Abstract 6574: Plant-derived vesicles as potential therapy for neuroendocrine prostate cancer

Abstract Background: Neuroendocrine prostate cancer (NEPC) is a highly aggressive lethal variant of prostate cancer (PCa) with extremely poor survival times (<1 year). Clinical management of NEPC is currently challenging as there are limited treatment options for these patients. These patients are treated with platinum-based chemotherapy that is associated with toxicity and relapses. This emphasizes the need for newer, more effective therapeutic interventions against this challenging disease. The overall objective of this study was to develop an effective, non-toxic, cheap yet scalable extracellular vesicle (EV)/nanovesicle-based therapeutic intervention against NEPC. Methods: We isolated intact nanovesicles from pomegranate juice, referred to as POM-EVs, using a combination of ultracentrifugation and filtration. Vesicles were characterized by Nanosight Tracking Analyses and Electron Microscopy. Further, we examined the therapeutic potential of POM-EVs in a panel of prostate cell lines in vitro. Prostate cancer cell lines were treated with POM-EVs for 7 days followed by assessment of cellular proliferation, apoptosis, RNA analyses and Western blot analyses. To understand the mechanistic basis of POM-EV induced alterations in NCI-H660 cells, we performed next generation RNA sequencing in control vs POM-EV treated NCI-H660 cells on Illumina HiSeq platform. To examine the effect of POM-EVs in NEPC, we established LuCaP 145.1 tumors in FOX-Chase SCID mice. Once established, animals were divided into two groups: Control and Test (n=5/group). Test mice were administered POM-EVs via tail vein twice a week. Controls included xenografts treated with PBS. Tumor volumes were measured regularly. Further, studies were conducted to assess active moieties of POM-EVs with therapeutic activity in NEPC. Results: POM-EVs led to a significant reduction in viability of neuroendocrine cell lines, NCI-H660 and LASCPC-01 as assessed by MTT assay. We further performed apoptosis assay that showed that POM EV treatment led to a significant increase in apoptotic populations. POM-EV treated mice showed significant regression of LuCaP145.1 tumors. Sequencing studies identified that genes involved in ECM-receptor interaction, focal adhesion, proteoglycans in cancer and small cell lung cancer genes were significantly impacted by treatment with POM-EVs. Remarkably, POM-EVs led to significantly attenuated levels of key proneural/neuronal transcription factors. Conclusions: Systemic administration of POM-EVs can be employed as a novel treatment modality in neuroendocrine prostate cancer. Citation Format: Sharanjot Saini, Amritha Sreekumar. Plant-derived vesicles as potential therapy for neuroendocrine prostate 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 6574.