Abstract 1797: Dendrimer cisplatin and salinomycin complexes as a new combination therapy for ovarian cancer

Abstract Background: Ovarian cancer (OC) is the most lethal gynecologic cancer that initially responds to platinum-based therapy but often becomes resistant, leading to high mortality rates. Given the heterogeneity of OC, it is critical to develop a safe and effective drug combination that targets different tumor cell populations, including chemosensitive, resistant, and cancer stem cells (CSCs). In this study, we evaluated the efficacy of nanocarriers designed to specifically target CD44-expressing OC cells utilizing hyaluronic acid (HA)-conjugated poly(amidoamine) (PAMAM) dendrimer complexes of cisplatin and salinomycin to treat OC. Methods: The efficacy of HA-dendrimer-cisplatin (HA-CIS) and HA-dendrimer-salinomycin (HA-SAL) nanoformulations on cell viability, survival, and apoptosis of established and patient-derived OC cells were examined by Cell Titer Glo, colony formation, and Annexin V assays, respectively. Stemness and self-renewal of CSCs were examined using sphere formation and extreme limiting dilution assays. Mechanistic studies employed RNA-sequencing, RT-qPCR, Western blotting, and immunohistochemistry. The effect of combination therapy on DNA double-strand break (DSB) repair was determined using gH2AX, RAD51 foci, and comet assays. Orthotopic, PDX, and PDEX models were used for the preclinical evaluation. Results: The combination of HA-CIS and HA-SAL synergistically reduced the cell viability, survival, and self-renewal and promoted apoptosis of OC cells. RNA-seq studies showed that HA-CIS upregulates the DNA-DSB repair pathway, specifically homologous recombination (HR). However, combination treatment resulted in the attenuation of HR. Accordingly, combination therapy significantly decreased the DNA repair ability of OC cells, which was evident from increased gH2AX foci formation and reduced RAD51 foci formation. Further, comet assays demonstrated enhanced DNA damage with combination treatment compared to monotherapy. Importantly, the combination treatment of HA-dendrimer-CIS and HA-dendrimer-SAL significantly reduced tumor progression in orthotopic intrabursal models and in patient-derived xenograft (PDX) and explant (PDEX) models. Conclusions: Our results establish that HA-dendrimer-CIS and HA-dendrimer-SAL combination therapy may represent a novel therapeutic combination for treating OC. Citation Format: Sridharan Jayamohan, 1 Sushesh Srivatsa Palakurthi, 2 Jessica D. Johnson, 1 Salvador C. Alejo, 1 Prabhakar P. Venkata, 1 Diksha Jamwal, 1 Suryavathi Viswanadhapalli, 1 Rajeshwar R. Tekmal, 1 Edward Kost, 1 Ratna K. Vadlamudi, 1 Srinath Palakurthi, 2 Gangadhara R. Sareddy1. Dendrimer cisplatin and salinomycin complexes as a new combination therapy for 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 1797.