669. rAAV-Based and Intraprostatically Delivered miR-34a Therapeutics for Efficient Inhibition of Prostate Cancer Progression

Abstract

Prostate cancer (PCa) is the second most common diagnosed cancer and the fifth cause of cancer-related mortality for males worldwide. At present, there is no effective treatment for PCa. Towards further understanding molecular mechanism and developing therapeutics for PCa, we investigated the role of miR34a in PCa progression. Previous studies have reported that miR-34a was significantly downregulated in PCa cells; therefore, modulation of miR34a expression might be a promising therapeutic approach for PCa treatment. To this end, we first verified the downregulation of miR34a in prostate tumor from transgenic adenocarcinoma mouse prostate (TRAMP) model. We found that overexpression of miR-34a could significantly inhibit the cell cycle of PC3 cells (a human PCa cell line) by prolonging G1 and shortening S phases through targeting cyclin D1 (CCND1). To investigate if in vivo gene delivery of pri-miR34a to the prostates of TRAMP mice can inhibit PCa progression, we opted to screen 12 serotypes of rAAVs, an efficient and safe in vivo gene delivery platform with serotype dependent tissue tropisms for efficient prostate in vivo and PCa cell in vitro transduction. Among several leading candidate vectors (i.e. AAV6.2, AAV7 and AAV9) identified, we first tested the concept of intraprostatic injection of rAAV9 pri -miR34a (4×1011 GCs/prostate) to 8-week old TRAMP mice for inhibition of PCa progression. We observed that the treatment lowered body weights significantly (p < 0.05) as compared to the control group starting from 24 weeks after injection, likely resulted from the higher tumor burden in the control group. rAAV9.pri -miR34a treatment also significantly extended the lifespan of TRAMP mice (p < 0.05). Moreover, we confirmed that the proliferation and neoplasia in the treated prostates were significantly diminished when compared to those in the control group. Currently, the experiments are under the way to elucidate the molecular mechanism of overexpressed miR34a to slow down PCa progression. Taken together, our results demonstrated, for the first time, the potentials of rAAV-mediated efficient modulation of miRNA expression in the prostate for inhibiting PCa progression and studying molecular mechanisms in PCa development.