The goal of my training program is to continue the work I have begun in a scientific environment with appropriate mentorship and input, so that I will be effective in translating findings in the laboratory to help prostate cancer patients in the clinic. The focus of my work relates to the importance of androgen biology in prostate cancer, and my mentors for this proposal have expertise in androgen metabolism (Jean Wilson and Richard Auchus), androgen receptor (AR) biology (Michael McPhaul), prostate cancer animal models (JT Hsieh), and mechanisms of transcription and novel approaches to chemistry (Thomas Kodadek). These senior and accomplished mentors provide expertise to this proposal that also complements one another.

The research plan is laboratory-based and focuses on the clinical problem of castration-resistant prostate cancer (CRPC) and is therefore very much clinically relevant. Furthermore, accomplishment of the specific aims may directly lead to clinical trials for prostate cancer.

A fundamental question in prostate cancer research is how is AR reactivated to drive CRPC, and how can it be targeted to lead to new therapies. Manganese superoxide dismutase (SOD2), which is responsible for neutralizing reactive oxygen species (ROS), is one of the most strongly suppressed genes in CRPC and is essentially turned off. This observation and preliminary data in this proposal suggest that turning off SOD2 functions in CRPC to turn AR back on, driving the tumor.

The fundamental hypothesis of this proposal is that turning off the SOD2 gene in CRPC plays a direct role in turning AR on, leading to CRPC growth. Furthermore, this may occur through the production of androgens in the tumor.

Specific Aims:

1) Determine if AR is indeed switched back on when SOD2 is turned off.

2) Determine whether turning on AR by shutting down SOD2 occurs through the production of testosterone in the tumor.

3) Determine how shutting down SOD2 changes the growth of AR-expressing prostate cancer, and whether this mimics CRPC.

This proposal seeks to answer questions as to the cause of prostate cancer recurrence after androgen deprivation. Therefore, it applies to patients with CRPC, and it may help them with a better understanding of the process of AR activation in CRPC and how to reverse it, and it may lead to clinical trials for patients with CRPC. Essentially, the hypothesis is that SOD2 shutdown leads to an increase in ROS, which turns AR back on, leading to CRPC. If the hypothesis is proven correct, it may mean that a potential therapy for CRPC is treatment with antioxidants (which counter ROS), which are nontoxic and should turn off AR. If true, this would be a tremendous finding and should lead to clinical trial design within one year. Unlike new drugs which first must be evaluated with toxicity studies, this could be skipped with antioxidants, such as N-acetylcysteine and Vitamin C, which are in clinical use.

These studies may determine that SOD2 down-regulation is a major mechanism of resistance to hormonal therapy and functions by activating AR. The ultimate impact of this work may be borne out by the demonstration that a major mechanism of AR activation and CRPC growth is reversible by treatment with antioxidants, directly leading to clinical trials in patients with CRPC.