Targeting p300 to Overcome PARP inhibitor resistance induced by acidic tumor microenvironment

University Of Tx Md Anderson Can Ctr, Houston TX

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Abstract

The overall goal of this proposal is to develop a novel strategy to improve efficacy and/or overcome resistance to PARP inhibitors induced by acidic tumor microenvironment by targeting epigenetic regulator p300 and the associated pathway. PARP inhibitors (PARPi) such as olaparib are FDA-approved for the maintenance and treatment of epithelial ovarian cancer (EOC) patients with impaired homologous recombination (HR) pathways, most notably with BRCA1/2 mutations (also known as homologous recombination deficiency or HRD). However, resistance to PARP inhibitors remains a major unmet clinical need. This is a hypothesisdriven translational study, and the findings will be pivotal for evaluating whether inhibition of p300 and the associated pathway in combination with PARPi represents an effective approach to improve efficacy and/or overcome resistance to PARP inhibitors. Substantial evidence shows that tumors exhibit a lower extracellular pH compared to normal tissues. Our preliminary data show that acidic extracellular pH causes resistance to PARP inhibitors such as olaparib in HRD EOC cells. Our CRISPR screen revealed p300, an epigenetic transcription activator, as a top hit whose inhibition sensitizes cells to olaparib in acidic pH. Mechanistically, our preliminary data indicated that in a p300-dependent manner, acidic pH suppresses the non-homologous end joining (NHEJ) DNA double-strand break (DSB) repair pathway and reduces PARP trapping, two wellcharacterized mechanisms of PARP inhibitor resistance. Our central hypothesis is that targeting p300 and the associated pathway is a promising therapeutic target to improve the efficacy and/or overcome the resistance to PARP inhibitors caused by acidic tumor microenvironment in HRD ovarian cancers. Three Specific Aims are proposed: Aim 1 will investigate a combined therapeutic strategy of targeting p300 and PARPi in HRD EOC cells and patient-derived xenografts; Aim 2 will explore the combination of inhibition of p300 and the associated pathway and PARPi in patients with HRD non-mucinous EOC in clinical trials ; and Aim 3 will identify biomarkers that correlate with response to the proposed combination in HRD EOCs. The proposed studies are highly innovative because they challenge current research/clinical paradigms for PARP inhibitor-resistant ovarian cancer, contribute to new concepts for epigenetic therapeutics, reveal new mechanistic insights into the acidic tumor microenvironment, and utilize innovative methods to explore new intervention strategies for PARP inhibitor resistance in EOC. The proposed studies are of high impact because they will develop novel therapeutic strategies to improve the efficacy and/or overcome the resistance of PARP inhibitors by normalization of acidic or targeting p300 in combination with PARPi, a major challenge in the clinical management of ovarian cancer.