Abstract 4193: Novel APE1 endonuclease inhibitors as precision oncology therapeutics in high grade serous ovarian cancers discovered and developed from crystallography-based fragment library screening

Abstract Our preclinical data show APE1 could be a synthetic lethality (SL) target in BRCA deficient ovarian cancers. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by increased risk for breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers) and other solid tumours (including pancreatic cancers and prostate cancers). About 10-20% of TNBC patients harbor germline BRCA mutations resulting in homologous recombination deficiency (HRD), and even amongst wild-type BRCA patients, somatic mutations occur more frequently producing a range of HRD phenotypes collectively termed as “BRCAness”. In epithelial ovarian cancers, germ-line BRCA mutations can be detected in up to 20% of high serous ovarian cancers, and up to 50% of somatic tumours can also manifest a HRD phenotype. PARP1 inhibitor (Niraparib, Olaparib, Rucaparib) maintenance therapy improves progression-free survival in BRCA germline deficient ovarian cancer or platinum sensitive ovarian cancers. Olaparib and Talazoparib are approved for use in BRCA germ-line deficient breast cancers. A response rate to PARPi of up to 60% has been described in clinical studies. Routine clinical use has shown that not all patients with BRCA deficient cancers respond to PARPi either due to intrinsic or acquired resistance. The search is on for other SL targets in BRCA/HRD deficient cancers that either bypass PARPi resistance or are more effective than PARP blockade. We evaluated APE1 protein expression in human epithelial ovarian cancers, correlated with clinicopathological features and survival outcomes and compared APE1 transcript levels in a panel of solid tumours and normal tissue. APE1 transcripts were evaluated in publicly available ovarian cancer clinical datasets (n=1257) for clinical outcomes. Highest levels of transcripts were observed in ovarian cancers compared to other solid tumours. When compared to normal ovarian tissue, there was striking elevation of transcripts in ovarian cancer tissues. High mRNA expression was associated with poor progression free survival (PFS) (p=0.00019). High nuclear APE1 protein expression was seen in 64% of tumours, a feature associated with high grade serous ovarian cancer, poor PFS and poor overall survival. XPTx-91 and XPTx-387 have biochemical IC50s of 250-500 nM. Optimized compounds were screened for selective toxicity in PEO1 (BRCA2 deficient, platinum sensitive, PARPi sensitive) and PEO4 (BRCA2 proficient, platinum resistant, PARPi resistant) cell lines. Several compounds screened in MTS cell proliferation assay showed preferential cytotoxicity in PEO1 cells compared to PEO4 cells. Further cell based (clonogenics, 3D spheroids) and functional assays (DNA double strand break accumulation, cell cycle progression and apoptosis) are ongoing. Citation Format: Debanu Das, Ashley Deacon, Matthew Duncton, David M. Wilson III, Mashael Algethami, Ayat Leshan, Emad A. Rakha, Çağla Tosun, Srinivasan Madhusudan. Novel APE1 endonuclease inhibitors as precision oncology therapeutics in high grade serous ovarian cancers discovered and developed from crystallography-based fragment library screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4193.