? Prostate cancer is the second leading cause of cancer death in US men. Prostate cancer is highly dependent on androgen stimulation mediated through the androgen receptor (AR) for growth and proliferation. For those with advanced PCa, androgen ablation remains the foundation of therapy. Current methods of androgen ablation focus on diminishing circulating androgen or preventing androgen-AR interactions. Despite these efforts, almost all men progress to androgen independent (AI) PCa while on hormonal therapy. Interestingly, the AR continues to be expressed and is probably active in the majority of cases. However, no available therapy is known to interfere with AR function in AI PCa. This proposal focuses on using antisense technology to downregulate AR expression in androgen- independent PCa. AVI BioPharma has pioneered the development of phosphorodiamidate morpholino oligomers (PMOs), the third generation of antisense molecules that have overcome the limitations of earlier compounds. The PMO agents have been identified to be safe in a human Phase I study and are currently in late phase clinical trials for restenosis post coronary angioplasty, for polycystic kidney disease, and for a metabolic redirection trial. The long-term objective of this proposal is to determine the therapeutic value of inhibiting AR expression in human androgen-independent prostate cancer. Preliminary data in human LAPC-4 xenografts show that a PMO to the human AR can specifically and significantly downregulate AR expression along with reduction in prostate specific antigen (PSA) levels. PSA is a prognostic marker in PCa and is regulated by AR. Central Hypothesis: AR activation plays an important role in androgen-independent PCa, and downregulation of AR expression using the PMO-based antisense strategy is a novel mechanism-based therapeutic regimen for AI PCa.
The specific aims of this proposal are: 1) To identify the PMO antisense sequence that maximizes in vivo human AR downregulation, while minimizing the non-antisense effects; and, 2): To determine the optimal dose and schedule of the PMO antisense identified in Aim 1 to downregulate AR in the murine PCa xenograft models. Based on these data, future pharmacokinetic and toxicology animal studies will allow proceeding to human phase I testing in a timely and efficient manner. ? ? ?
| Ko, Yoo-Joung; Devi, Gayathri R; London, Carla A et al. (2004) Androgen receptor down-regulation in prostate cancer with phosphorodiamidate morpholino antisense oligomers. J Urol 172:1140-4 |
