Abstract 2716: Further development of microRNA-34a therapeutics to target castration-resistant prostate cancer

Abstract

Abstract Prostate cancer (PCa) is heterogeneous and typically presents with multiple distinct cancer foci. Androgen receptor signaling inhibitors (ARSIs) are standard-of-care therapies for advanced PCa and can prolong patient survival by months. Treatment-naïve PCa harbors a population of stem-like cells (AR-/lo) functionally defined as PCa stem cells (PCSCs). During cancer progression or upon therapeutic treatment, non-CSCs may undergo cellular plasticity and be reprogrammed to PCSCs. As a result, PCSCs may become the predominant cell population in advanced (Gleason 9/10) and ARSI-resistant tumors, and the “root cause” for drug resistance. However, current ARSI-based treatment regimens primarily target AR+ CRPC cells or clones but largely ignore AR-/lo cells. microRNA-34a (miR-34a), a tumor-suppressive miRNA dysregulated in PCa, is a potent PCSC inhibitor by targeting cellular processes essential for CSC survival and functions. Here we aim to develop novel miR-34a therapeutics to target PCa cell heterogeneity and CRPC. miR-34a expression negatively correlates with the tumor stage in PCa samples. And miR-34a expression is significantly reduced in p53 mutated tumors. We explored two novel miR-34a delivery platforms. The first is packaging-free ligand-mediated conjugate utilizing 2- [3-(1,3-dicarboxy propyl) ureido] pentanedioic acid (DUPA) as a high-affinity binding ligand for prostate-specific membrane antigen (PSMA), which is upregulated in PCa. The second platform uses cationic lipid nanoparticles to package miR-34a (LNP-miR-34a). We show that during PCa progression and upon treatment, PSMA expression is upregulated and continues to be highly expressed in CRPC and PSMA expression level negatively correlates with overall survival in PCa. Moreover, DUPA-conjugate can specifically target PSMA-expressing PCa both in vitro and in vivo. DUPA-miR-34a significantly induces target gene silencing in vitro. On the other hand, LNP show good encapsulation efficiency for miR-34a, LNP-miR-34a significantly repressed cell proliferation by downregulating critical stemness factors in a dose-dependent manner. Meanwhile, we are pursuing chemical modifications of the miR-34a mimics aiming to improve serum stability and future in vivo applications. Both fully modified miR-34a (FM-miR-34a) and partially-modified-miR-34a (PM-miR-34a) exhibit improved serum stability without compromising the functionality. Our data suggest that DUPA-miR-34a represents a promising novel therapeutic for PCSC-enriched CRPC that continue to express PSMA, whereas LNP-miR-34a could be a systemic therapeutic for CRPC treatment in the combinatorial setting. miR-34a, as a direct target and a major mediator of p53 functions, may represent an effective replacement therapeutic in p53-mutated advanced PCa. Citation Format: Wen (Jess) Li, Xiaozhuo Liu, Ahmed M. Abdelaal, Sudarsan Kasireddy, Yafei Su, Yun Wu, Andrea L. Kasinski, Dean G. Tang. Further development of microRNA-34a therapeutics to target castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2716.