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Wilbert Zwart Group

Hormones and Cancer

Our Focus

We study epigenetic regulation and hormonal action in cancer. Steroid hormone receptors are critical drivers in the development and progression of multiple cancer types. Where we stand today, hormonal therapies represent the first and most-successful targeted therapies in the treatment of breast cancer and prostate cancer patients, yet resistance is commonly observed. We mainly focus on prostate cancer and breast cancer, but also study hormone receptor action other cancer types, including endometrial cancer and lung cancer. Strong parallels and shared biological features exist between hormone-regulated cancers, presenting a unique opportunity for synergism of projects in the lab.

Our goal

Our ultimate goal is to better understand hormonal signaling and elucidate the mechanisms of therapy resistance, ultimately contributing to personalized treatment, identification of novel therapeutic options and limiting over-treatment.

Recent achievements

As major achievements, we identified distinct subsets of Androgen Receptor/chromatin interactions that enabled the identification of prostate cancer patients with an ultra-high risk of relapse in the primary disease setting (Stelloo et al., 2015), and identified a previously unknown subtype of primary prostate cancer, demarcated by low Androgen Receptor activity (Stelloo et al., 2018). In comparing Androgen Receptor cistromics between healthy tissue and primary tumors, the tumor-gained Androgen Receptor sites are enriched for somatic mutations and prostate cancer risk SNPs, out of which a minor subset directly impact Androgen Receptor biology (Mazrooei et al., 2019). In the transition from primary tumors to castration resistant metastases, Androgen Receptor chromatin profiles reprogram again, re-activating decommissioned developmental fetal enhancers (Pomerantz et al., 2020). By implementing our technologies in prospective clinical trials, we could identify a novel therapy resistance mechanism in prostate cancer, revolving around circadian rhythm regulators (Linder et al., 2022).

Clinical translation

Our team is critically involved in multiple industry sponsored investigator-initiated phase II clinical trials. As such, we have long-term collaborations with numerous pharmaceutical companies, and secured multiple patents for novel drug combinations in cancer treatment and biomarkers for drug resistance.

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    Members

    Wilbert Zwart
    Oncode Investigator

    Anniek Zaalberg
    Phd Student

    Chayenne Veerman
    Phd Student

    Emma Minnee
    Phd Student

    Emira Visser
    Phd Student

    Isabel Mayayo Peralta
    Phd Student

    Jeroen Kneppers
    Phd Student

    Kim van der Zande
    Phd Student

    Karianne Schuurman
    Technician

    Marit de Wissel
    Technician

    Nils Eickhoff
    Phd Student

    Nunno Padrao
    Phd Student

    Suzanne Beerthuijzen
    Technician

    Sebastian Gregoricchio
    Post Doc

    Simon Linder
    Phd Student

    Stefan Prekovic
    Senior Postdoc Fellow

    Tesa Severson
    Associate Staff Scientist

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    Contact Information

    Wilbert Zwart
    Oncode Investigator

About Wilbert Zwart

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    My research

    Wilbert Zwart is a senior group leader at the Netherlands Cancer Institute, division of Oncogenomics, where he started his independent lab in 2011. In 2003, he obtained his BSc and MSc at the University of Utrecht. In 2009, he received his Ph.D. (cum laude) from the University of Leiden, based on his work at the Netherlands Cancer Institute in the groups of Rob Michalides and Jacques Neefjes. Funded by a Dutch Cancer Society KWF fellowship, he performed his postdoctoral training with dr. Jason Carroll at the Cancer Research UK Cambridge Research Institute, where he studied cofactor genomics in breast cancer (2009-2011). He joint Oncode Institute as junior groupleader in 2018, and got promoted in 2022 to Oncode senior groupleader. He is appointed as Professor Functional Genomics in Oncology at the Eindhoven University of Technology, and serves as chair for the NKI Translational Research Board and as theme leader Precision Oncology at the NKI. He leads the Oncode Research theme 5, “Identification of critical drug combinations and biomarkers for personalized cancer treatments.”

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    Awards

     

    • 2022 Best research article of the year, non-clinical, Dutch Endocrine Society
    • 2021 Movember-Distinguished Gentleman's Ride-PCF Challenge Award (co-recipient)
    • 2021 IDEA Development Award, Department of Defense CDMRP
    • 2021 Nominee Prix Galien Research Award 2021
    • 2021 Best research article of the year, non-clinical, Dutch Endocrine Society
    • 2020 Supervision of “Best PhD thesis of the Year Award”, Dutch Endocrine Society
    • 2019 IDEA Development Award, Department of Defense CDMRP
    • 2019 ASPIRE Award, The Mark Foundation
    • 2018 NWO Netherlands Scientific Organization TOP-laureate, co-application with Reuven Agami
    • 2016 NWO Netherlands Scientific Organization VIDI-laureate
    • 2016 Best research article of the year, clinical, Dutch Endocrine Society
    • 2014 Pezcoller Fellowship
    • 2014 Bas Mulder Award, Alpe d’HuZes/ Dutch Cancer Society
    • 2011 NWO Netherlands Scientific Organization VENI-laureate
    • 2009 Thesis Award-Royal Dutch Microscopy Society
    • 2009 Dutch Cancer Society KWF fellowship
    • 2009 NWO Netherlands Scientific Organization Rubicon
    • 2009 PhD Thesis Cum Laude
    • 2008 NKI-AVL Award
    • 2006 Symposium Award Dutch Cancer Society
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    Key publications

    1. Mazrooei P, Kron KJ, Zhu Y, Zhou S, Grillo G, Mehdi T, Ahmed M, Severson TM, Guilhamon P, Armstrong NS, Huang V, Yamaguchi TN, Fraser M, van der Kwast T, Boutros PC, He HH, Bergman AM, Bristow RG, Zwart W*, Lupien M*. Cistrome Partitioning Reveals Convergence of Somatic Mutations and Risk Variants on Master Transcription Regulators in Primary Prostate Tumors. Cancer Cell. 2019 Dec 9;36(6):674-689.e6.
    2. Linder S, Hoogstraat M, Stelloo S, Eickhoff N, Schuurman K, de Barros H, Alkemade M, Bekers EM, Severson TM, Sanders J, Huang CF, Morova T, Altintas UB, Hoekman L, Kim Y, Baca SC, Sjöström M, Zaalberg A, Hintzen DC, de Jong J, Kluin RJC, de Rink I, Giambartolomei C, Seo JH, Pasaniuc B, Altelaar M, Medema RH, Feng FY, Zoubeidi A, Freedman ML, Wessels LFA, Butler LM, Lack NA, van der Poel H*, Bergman AM*, Zwart W*. Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence Cancer Discov. 2022 Sep 2;12(9):2074-2097.
    3. Pomerantz MM, Qiu X, Zhu Y, Takeda DY, Pan W, Baca SC, Gusev A, Korthauer KD, Severson TM, Ha G, Viswanathan SR, Seo JH, Nguyen HM, Zhang B, Pasaniuc B, Giambartolomei C, Alaiwi SA, Bell CA, O'Connor EP, Chabot MS, Stillman DR, Lis R, Font-Tello A, Li L, Cejas P, Bergman AM, Sanders J, van der Poel HG, Gayther SA, Lawrenson K, Fonseca MAS, Reddy J, Corona RI, Martovetsky G, Egan B, Choueiri T, Ellis L, Garraway IP, Lee GM, Corey E, Long HW, Zwart W*, Freedman ML.* Prostate cancer reactivates developmental epigenomic programs during metastatic progression. Nat Genet. 2020 Aug;52(8):790-799.
    4. Prekovic S, Schuurman K, Mayayo-Peralta I, Manjón AG, Buijs M, Yavuz S, Wellenstein MD, Barrera A, Monkhorst K, Huber A, Morris B, Lieftink C, Chalkiadakis T, Alkan F, Silva J, Győrffy B, Hoekman L, van den Broek B, Teunissen H, Debets DO, Severson T, Jonkers J, Reddy T, de Visser KE, Faller W, Beijersbergen R, Altelaar M, de Wit E, Medema R, Zwart W. Glucocorticoid receptor triggers a reversible drug-tolerant dormancy state with acquired therapeutic vulnerabilities in lung cancer Nat Commun. 2021 Jul 16;12(1):4360.
    5. Severson TM, Kim Y, Joosten SEP, Schuurman K, van der Groep P, Moelans CB, Ter Hoeve ND, Manson QF, Martens JW, van Deurzen CHM, Barbe E, Hedenfalk I, Bult P, Smit VTHBM, Linn SC, van Diest PJ, Wessels L, Zwart W. Characterizing steroid hormone receptor chromatin binding landscapes in male and female breast cancer. Nat Commun. 2018 Feb 2;9(1):482.
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