Sunday, May 18, 2025
5/18/2025
Enhancing endoplasmic reticulum stress in ovarian cancer - Project Summary/Abstract Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. Despite initial response to chemotherapy, most OCa patients become resistant and progress to metastatic disease. Long-term prognosis of OCa is dismal, and new therapeutic strategies are desperately needed to improve OCa patient survival. The rapidly proliferative OCa cells have a high demand for de novo protein synthesis, which results in an enhanced basal level of endoplasmic reticulum (ER) stress. Indeed ER-stress associated proteins GRP78, PERK, and ATF6 are overexpressed in OCa compared to normal tissues. ER stress triggers the compensatory unfolded protein response (UPR), which can either restore homeostasis or activate cell death. We reasoned that the high basal level of ER stress in OCa represents a critical vulnerability, and drugs that further aggravate this already engaged system in OCa may exhaust its protective features and contribute to apoptosis induction. Towards that end, we have identified a first-in-class compound, the oligobenzamide ERX-208, which enhances ER stress in OCa cells but not in primary epithelial cells. ERX-208 significantly reduced the growth of OCa xenografts, patient-derived explant, and patient-derived xenografts. Unbiased CRISPR knockdown screens identified the lysosomal acid lipase A (LIPA) protein as the critical target of ERX-208: knockdown of LIPA abrogates response to ERX-208, while reconstitution of LIPA restores ERX-208 response. We have shown that the binding of LIPA to ERX-208 is critical for the ability of ERX-208 to induce ERS and subsequently apoptosis in OCa cells. The objective of this proposal is to conduct mechanistic studies to identify the precise mechanism of action of ERX-208 in OCa, to optimize the “lead” ERX- 208 analog with improved pharmacologic and pharmacokinetic features and to validate that ERX-208 can overcome the heterogeneity of OCa. Our overarching hypothesis is that the binding of ERX-208 to LIPA enhances ERS and induces apoptosis in OCa and targets a critical vulnerability in OCa. Aim1 studies will establish molecular correlates of ERX-208 in OCa cells using unbiased transcriptomics and proteomics, define ultrastructurally how ERX-208 binding to LIPA causes ERS/UPR, define specific interactions between ERX-208 and LIPA with unbiased mutagenesis and define LIPA binding partners disrupted by ERX-208 and their effect on ERS/UPR pathways. Aim 2 studies will use medicinal chemistry approaches to generate few ERX-208 analogs for enhanced specificity for LIPA, define the maximum tolerated dose, dose-ranging studies for ERX-208, and determine PK, PD, and toxicity to therapeutic ratios. Aim 3 studies will test the efficacy of ERX-208 in blocking OCa progression in vivo using clinically relevant orthotopic xenograft, syngeneic mouse models, patient-derived explant, organoids and patient-derived xenograft models. We believe that our studies will establish a novel therapeutic strategy (enhancing ERS), novel therapeutic target (LIPA), novel therapeutic agents (ERX- 208/analogs) and the preclinical rationale for further clinical translation for patients with advanced OCa.
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