Abstract 4759: Novel treatment approach for efficacy outcome in androgen dependent and independent prostate cancer orthotopic mice models

Abstract Prostate cancer is one of the leading cause of deaths worldwide. Orthotopic injection of cancer cells into mouse prostate remains significant challenge and orthotopic mouse models resemble human pathophysiology. In the current study Androgen dependent (LNCaP VCaP and VCaP-EnzR) and Androgen independent (PC3) cells were orthotopically inoculated (1x10^6 cells) into anterior prostate of male athymic nude mice. Seven to eleven days post implantation, the preclinical efficacy of Enzalutamide (15mg/kg, PO QD x 6 weeks) and Docetaxel (DTX; 7.5mg/kg, i.p Q7D x 6 weeks) as standalone and combination treatment was evaluated. Body weight, clinicals signs, mortality was monitored up to 7 weeks. Terminally prostate was harvested, weighed, tumor volume (TV) was measured. Prostate, distant organs (lung, liver, and bone) were fixed in 10% NBF for metastatic evaluation by histopathology. In LNCaP and VCaP model standalone Enzalutamide treatment significantly reduced prostate weight and TV compared to vehicle control. However standalone DTX treatment resulted in moderate reduction of prostate weight and TV. Whereas combination of Enzalutamide with DTX demonstrated superior efficacy compared to respective standalone treatments. In the VCaP-EnzR model, docetaxel (DTX) treatment demonstrated significant antitumor activity both as standalone treatment and in combination with Enzalutamide. In contrast, Enzalutamide treatment did not reduce tumor volume and results were similar to control group. In PC3 model, the standalone DTX treatment exhibited highest antitumor activity followed by Enzalutamide therapy. The combination of Enzalutamide with DTX demonstrated superior efficacy compared with respective standalone treatments. Histopathological examination of prostate, lung, liver, and bone tissues in all treatment groups for LNCaP, VCaP & PC3 models revealed a significant reduction in organ metastasis with a clear progression of metastasis observed in the vehicle group.In conclusion, standalone hormone therapy slowed down primary tumor growth of androgen dependent prostate cancer by reducing androgen levels or blocking androgen receptors. The lack of response to enzalutamide in the VCaP-EnzR model likely reflects resistance mechanisms. In contrast, docetaxel targeting cell division, is effective regardless of AR signaling, allowing it to overcome enzalutamide resistance. In condition where prostate cancer became resistance to hormonal therapy, chemotherapy plays critical role in attacking prostate cancer cells irrespective of androgen status. This combination offers advantageous, multifaceted approach in treating metastatic resistant prostate cancer and improves treatment effectiveness, delay progression and potentially extending survival. Citation Format: Balaji Ramachandran, Satheeshkumar Rajendiran, Rajendran Venkidusamy, Raghu Patil, Sachin Joshi, Krishnappa Haladasappa. Novel treatment approach for efficacy outcome in androgen dependent and independent prostate cancer orthotopic mice models [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 4759.