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Treating Platinum Resistant Ovarian Cancer with a Combination of CD44 Blockade and PARP Inhibitor
National Technical Information Service; 2020.
Non-conventional in English | National Technical Information Service | ID: grc-753616
ABSTRACT
Chemo resistance 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 chemo resistance. We have furthermore shown that BRD4 (BET) inhibition reduces ALDH activity, thereby eradicating CSCs. The mechanism of suppression of ALDH activity is through down regulation of the ALDH1A1 super-enhancer associated non-coding enhancer RNA (eRNA). Notably, BRD4 genomic locus 19p13.12 is often amplified in HGSOC (~20%), and amplification/overexpression correlates with a poor prognosis in HGSOC patients. Therefore, we hypothesize that BRD4/BET inhibition may overcome chemotherapy resistance, and plan a phase I clinical trial to evaluate the combination of BET inhibitor INCB57643 (Incyte, Inc.) with carboplatin into 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 targetingBRD4 through BET inhibition. The goals of the proposal are 1) To conduct a Phase I clinical trial of combined BET inhibitor (INCB57643) and carboplatin inpatients with platinum-resistant HGSOC. 2) To identify companion biomarkers that correlate with response to combination therapy in HGSOC patients.
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Full text: Available Collection: Databases of international organizations Database: National Technical Information Service Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Language: English Year: 2020 Document Type: Non-conventional

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Full text: Available Collection: Databases of international organizations Database: National Technical Information Service Type of study: Experimental Studies / Prognostic study / Randomized controlled trials Language: English Year: 2020 Document Type: Non-conventional