Project 3: Repurposing Ceritinib for Ovarian Cancer Therapy

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ABSTRACT – PROJECT 3 The 5-year survival for advanced high-grade serous ovarian cancer (HGSOC) is <30%. The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) has increased progression-free survival in patients and may increase overall survival in some patients; however, the emergence of PARPi-resistant disease is an escalating clinical problem. Accordingly, there is a pressing need to identify novel therapies that enhance PARPi activity in HGSOC. Here we show that ceritinib, a small molecule kinase inhibitor approved for the treatment of ALK-positive non-small cell lung cancer, synergizes with PARPis. This synergy is not due to ceritinib-induced disruption of homologous recombination (HR) or ALK inhibition. Instead, ceritinib synergizes with PARPis, at least in part, by inhibiting mitochondrial respiration, which induces the production of reactive oxygen species (ROS) and consequent induction of DNA damage that is repaired via the PARP-dependent base excision report (BER) pathway. Consistent with this mechanism of action, we show that a ceritinib + PARPi combination is synergistic in HR-proficient and -deficient ovarian cancer cell lines. Moreover, in HGSOC patient-derived xenograft (PDX) models, ceritinib + olaparib (C+O) induces tumor regressions and extends mouse survival more effectively than olaparib alone. These observations raise the possibility that C+O will extend progression-free survival or prevent the emergence of PARPi resistance in HGSOC. Despite this progress, it remains unclear i) whether C+O can be safely given to patients, ii) whether C+O has activity against HGSOC in patients, and iii) how to identify the ovarian cancers that will be most responsive to C+O. To begin the process of repurposing ceritinib for ovarian cancer, we propose to i) perform a phase Ib trial of C+O with an expansion cohort and correlative studies in platinum-sensitive relapsed ovarian cancer; ii) identify genes and pathways, including DNA repair pathways, that affect C+O cytotoxicity in order to provide additional insight into the action of this combination and potentially identify biomarkers of response; and iii) use PDX models to assess potential genotypic and phenotypic differences that correlate with antitumor responses to C+O. The overarching goals of these studies are to better understand the mechanism(s) of action of the C+O combination and identify ovarian cancers most likely to respond to this combination in a future phase II trial in HGSOC. These studies, which utilize the Biospecimens, Biostatistics and Bioinformatics, and Animal Models Cores, are designed to facilitate the repurposing of ceritinib in combination with PARPis as a new therapy to improve the outcomes of PARPi- treated HGSOC.