Targeting Homologous Recombination Repair In Cancer Cells

Malgorzata Krajewska

    Research output: ThesisThesis fully internal (DIV)

    1405 Downloads (Pure)

    Abstract

    Conventional radiotherapy and chemotherapy target tumor cells by inducing DNA damage. Their combined application has contributed to increased survival and cure rates in numbers of patients. However, overall poor efficacy and systemic adverse effects of high doses of radio-/chemotherapy point to an urgent need for improvement. Limitations of these treatment modalities can be partially explained by the activity of DNA repair pathways that allow cancer cells to counteract the therapeutic effect of radio- and chemotherapy. One especially important DNA repair pathway in this respect is homologous recombination (HR) repair. HR repair is used to accurately resolve highly cytotoxic DNA double strand breaks (DSB). This repair pathway is found compromised in various cancers, including hereditary breast and ovarian cancer. Specifically, hereditary breast and ovarian cancers with germline mutations in the BRCA1/2 genes show defects in HR repair. Intriguingly, tumor cells with defective HR repair show increased sensitivity to DNA damaging agents including ionizing radiation as well as specific chemotherapeutics. These observations suggest that therapeutic inactivation of HR repair may sensitize HR-proficient tumor cells to radio-/chemotherapy and thereby improve therapeutic options for various cancer types. In this thesis, we investigated pathways that regulate the efficiency of HR repair with the aim to uncover how HR repair can be therapeutically inactivated in cancer cells to enhance the cytotoxic effects of radio- and chemotherapy. Additionally, we identified vulnerabilities of HR-deficient tumor cells and tested whether these could be exploited for targeted cancer therapy.
    Translated title of the contributionHomologe Recombinatie Reparatie als Aangrijpingspunt In Kanker Cellen
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • University of Groningen
    Supervisors/Advisors
    • van Vugt, Marcel, Supervisor
    • de Vries, Liesbeth, Supervisor
    Award date30-Jun-2014
    Place of Publication[S.l.]
    Publisher
    Print ISBNs978-90-367-7113-9
    Electronic ISBNs978-90-367-7112-2
    Publication statusPublished - 2014

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