(Epi)genetic characterization of chemotherapy response in ovarian cancer: Finding better markers, models and targets for therapy

Tushar Tomar


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    The major obstacle for successful treatment of advanced stage ovarian cancer (OC) patients comes from platinum-based chemotherapy resistance. In cancer, the (epi)genetic alterations play a crucial role in the regulation of genes related to response towards chemotherapy. Identification of (epi)genetically-regulated key genes that modulate platinum response in OC, may predict response to therapy, and facilitates novel treatment strategies to overcome platinum resistance. Furthermore, development of patient-tailored therapies demands advanced clinically relevant models.

    The primary objective of this thesis concerns identification and functional validation of robust (epi)genetic chemoresponse biomarkers in OC. We perfomed (epi)genome-wide analysis of OC patient tumors using next-generation sequencing, global DNA methylome pattern, gene expression profiles and identified novel chemoresponse markers that may serve as putative targets. We validated these novel markers on various independent patient cohorts as well as functionally validated them on large panel of OC cell lines. Furthermore, we established patient-derived xenograft (PDX) mouse models for OC and characterized them at histological and (epi)genomic level. Moreover, we utilized these patient-mimicking PDX models to identify novel chemoresponse markers and real-time monitoring of chemoresponse-related targets like VEGF and IGF-1R using advanced optical imaging.

    In conclusion, results presented in this thesis contribute to our knowledge regarding the complex interaction between the (epi)genome and chemoresistance in OC. Furthermore, models were established for future cancer research to validate novel targets and treatment options. These results may have an impact on chemoresistance management of OC in the near future.
    Originele taal-2English
    KwalificatieDoctor of Philosophy
    • de Jong, Steven, Supervisor
    • van der Zee, Ate, Supervisor
    • Wisman, Bea, Co-supervisor
    Datum van toekenning10-okt-2016
    Plaats van publicatie[Groningen]
    Gedrukte ISBN's978-90-367-9134-2
    Elektronische ISBN's978-90-367-9135-9
    StatusPublished - 2016

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