Scientific Objective and Rationale: The role of androgen receptor in prostate cancer is well-established, but hormone-independent androgen receptor-dependent gene activation and resistance to selective androgen response mediators invariably occur. While our laboratory has contributed to the understanding of such drug resistance, we have recently obtained evidence of a new, unexpected aspect of androgen/androgen receptor control of prostate gene expression programs. This underlies a surprising effect of androgens, acting through the androgen receptor, to cause a rapid pattern of long distance, interchromosomal interaction, and initial evidence of a three-dimensional change in nuclear architecture that establishes a network of interactions important for androgen-regulated gene programs, such as a new mechanisms that, once fully described, provide a potentially powerful new target for therapeutic intervention.

Applicability of the Research: SARM-resistant and ligand-independent prostate cancers are a major clinical problem, and new approaches are important because they stimulate novel ideas for resistance to prostate cancer or for new therapeutic approaches to cancers. Our research program is focused on the effects of inflammatory signals on androgen receptor action. This recently led to a surprising finding that offers a novel therapeutic target, which is based on the finding that liganded androgen receptor causes rapid, specific interchromosomal interactions, targeted to distinct territories that are apparently mediated by a complex including actin-fold proteins. This discovery could provide alternative targets to abrogate ligand-independent programs of androgen receptor-induced programs, as well as a new way to understanding and approach to gene translocation events in prostate cancer. As drugs for "cytoskeletal pathways" are highly studied, this could rapidly impact the clinical arena. The immediate impact will be on our basic ideas about androgen receptor actions, and new approaches to blocking pathological AR-mediated gene expression programs.

Likely Contributions:

1. Discovery of new, previously unexpected, mechanisms of gene regulation by androgen receptors and with the finding of massive changes in nuclear architecture in response to androgens.

2. Defining the molecular mechanisms by which androgens cause rapid networks of interchromosomal interactions to permit its modulation.

3. Identification of new therapeutic targets to block pathological androgen receptor mediated gene response programs.

4. Identification of a novel, basic mechanism potentially underlying gene translocation events in cancers.

How does the Research Enhance Studies in the Field?: The research proposed under this application has broad implications to cancer biology and our understanding of sex-steroid receptor actions, and will launch a massive research effort in this area -- the roles of nuclear architecture in androgen receptor action in normal and cancer cells. The series of experiments proposed will provide the critical data to exploit this discovery for modulating androgen receptor-dependent aspects of prostate cancer.