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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 target discovery

The Peeper laboratory develops and uses function-based genomic approaches to better understand the mechanistic principles of cancer progression, and to identify novel therapeutic targets for achieving more durable clinical responses for cancer patients. We have two main strategies: first, we wish to increase our understanding of how cancer cells originate and function, define their rewired signaling networks and subsequently expose their weaknesses. This will allow for the identification of specific and pharmacologically tractable vulnerabilities. Second, we wish to determine how we can manipulate various cell types from the patient's own immune system to enhance their cytotoxicity towards tumor cells. This approach should uncover new therapeutic targets on immune cells. By focusing on these two main research arms, our objective is to contribute to the development of combinatorial therapies, which simultaneously eliminate the patients' tumor cells and harness their immune cells.

Function-based genomic screens

We use various experimental approaches to achieve these goals. A major tool in the laboratory is function-based genomic 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 a high-throughput manner. Candidate genes are subsequently analyzed by our own bioinformaticians. Often, their computational approaches yield additional insight into the signaling pathways affected by the screen hits. Eventually, screen hits are validated and characterized in-depth in a clinically relevant context, for example, patient-derived tumor xenografts (PDX). 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, Daniel Peeper and Christian Blank (a clinician researcher/medical oncologist) recently engaged in a partnership to complement our respective basic and clinical 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.

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 melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDX as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAFV600E protein harboring a kinase domain duplication (BRAFV600E/DK) in approx. 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 utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.

Developing systems to integrate targeted and immunotherapy

Exciting advances have been made for immunotherapy in melanoma, and 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. While the first generation of clinical results are unprecedented, it is clear that large groups of patients will not, or only temporarily, benefit from immunotherapy, partly as a result of resistance. Therefore, in collaboration with the group of Ton Schumacher at NKI, we are building in vitro and in vivo systems to study tumor cell : T cell interactions. We also use these systems to perform function-based screens to develop combinatorial targeted and immunotherapy regimens to achieve more durable clinical responses.

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 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 pharma 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.

Melanoma progression

Previously, in a longstanding collaboration with prof. Mooi (VUmc), we were the first to discover that melanocytic nevi (moles) undergo oncogene-induced senescence (OIS) in vivo. We also obtained in situ evidence that reduction of PTEN levels causes abrogation of OIS and thereby contributes to melanoma progression. We also discovered that cells entering OIS show a massive loss of nuclear envelope proteins as a consequence of their degradation by the autophagy machinery. More recently, we collaborated with the group of Bas van Steensel (NKI) to use DamID analysis to investigate the changes in genome-nuclear lamina (NL) interactions in BRAFV600E-induced senescence. We found that these cells lose most of their constitutive LADs (cLADS), with multiple genes relocating to the NL. Unexpectedly, they were not repressed, implying new mechanisms tethering cLADs to the NL to repress gene expression.

Targeting cancer cell metabolism

We have previously discovered by metabolic profiling (in collaboration with prof. Eyal Gottlieb, Glasgow) 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 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, which we are currently exploring. Furthermore, we are functionally mining the metabolome for potential new therapeutic targets.

Breast cancer metastasis: mechanism and drug target identification

We have previously discovered a novel critical mediator of breast cancer metastasis, the Fra-1 transcription factor. Fra-1 depletion reduced metastatic potential by >3 orders of magnitude. In a parallel in vivo and in vitro genetic shRNA dropout screen, we recently identified a synergistic interaction between EGFR and ROCK inhibitors, warranting their further validation of as combined pharmacologic targets for breast cancer. Underscoring a more general role for Fra-1 in cancer, we recently demonstrated that it is an important determinant of the metastatic potential of human colon cancer cells, too, and that the Fra-1 classifier can be used as a prognostic predictor in colon cancer patients.

Co-workers

Apriamashvili, G.

Georgi Apriamashvili

Master Student

Experience

The possibility to mobilizethe immune system for cancer treatment has gained enormous momentum in recent years and yielded impressive success stories. Under the supervision of Ali Can Sahillioglu I am working on possible improvements for cancer immunotherapy, which are needed to make the treatment more successful and bearable for patients.

 

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Xinyao Huang

PhD 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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Kristel Kemper

Postdoctoral Fellow

Experience

After internships with Hein te Riele (NKI, Amsterdam) and Bob Weinberg (Whitehead Institute, Boston), I've completed my Master Biomedical Sciences at the University of Amsterdam cum laude. In 2006, I've received an AMC Graduate School Scholarship and started my PhD with Jan Paul Medema (AMC, Amsterdam). In 2012, I've defended my thesis entitled "Molecular identification and targeting of colorectal cancer stem cells". Since November 2011, I've joined the Peeper group, where I'm responsible for creating a patient-derived xenograft (PDX) platform of metastatic melanoma. Using this platform, I'm performing in vivo screens to identify new drug targets for melanoma.

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Xiangjun Kong

Postdoctoral fellow

Experience

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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 started as a bioinformatician in R&D at the NKI spinoff Agendia (Amsterdam). In 2009 I started my PhD in the groups of Bauke Ylstra and Gerrit Meijer (VUmc-CCA). Early 2014 I wilI defend my PhD thesis entitled 'Detection and relevance of focal chromosomal copy number aberrations in cancer'.

In September 2013 I joined the Peeper group, where I will study drug-resistance and combination therapies for personalized medicine in cancer, including melanoma.

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Thomas Kuilman

Postdoctoral fellow

Experience

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Aida Shahrabi

Technician

Experience

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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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Julia Boshuizen

MD, Phd student

Experience

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Juliana De Carvalho Neme Kenski

PhD student

Experience

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Ligtenberg, Maarten

Maarten Ligtenberg

Postdoc

Experience

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Kun-Hui Lu

Postdoc

Experience

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David Vredevoogd

PhD 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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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'm currently studying the role of pyruvate dehydrogenase kinase 1 in melanoma. I'm also establishing functional genetic screens to identify novel metabolic targets in melanoma and tumour-targeting immune cells.

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Research updates View All Updates

Key publications View All Publications

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

    Nat Commun. 2014 Dec 15;5:5712. doi: 10.1038/ncomms6712.

    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, et al.

    Link to PubMed
  • Parallel In Vivo and In Vitro Melanoma RNAi Dropout Screens Reveal Synthetic Lethality between Hypoxia and DNA Damage Response Inhibition.

    Cell Rep. 2014 Nov 20;9(4):1375-86. doi: 10.1016/j.celrep.2014.10.024. Epub 2014 Nov 6.

    Possik PA, Müller J, Gerlach C, Kenski JC, Huang X, Shahrabi A, Krijgsman O, Song JY, Smit MA, Gerritsen B, Lieftink C, Kemper K, Michaut et al.

    Link to PubMed
 
 

Recent publications View All Publications

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

    Cell Rep. 2016 Jun 28;16(1):263-77. doi: 10.1016/j.celrep.2016.05.064. PMID: 27320919

    Kemper K, Krijgsman O, Kong X, Cornelissen-Steijger P, Shahrabi A, Weeber F, van der Velden DL, Bleijerveld OB, Kuilman T, Kluin RJ,...

    Link to Pubmed
  • Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts

    EMBO Mol Med. 2015 Jun 23;7(9):1104-18. doi: 10.15252/emmm.201404914. PMID: 26105199

    Kemper K, Krijgsman O, Cornelissen-Steijger P, Shahrabi A, Weeber F, Song JY, Kuilman T, Vis DJ, Wessels LF, Voest EE, Schumacher TN,...

    Link to Pubmed
 

Contact

  • Office manager

    Karin Hageman

  • E-mail

    k.hageman@nki.nl

  • Telephone Number

    +31 20 512 2099

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