R, Berkers CR, Qin W, Bernards R. A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. Elife. 2020;9
Wang C, Wang H, Lieftink C, du Chatinier A, Gao D, Jin G, Jin H,
Beijersbergen RL, Qin W, Bernards R. CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma. Gut. 2020;69(4):727-736