2. Academic Validation
  3. Therapeutic optimization of LIPA targeting to induce endoplasmic reticulum stress and cell death in ovarian cancer

Therapeutic optimization of LIPA targeting to induce endoplasmic reticulum stress and cell death in ovarian cancer

  • Oncogene. 2026 Mar;45(8):790-804. doi: 10.1038/s41388-026-03689-w.
Suryavathi Viswanadhapalli 1 2,  Tae-Kyung Lee 3,  Scott Elmore 3,  Gaurav Sharma 1,  Rahul Gopalam 1,  Durga Meenakshi Panneerdoss 1,  Xihui Liu 4,  Karla Parra 4,  Tanner Reese 4,  Michael Hsieh 4,  Uday P Pratap 1 2,  Xue Yang 1,  Behnam Ebrahimi 1,  Xiaonan Li 1,  Henry Neal 3,  Chia-Yuan Chen 3,  Kara Kassees 3,  Christian Cervantes 5,  Adriana Baker 1,  Panneerdoss Subbarayalu 6 7,  Paulina Ramirez 1,  Yasmin A Lyons 1,  Zhao Lai 7 8,  Yidong Chen 7 9,  Joseph W Boerma 10,  Peter M LoCoco 10,  Nicholas A Clanton 10,  Zhenming Xu 5,  Manjeet Rao 6 7,  Tekmal Rajeshwar Rao 1,  Edward Kost 1,  Gangadhara R Sareddy 1 2,  Ganesh V Raj 11,  Jung-Mo Ahn 12,  Ratna K Vadlamudi 13 14 15
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, USA.
  • 2 Mays Cancer Center, UT Health San Antonio, San Antonio, TX, USA.
  • 3 Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, USA.
  • 4 Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA.
  • 5 Department of Microbiology, Immunology and Molecular Genetics, UT Health San Antonio, San Antonio, TX, USA.
  • 6 Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA.
  • 7 Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA.
  • 8 Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, USA.
  • 9 Department of Population Health Sciences, UT Health San Antonio, San Antonio, TX, USA.
  • 10 Voelcker Preclinical Pharmacology Core, Department of Chemistry, University of Texas San Antonio, San Antonio, TX, USA.
  • 11 EtiraRx, Pegasus Park, Dallas, TX, USA.
  • 12 Mays Cancer Center, UT Health San Antonio, San Antonio, TX, USA. [email protected].
  • 13 Department of Obstetrics and Gynecology, UT Health San Antonio, San Antonio, TX, USA. [email protected].
  • 14 Mays Cancer Center, UT Health San Antonio, San Antonio, TX, USA. [email protected].
  • 15 Audie L. Murphy South Texas Veterans Health Care System, San Antonio, TX, USA. [email protected].
PMID: 41651987 DOI: 10.1038/s41388-026-03689-w
Abstract

Ovarian Cancer (OCa) remains the most lethal gynecologic malignancy in the United States, with a five-year survival rate below 20%. Elevated basal levels of endoplasmic reticulum stress (ERS) have recently emerged as a therapeutic vulnerability in OCa. We have previously shown that the tris-benzamide ERX-41 can induce ERS and Cancer cell death in OCa by targeting LIPA. In this study, using iterative structure-activity relationship-guided studies to enhance activity in OCa, we identified a more potent ERX-41-derived analog, ERX-208. Importantly, ERX-208 consistently and significantly reduced cell viability in 23 OCa cell lines spanning five major histological OCa subtypes, with IC₅₀ values ranging from 50-100 nM, compared to ∼500 nM for ERX-41. Notably, ERX-208 showed minimal cytotoxicity toward normal ovarian surface epithelial cells, indicating Cancer cell selectivity. ERX-208 induced Apoptosis and suppressed colony formation in vitro in OCa cells. Mechanistic studies using RNA Sequencing, Western blotting, RT-qPCR, transmission electron microscopy, and immunohistochemistry validated robust activation of ERS pathways upon ERX-208 treatment. Through in silico molecular docking simulation and confirmatory detailed site-directed mutagenesis, we identified that ERX-208 binds to LIPA over a broader interaction surface than ERX-41. At the 10 mg/kg dose, ERX-208 demonstrated favorable biodistribution, no observable toxicity, and potent antitumor efficacy in vivo against established cell line-derived xenograft (CDX), patient-derived xenograft (PDX), and patient-derived explant (PDE) models. Immunohistochemical analysis of treated tumors demonstrated changes in expression of proliferative marker (ki67, decreased) and the ERS marker (GRP78, increased). These findings support the clinical advancement of ERX-208 for the treatment of patients with OCa.

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