Overcoming Platinum Resistance in Ovarian Cancer Through BET Inhibition
Technical Report,30 Sep 2018,29 Sep 2019
The Wistar Institute of Anatomy and Biology Philadelphia United States
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Chemoresistance is a major cause of the high mortality of ovarian cancer. For example, although high-grade serous ovarian carcinoma HGSOC initially responds well to platinum-based chemotherapy, relapse often occurs with decreased chemotherapeutic sensitivity. Substantial evidence suggests that cancer stem-like cells CSC contribute to chemotherapy resistance. Putative epithelial ovarian cancer EOC CSCs are typically characterized by increased aldehyde dehydrogenase ALDH activity due to concomitant upregulation of the ALDH1A1 gene. It has been demonstrated preclinically that suppression of ALDH activity by ALDH1A1 knock-down sensitizes EOC cells to chemotherapy, demonstrating the functional importance of ALDH activity in EOC chemoresistance. We have furthermore shown that BRD4 BET inhibition reduces ALDH activity, thereby eradicating CSCs. The mechanism of suppression of ALDH activity is through downregulation of the ALDH1A1 super-enhancer associated non-coding enhancer RNA eRNA. Notably, BRD4 genomic locus 19p13.12 is often amplified inHGSOC 20, and amplificationoverexpression correlates with a poor prognosis in HGSOC patients. Therefore, we hypothesize that BRD4BET inhibition may overcome chemotherapy resistance, and plan a phase I clinical trial to evaluate the combination of BET inhibitor INCB57643 Incyte, Inc. with carboplatin to establish MTD, tolerability, and preliminary efficacy of the combination. We propose embedded correlative science to identify populations most likely to respond to therapy. Our central hypothesis is that platinum resistance can be overcome through eliminating ALDH positive cancer stem-like cells by targeting BRD4 through BET inhibition. The goals of the proposal are 1 To conduct a Phase I clinical trial of combined BET inhibitor INCB57643 and carboplatin in patients with platinum-resistant HGSOC. 2 To identify companion biomarkers that correlate with response to combination therapy in HGSOC patients.
- Medicine and Medical Research