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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 is in the brand-new Division of Molecular Oncology and Immunology at NKI. We develop and use function-based genomic approaches to better understand the mechanistic principles of cancer progression, and to identify novel therapeutic targets and predictive biomarkers for achieving more durable clinical responses for cancer patients. We have two main strategies. First, we want to increase our understanding of how cancer cells function and rewire their signaling networks. This will expose their weaknesses and allow or the identification of pharmacologically tractable vulnerabilities. Second, we are manipulating various cell types from the patient's own immune system to enhance their specific cytotoxicity towards tumor cells. Also this approach should uncover new therapeutic targets, on immune cells. With these strategies, we aim to contribute to the development of combinatorial therapies, which simultaneously eliminate the patients' tumor cells and harness their immune cells.

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.

 

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 geneticfunctional 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.

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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Kong, Xiangjun

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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Kuilman, Thomas

Thomas Kuilman

Postdoctoral fellow

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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Boshuizen, Julia

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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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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Tomar, Tushar

Tushar Tomar

Postdoctoral fellow

Experience

I am molecular cancer biologist with training in translational medicinal research focusing on (epi)genomics of drug-resistance. I carried out my PhD research (2011-2016) at University Medical Center Groningen under supervision of Prof. Steven de Jong and Prof. Ate van der Zee. During my doctoral studies, I used whole (epi)genomic approaches along with functional validation methods in patient-derived cell lines and xenografts (PDX) models to identify predictive biomarkers to therapy response and investigate resistance mechanisms of gynecologic cancers towards chemotherapy.

 

In July 2017, I joined the Peeper Lab to work on discovering novel therapeutic targets and improving targeted- and immunotherapy in melanoma using functional (epi)genomics 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):263-77. 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, et al.

    Link to Pubmed
  • 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
 
 

Recent publications View All Publications

  • 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
  • Two-way communication between the metabolic and cell cycle machineries: the molecular basis

    Cell Cycle. 2015 Jul 3;14(13):2022-32

    Kaplon J, van Dam L, Peeper D.

    link to PubMed
 

Contact

  • Office manager

    Indra Francois

  • E-mail

    i.francois@nki.nl

  • Telephone Number

    +31 20 512 2099

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