Novel LIPA-Targeted Therapy for Treating Ovarian Cancer

Alexia B. Collier, Suryavathi Viswanadhapalli, Rahul Gopalam, Tae Kyung Lee, Kara Kassees, Karla Parra, Gaurav Sharma, Tanner C. Reese, Xihui Liu, Xue Yang, Behnam Ebrahimi, Uday P. Pratap, Megharani Mahajan, William C. Arnold, Adriana Baker, Chia Yuan Chen, Scott Terry Elmore, Panneerdoss Subbarayalu, Gangadhara R. Sareddy, Philip T. ValenteEdward R. Kost, Jung Mo Ahn, Ratna K. Vadlamudi

Research output: Contribution to journalArticlepeer-review

Abstract

Ovarian cancer (OCa) is the most lethal form of gynecologic cancer, and the tumor heterogeneities at the molecular, cellular, and tissue levels fuel tumor resistance to standard therapies and pose a substantial clinical challenge. Here, we tested the hypothesis that the heightened basal endoplasmic reticulum stress (ERS) observed in OCa represents an exploitable vulnerability and may overcome tumor heterogeneity. Our recent studies identified LIPA as a novel target to induce ERS in cancer cells using the small molecule ERX-41. However, the role of LIPA and theutility of ERX-41 to treat OCa remain unknown. Expression analysis using the TNMplot web tool, TCGA data sets, and immunohistochemistry analysis using a tumor tissue array showed that LIPA is highly expressed in OCa tissues, compared to normal tissues. ERX-41 treatment significantly reduced the cell viability and colony formation ability and promoted the apoptosis of OCa cells. Mechanistic studies revealed a robust and consistent induction of ERS markers, including CHOP, elF2α, PERK, and ATF4, upon ERX-41 treatment. In xenograft and PDX studies, ERX-41 treatment resulted in a significant reduction in tumor growth. Collectively, our results suggest that ERX-41 is a novel therapeutic agent that targets the LIPA with a unique mechanism of ERS induction, which could be exploited to treat heterogeneity in OCa.

Original languageEnglish (US)
Article number500
JournalCancers
Volume16
Issue number3
DOIs
StatePublished - Feb 2024

Keywords

  • ERX-41
  • LIPA
  • endoplasmic reticulum stress
  • lysosomal acid lipase A
  • ovarian cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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