Functional Analysis of Androgen Receptor in Prostate Epithelial Stem Cells

My major career goal is to lead a research laboratory to pursue my interests in hormone-refractory prostate cancer. Consequently, my studies should yield more insights into disease mechanisms and allow the design of more effective therapeutic strategies. The training plan for this application will emphasize on individualized research mentorship by Dr. Michael Shen, who is a leading expert on prostate cancer mouse models and stem cell biology. Under Dr. Shen's supervision, the training program will involve participation in lab research activities, such as lab meetings and journal clubs, interaction between lab members, as well as acquisition of essential expertise for prostate cancer research. I will also have various opportunities for intellectual enrichment and research networking, including training conferences, seminars and retreats organized in the stimulating environment of the Herbert Irving Comprehensive Cancer Center, as well as participation in thematic conferences and workshops during the two-year training period. Upon the completion of this training and research program, I will have developed and implemented a research project and will be highly competent to perform data analysis, leading to presentation of findings in scientific meetings, as well as publications in high-impact journals. Ultimately, I should be well prepared for career development grant applications and job interviews, thus leading to an independent investigator path focusing on end-stage prostate cancer.

The mainstay of prostate cancer treatment for more than five decades has been androgen-ablation therapy. Because most of the normal prostate as well as prostate cancer cells require androgens (such as testosterone) for their survival, the removal of androgens has been used successfully to treat prostate cancer patients. However, the tumor will eventually recur, indicating that a failure of treatment has taken place. At this stage, the tumor becomes hormone-refractory, ultimately resulting in lethality. Molecular analyses of hormone-refractory prostate cancer have previously shown that tumors survive due to their ability to produce or maintain high levels of androgen receptor (AR).

Stem cells are rare cells that can give rise to all the cell types existing in an adult tissue and can continue to divide throughout the life of the organism. Recently, it has been proposed that similar stem cells may be present in many cancers, and these cancer stem cells may represent desirable targets for effective therapies. Our laboratory has discovered a new type of stem cell (called castration-resistant Nkx3.1 expressing cells, CARNs), which can survive in the hormone-refractory state. Using genetically engineered mice, I can label CARNs with a fluorescent marker and have shown that CARNs can form prostate tissues when transplanted into other mice. Moreover, introducing CARNs with genetic changes that predispose to prostate cancer can cause tumor formation in mice, indicating that these cells can serve as the cells of origin for prostate cancer. Strikingly, these cells also produce AR protein, thus implying the ability of these cells to survive in a hormone-refractory state.

The proposed studies for this application will investigate the function of AR in CARNs. In particular, I will abolish AR produced in CARNs to evaluate whether CARNs can grow continuously and form prostate tissues in the absence of AR. Subsequently, I will perform experiments to eliminate AR in CARNs to assess if this will block their ability to form prostate cancer in mice.

My proposal is relevant for the understanding of hormone-refractory prostate cancer. If eradication of AR protein in CARNs will reduce their ability to grow, thus causing suppression of tumor formation, this would indicate that potent AR-targeted drugs should be clinically effective in prostate cancer patients. Consequently, these studies should lead to the refinement of therapeutic interventions and more effective treatment strategies in this end-stage disease.