Abstract B002: Innovative targeted therapy for metastatic prostate cancer using non-statin <i>HMGCR</i> inhibitor: insights from patient-derived organoids and clinical data in Hong Kong

Abstract Prostate cancer is one of the most frequent malignancies in males, and its course and treatment response can vary greatly. Statins, widely used cholesterol-lowering medications that target the HMG-CoA reductase gene (HMGCR), have been investigated for their potential role in prostate cancer development and progression. Statin resistance in prostate cancer may entail a variety of biochemical processes, such as changes in lipid metabolism, which allow cancer cells to persist despite statin therapy. This study examines the impact of non-statin HMGCR inhibitors (plant-derived compounds) on biopsies of metastatic castration-resistant prostate cancer (mCRPC) and mHSPC. We performed RNA sequencing data between control and non-statin HMGCR inhibitor treatment groups in PC3 (statin-sensitive, androgen-receptor negative prostate cancer cell line), DU145 (statin-resistant, androgen-receptor negative prostate cancer cell line) and LNCaP (androgen-receptor positive prostate cancer cell line). Then, The samples of mCRPC and mHSPC in Hong Kong taken during the biopsy was cultured in Aggrewell 400 to form 3D organoid. Then, we treated the organoid has statin medications and non-statin HMGCR inhibitor with futher functional and cellular phenotypes. The results of RNA-sequencing data revealed the significantly down regulation of HMGCR in DU145 cell line after treated with non-statin HMGCR inhibitor while showed no significant effect in PC3 and LNCaP. In patient-derived organoids, we found that mCRPC organoid with high level of HMGCR after statin medications has lower HMGCR after treated with non-statin HMGCR inhibitor. HMGCR level in statins-sensitive mCRPC and mHSPC samples were not significantly downregulated after non-statin HMGCR inhibitor treatment. The knock-down and overexpression of HMGCR mCRPC organoid with high level of HMGCR showed that HMGCR is target of non-statin HMGCR inhibitor in MTT assay and the total cholesterol after non-statin HMGCR inhibitor is lower after treatment (p &amp;lt; 0.05). Moreover, mCRPC organoid with high level of HMGCR form less 3D aggregation after non-statin HMGCR inhibitor treatment. Thus, we confirmed that our non-statin HMGCR inhibitor reduces tumor metastasis and 3D spheroid formation in statin-resistant mCRPC. This case illustrates the importance of integrating novel agents early in treatment showing high response of mCRPC to non-statin inhibitor with lower metastatic ability. This revealed high clinical impact and further translational insight to mHSPC with statin resistant signature as well. Citation Format: Salida Ali, Yao CHI, Rong NA. Innovative targeted therapy for metastatic prostate cancer using non-statin HMGCR inhibitor: insights from patient-derived organoids and clinical data in Hong Kong [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B002.