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Molecular Oncology & Immunology: Daniel Peeper

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Daniel Peeper, Ph.D. ProfessorGroup Leader, Head of Division

About Daniel Peeper

FUNCTIONAL GENOMICS FOR CANCER AND IMMUNE CELL THERAPY

The Peeper laboratory uses function-based, genome-wide experimental strategies to develop rational combinatorial cancer treatment, targeting both cancer and immune cells. By screening for novel therapeutic targets and predictive biomarkers, we aim to achieve more durable clinical responses for patients. On the one hand, we're increasing our understanding of how cancer cells rewire their signaling networks, to expose and exploit new pharmacologically tractable tumor susceptibilities, also in the context of immunotherapy. On the other, we're manipulating various cell types from the patient's own immune system to boost their specific cytotoxicity towards tumor cells. With these approaches, we
are developing new rational combinatorial therapies, which simultaneously eliminate the patients' tumor and harness their immune system.

RESEARCH

Function-based genomic screens

We use various experimental approaches to achieve these goals. A major tool in the laboratory is function-based, genome-wide screens: we have been developing and employing in vitro and in vivo genetic functional perturbation screens, for several cancer types, including melanoma and lung and breast cancer. Hits are identified in specific experimental settings allowing to identify essential gene functions in an efficient high-throughput manner. Candidates are analyzed by our own bioinformaticians. Often, their computational approaches provide additional insight into the signaling pathways affected by the screen hits. Eventually, identified genes are validated and characterized in-depth in a clinically relevant context, for example, patient-derived tumor xenografts (PDX) and humanized mouse models. The outcome of these strategies is the identification of druggable pathways as well as predictive biomarkers.

Clinical translation

The objectives outlined above imply that a central goal of our laboratory is to translate our findings to the benefit of the patient, taking advantage of our comprehensive cancer institute. To maximize these efforts, PI Daniel Peeper and Christian Blank (a clinician researcher) recently engaged in a partnership to complement our basic, translational and clinical fields of expertise. This warrants not only the clinical relevance of our research questions, but also facilitates translation of our laboratory findings (therapeutic targets, prognostic and predictive biomarkers) to the clinic, particularly by initiating trials that are run here at NKI.

An in vivo preclinical platform for melanoma

The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established in collaboration with our clinical colleagues Haanen, Blank and Schumacher a large collection of PDX, derived from BRAFV600E, NRASQ61, or BRAFWT/NRASWT melanomas prior to treatment with BRAF inhibitor and after resistance had occurred. To demonstrate the utility of this platform, we took advantage of PDX as a limitless source and screened tumor lysates for new resistance mechanisms. We identified a BRAFV600E protein harboring a kinase domain duplication (BRAFV600E/DK) in ≈10% of the cases, both in PDX and in an independent patient cohort. While BRAFV600E/DK depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAFV600E/DK-expressing cells. These results illustrate the value of this platform and warrant clinical validation of BRAF dimerization inhibitors and BRAFV600E/DK as a predictive biomarker for this group of melanoma patients.

Developing systems to integrate targeted and immunotherapy

Exciting advances have been made also for immunotherapy of melanoma, and indeed an increasing number of other cancer types. Several modes of activation are currently exploited to trigger patients' own immune systems to allow for tumor eradication. Notwithstanding these clinical advances, it is clear that large groups of patients will not, or only temporarily, benefit from immunotherapy, mostly because of resistance. Therefore, in collaboration with the group of Ton Schumacher at NKI, we have built in vitro and in vivo systems to study tumor cell : T cell interactions. We use these systems to perform function-based screens to develop combinatorial targeted and immunotherapy regimens to achieve more durable clinical responses.

Similar matched epitope/TCR systems have now been set up for lung cancer, also to use large-scale genetic perturbations for the identification of predictive biomarkers and new therapeutic targets.

Understanding and overcoming targeted drug resistance in melanoma

We previously found that the lack of the melanoma transcription factor MITF is associated with severe resistance to a range of targeted inhibitors. Both in intrinsic and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. Drug cocktails containing AXL inhibitor enhanced melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. On the basis of these results, we engaged in a collaboration with the Dutch pharma company Genmab to explore clinical translation of these findings. For example, we are studying whether an AXL antibody-drug conjugate can serve as a new melanoma therapeutic.

Targeting cancer cell metabolism

We have previously discovered by metabolic profiling (icw. Eyal Gottlieb) and functional perturbations that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAFV600E. While the activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress, abrogation of oncogene-induced senescence (OIS) coincided with reversion of these processes. Enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAFV600E-driven melanoma development. Depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition and caused regression of established melanomas. These results revealed a mechanistic relationship between BRAF OIS and identified a key metabolic signaling axis that may be exploited therapeutically. Recently, we have begun to functionally mine the metabolome for potential new therapeutic targets, both in tumor and immune cells.

Cancer drug addiction

Observations from cultured cells, animal models and patients raise the possibility that the dependency of tumors on the therapeutic drugs to which they have acquired resistance represents a vulnerability with potential applications in cancer treatment. However, for this drug addiction trait to become of clinical interest, we had to define the mechanism that underlies it. We performed an unbiased CRISPR-Cas9 knockout screen on melanoma cells that were both resistant and addicted to inhibition of BRAF, to functionally mine their genome for 'addiction genes'. We discovered a signalling pathway comprising ERK2 and the JUNB/FRA1 transcription factor, disruption of which allowed addicted tumour cells to survive on treatment discontinuation, irrespective of the acquired drug resistance mechanism and which was conserved in ERGFRi-resistant lung cancer cells. As a PoC, we show that drug holiday synergized with chemotherapy. These results uncover a pathway that underpins drug addiction in cancer cells, which may help to guide the use of alternating therapeutic strategies for enhanced clinical responses in drug-resistant cancers.

Co-workers

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Dr. med. Astrid Alflen

Research associate

Experience

During my medical training I did basic research on the effect of phytoestrogens on proliferation and on the stem cell signature of malignant testicular germ cell tumor cell lines. I completed my training and medical thesis in 2013 at the Georg August University, Goettingen (Germany). Since working as a resident physician in hematology and medical oncology at the University Medical Center Mainz (Germany) I was engaged in research again, mostly in the field of innate immunity. I analyzed the impact of targeted therapies on neutrophil functions and thereby on the susceptibility to infections of patients, working with human samples and mouse models.

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Apriamashvili, G.

Georgi Apriamashvili

Ph.D. student

Experience

After obtaining my Bachelor's degree in Biomedicine at the University of Wuerzburg in 2013, I enrolled for the Master's Program Life Science and Technology at Leiden University. During my Master's internship I worked in the group of Ton Schumacher on regulating T cell activity in the context of adoptive T cell transfer. Shortly after graduating from Leiden University in 2016, I started as a PhD Student in the group Daniel Peeper. Here I focus on developing new strategies for immunotherapies using functional genomic screens.

 

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Boshuizen, Julia

Julia Boshuizen

MD, Ph.D. student

Experience

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De Bruijn, Beau

Beau de Bruijn

Technician

Experience

After obtaining my bachelor's degree at Saxion University of Applied Sciences, I started the Master's program Oncology at VU Amsterdam. During my Master's I performed internships at the labs of Hein te Riele, the Netherlands Cancer Institute, where I optimized a procedure for targeted gene modification in HAP1 cells, and Michael Gough, Providence Cancer Center, Portland OR, where I studied the effect of STING ligands on different immune cells. After graduating with honors and a Top Master title in 2017, I joined the Daniel Peeper Lab as research technician. Here I will work on different projects, specifically performing animal experiments. 

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Juliana De Carvalho Neme Kenski

Ph.D. student

Experience

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Xinyao Huang

Ph.D. student

Experience

Xinyao Huang obtained her Bachelor's degree in Applied Sciences with a major in Biochemistry at the Hogeschool van Arnhem en Nijmegen, The Netherlands. She subsequently followed the Oncology program in Biomedical Sciences at the University of Amsterdam. After rotations in Rene Bernards' group at the NKI and Yang Shi's lab at the Harvard Medical School, she joined the Peeper lab as a PhD student in 2013.

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Ibanez Sofia

Sofía Ibáñez Molero

Ph.D. student

Experience

Sofía Ibáñez Molero received her Bachelor's degree in Biotechnology in 2016 and she completed her Master's in Biotechnology and Molecular Biology in 2017 in the University of Murcia, Spain. During this time, she focused on deciphering the role of oxidative stress produced by Duox1 in melanoma progression and aggressiveness. She did two internships, in the Prof. Steve Wilson's group in the University College of London and in Prof. Adam Hurlstone's group in the University of Manchester. In the last one she collaborated in the study of IFNg in inflammation induced adaptative resistance to immunotherapy. In 2018 she joined Prof. Daniel Peeper's group as a PhD to study immunotherapy resistance in melanoma and lung cancer.

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Oscar Krijgsman

Postdoctoral fellow

Experience

After internships at the DKFZ (Heidelberg, Germany) and the VUmc (Amsterdam) I completed my Masters in Bioinformatics at the VU university in Amsterdam. Following my masters I worked as a bioinformatician in R&D at the NKI spinoff Agendia (Amsterdam). In 2009 I started my PhD in the group of Bauke Ylstra and defended my PhD thesis in March 2015.

In September 2013 I joined the Peeper group, where I study drug-resistance and combination therapies for personalized medicine in cancer. In the last years the focus of the lab and my research shifted from resistance to targeted therapies to resistance and prediction of responds to Immune-checkpoint blockade, the current first line treatment for melanoma and lung cancer.

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Lévy, Pierre

Pierre Lévy

Postdoctoral fellow

Experience

During my MSc and PhD, I worked in the team of Fabien Zoulim at the Cancer Research Centre of Lyon (France), where I described the tumour-like reprogramming of glutamine metabolism induced by hepatitis C virus. After a career break traveling around South America, I joined the Peeper group at the NKI as a postdoc. I am currently working on overcoming the inhibitory effect of low nutrients on CD8 T cell anti-tumour function.

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Ligtenberg, Maarten

Maarten Ligtenberg

Postdoc

Experience

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Chun Pu Lin

Chun-Pu Lin

Ph.D. student

Experience

I received my B. S. degree in life science and M. S. degree in molecular and cellular biology from National Tsing Hua University. My master study was focused on epigenetic regulation of breast cancer cell proliferation under hypoxia. After graduation, I had been working in international pharmaceutical companies as medical affair specialists. In 2016, I did an internship training in Ludwig Center for Cancer Research at the University of Lausanne, studying tissue resident memory T cells in mouse model. In 2018, I joined Prof. Daniel Peeper's lab as a PhD student.

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Schieven, Sebastiaan

Sebastiaan Schieven

Ph.D. student

Experience

In 2017 I obtained my master degree in Life Science & Technology at Leiden University. During the first year of my master, I did an internship at the Institute of Biology Leiden under supervision of Prof. B. Ewa Snaar-Jagalska. Here, I focussed on how the actin cytoskeleton of prostate cancer stem cells might influence their stemness and migratory properties using zebrafish as model organism. In addition, I worked at the Hubrecht Institute in Hans Clevers' group during which I investigated mechanisms of invasiveness in primary lung cancer organoids. I joined the Peeper lab in 2018 as a Ph.D. student to investigate and characterize phenotype switching in melanoma for subsequent targeting.

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Terry, Alexandra

Alexandra Terry

Postdoctoral fellow

Experience

I completed my PhD in the group of Barbara Fazekas at the Centenary Institute for Medical Research in Sydney, Australia, where I investigated the role of CD4+ T cells and regulatory T cells in tumour immunity. After completion of my degree I joined the Peeper group at the NKI as a postdoc to investigate the genomic factors responsible for immunotherapy resistance in melanoma and lung cancer.

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Nils Visser

Lab Manager, Technician

Experience

In 2006 I received my Bachelors degree at the university of Applied Sciences in Leiden, the Netherlands, specialising in animal experimentation.

2006-2008: Research technician in the group of Dr. Peter ten Dijke at the LUMC.

2008-2011: Research technician in the group of Dr. Fiona Stewart at the Netherlands Cancer Institute.

2011-present I joined the Peeper Lab as research technician and since 2012 also hold the position of laboratory manager of the division of Molecular Oncology.
The projects I'm working on are aimed at the discovery and validation of new breast cancer targets, and the according development of new drugs.

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Vliet van, Alex

Alex van Vliet

Ph.D. student

Experience

I have a master's degree in bioinformatics and systems biology from the Vrije Universiteit Amsterdam/Universiteit van Amsterdam. During my master's I interned at the Peeper lab at the NKI, where I expanded the functionality of the CopywriteR software package for copy number aberration detection, and the Korbel lab at EMBL Heidelberg, where I developed and implemented a method for
translocation detection in single-cell template strand sequencing data (Strand-seq). At the tail end of 2018 I returned to the Peeper lab to start my bioinformatics PhD, where I will work on immunotherapy resistance in lung cancer.

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David Vredevoogd

Ph.D. student

Experience

Having obtained my bachelor's degree in Psychobiology, I started a master in Biomedical Sciences with a specific focus on immunology at the University of Amsterdam in 2013.  During my studies I enrolled in two internships, one in the lab of prof. Marieke van Ham regarding regulatory B cells and another, in the lab of prof. Ton Schumacher, on the mechanisms by which a resident memory T cell population is established. After graduating with honors (cum laude) in 2015, I started my PhD in the lab Daniel Peeper. In his lab, I now focus on identifying new targets for immunotherapy in melanoma by using functional genetic screens.

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Research updates View All Updates

Key publications View All Publications

  • BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts

    Cell Rep. 2016 Jun 28;16(1):263-277.

    Kemper K, Krijgsman O, Kong X, Cornelissen-Steijger P, Shahrabi A, Weeber F, van der Velden DL, Bleijerveld OB, Kuilman T, Kluin RJ, Sun C, Voest EE, Ju YS, Schumacher TN, Altelaar AF, McDermott U, Adams DJ, Blank CU, Haanen JB, Peeper DS.

    Link to Pubmed
  • Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

    Nat Commun. 2014 Dec 15;5:5712.

    Müller J, Krijgsman O, Tsoi J, Robert L, Hugo W, Song C, Kong X, Possik PA, Cornelissen-Steijger PD, Foppen MH, Kemper K, Goding CR, McDermott U, Blank C, Haanen J, Graeber TG, Ribas A, Lo RS,Peeper DS.

    Link to Pubmed
 
 

Recent publications View All Publications

  • Augmenting Immunotherapy Impact by Lowering Tumor TNF Cytotoxicity Threshold.

    Cell. 2019 Jul 25;178(3):585-599.e15.

    Vredevoogd DW, Kuilman T, Ligtenberg MA, Boshuizen J, Stecker KE, de Bruijn B, Krijgsman O, Huang X, Kenski JCN, Lacroix R, Mezzadra R, Gomez-Eerland R, Yildiz M, Dagidir I, Apriamashvili G, Zandhuis N, van der Noort V, Visser NL, Blank CU, Altelaar M, Schumacher TN, Peeper DS.

    Link to Pubmed
  • In vivo ERK1/2 reporter predictively models response and resistance to combined BRAF and MEK inhibitors in melanoma

    Mol Cancer Ther. 2019 Jul 3. pii: molcanther.1056.2018.

    Sanchez IM, Purwin TJ, Chervoneva I, Erkes DA, Nguyen MQ, Davies MA, Nathanson KL, Kemper K, Peeper DS, Aplin AE.

    Link to Pubmed
 

Contact

  • Office manager

    Stephanie Timmer

  • E-mail

    s.timmer@nki.nl

  • Telephone Number

    +31 20 512 2099

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