Abstract 4315: PELP1 oncogene targeted therapy for the treatment of ovarian cancer

Abstract Background: Ovarian cancer (OCa) is the most lethal of all gynecologic malignancies in the United States. Despite the initial responses observed in OCa patients to standard combinations of surgical and cytotoxic chemotherapy, roughly 80% of these patients will develop recurrence and ultimately succumb to chemotherapy-resistant disease. Novel targeted therapies for the treatment of OCa are needed. The oncogene PELP1 is highly expressed in a variety of cancers including OCa. The suppression of PELP1 is shown to reduce the proliferation of cancer cells and renders therapy-resistant cells more susceptible to chemotherapy. We have recently developed a novel inhibitor SMIP34 that binds and degrades PELP1. The purpose of this study is to evaluate the efficacy of SMIP34 in the treatment of OCa. Methods: We have used multiple established and patient-derived OCa models that represent all 4 types of OCa. SMIP34 was used for the inhibition of PELP1 oncogenic functions. The effect of SMIP34 on OCa cell viability was examined by MTT assays. The efficacy of SMIP34 on cell survival and apoptosis was determined using clonogenic assays, Annexin V/PI labelling and caspase 3/7 assays respectively. Mechanistic studies were performed using western blotting, RTq-PCR and RNA-seq analyses. The effect of SMIP34 on STAT3 signaling was examined using reporter gene assays. The efficacy of PELP1 inhibitor on tumor growth was examined using ex vivo patient derived explants (PDEX), patient-derived organoids (PDO), and in vivo patient-derived xenograft models (PDX). Results: Utilizing several established and primary OCa cells, we found that SMIP34 decreased cell viability, impaired colony formation capacity, and induced apoptosis. SMIP34 markedly diminished the viability of OCa cells resistant to carboplatin, cisplatin, and taxol. SMIP34 therapy reduced STAT3 reporter activity. Western blot analysis confirmed that treatment with SMIP34 decreased the phosphorylation of PELP1 regulated survival pathways including STAT3, mTOR and AKT. Mechanistically, SMIP34 interaction with PELP1 facilitates its degradation along with its associated protein complex, which includes TEX10, LAS1L, and SENP3. Biochemical analysis confirmed that SMIP34 decreased ribosome biogenesis and new protein synthesis. RT-qPCR demonstrated that SMIP34 therapy decreases the expression of PELP1 target genes. RNA-seq analysis indicated that SMIP34 therapy downregulated cell cycle genes and induced apoptosis. Utilizing PDEX and PDO ex vivo, assays we show that SMIP34 markedly reduced tumor proliferation as assessed by Ki67 staining. Moreover, SMIP34 (20 mg/kg/IP) administration in vivo markedly inhibited tumor progression in patient-derived xenografts. Conclusions: Collectively our results using in vitro, ex vivo, and in vivo models suggest that SMIP34 may serve as potential therapeutic for treating OCa by inhibiting PELP1 oncogenic signaling. Citation Format: Gaurav Sharma, Behnam Ebrahimi, Arhan Rao, William C. Arnold, Hariprasad Vankayalapati, Rajeshwar R. Tekmal, Suryavathi Viswanadhapalli, Ratna K. Vadlamudi. PELP1 oncogene targeted therapy for the treatment of ovarian cancer [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 4315.