# Targeting p300 to Overcome PARP inhibitor resistance induced by acidic tumor microenvironment > **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $340,366 ## Abstract Project 4 PROJECT SUMMARY/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. PARP inhibitors 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 hypothesis-driven translational study, and the findings will be pivotal for evaluating whether IACS16559, a p300 inhibitor developed by the MD Anderson Cancer Center, in combination with olaparib represents an effective approach to improve efficacy and/or overcome resistance to PARP inhibitors. Thus, the p300 inhibitor is readily available for immediate translation in ovarian cancer. 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 well-characterized mechanisms of PARP inhibitor resistance. Our central hypothesis is that targeting p300 using clinically applicable small molecule inhibitor IACS16559 is a promising therapeutic strategy 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 olaparib in HRD EOC cells and patient-derived xenografts; Aim 2 will explore the combination of p300 inhibitor IACS16559 and olaparib in patients with HRD non-mucinous EOC in a Phase 1 clinical trial; and Aim 3 will identify biomarkers that correlate with response to IACS16559 and olaparib 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 targeting p300 with IACS16559 in combination with olaparib, a major challenge in the cli... ## Key facts - **NIH application ID:** 10931368 - **Project number:** 5P50CA281701-02 - **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR - **Principal Investigator:** Rugang Zhang - **Activity code:** P50 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $340,366 - **Award type:** 5 - **Project period:** 2023-09-19 → 2028-07-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10931368 ## Citation > US National Institutes of Health, RePORTER application 10931368, Targeting p300 to Overcome PARP inhibitor resistance induced by acidic tumor microenvironment (5P50CA281701-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10931368. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*