In the Jones lab, we study the androgen receptor and its involvement in human disease. Therapies targeting the androgen receptor (AR) are used to treat a wide array of human diseases, including prostate cancer (PCa). AR activation is often considered to be a simple consequence of hormone ligand binding; in truth, AR activation is much more complicated, with tissue-specific cellular pathways regulating the process at multiple points. Each of these points represents a potential therapeutic target, one that is distinct from ligand binding. However, all current approaches to control AR activity function through the ligand binding pocket of AR, either activating AR activity, or inhibiting it by limiting endogenous hormone binding. In the setting of PCa, these ‘hormone-blocking’ therapies are initially effective at controlling disseminated PCa, but they eventually fail, leading to terminal castration resistant prostate cancer (CRPC). Furthermore, these therapies act systemically, inhibiting AR activity in other tissues, leading to debilitating side-effects that cause many patients to discontinue the treatment.
Regulating AR activity by means other than manipulating ligand binding could lead to new AR inhibitors that retain efficacy against PCa when current anti-androgen treatments fail. It may also lead to the development of tissue-selective AR modulators (SARMs), which could be used to circumvent the side-effects associated with systemic anti-androgen treatment or to treat other conditions associated with AR activity.
The goals of our lab are to understand how the cell ‘indirectly’ controls AR activity through cross-talk and leverage that information to create treatments for a variety of AR-dependent diseases. Two of the main clinical objectives are to
identify prostate-selective AR inhibitors that are effective against CRPC, and muscle/brain/bone-
selective AR agonists for ‘prostate-safe’ androgen replacement therapies for aging men. During the process of developing treatments for these diseases, we hope to learn more about the mechanisms of this ‘indirect’ regulation and how such regulation is involved in the tissue-selective activities of AR.
In order to identify drugs and cellular pathways that ‘indirectly’ control AR activity, we created a cell-based assay to monitor AR conformation change and nuclear translocation, two points of regulation that are distinct from ligand binding (see figure).
The full-length androgen receptor was cloned between CFP and YFP. When expressed in cells, this fusion protein is located primarily in the cytoplasm. Upon addition of hormone ligand (DHT), AR undergoes an intramolecular conformation change that we can measure by Fluorescence Resonance Energy Transfer (FRET; indicated by the colored lightning bolts). The AR reporter also translocates to the nucleus, which we can measure by fluorescence microscopy. Both of these measurements can be made in high-throughput.
Using this system, we discovered several anti-androgens with unique, non-competitive mechanisms of action. One of these compounds, pyrvinium, was found to inhibit AR activity in vivo, and appears to have some selectivity for the prostate. A biotech company was formed to foster the clinical development of this and related compounds, but we are still working to understand how pyrvinium inhibits AR in a tissue-selective fashion
(Project 1). By performing chemical and genetic screens, we have identified several cellular pathways that potentially control AR activity by cross-talk mechanisms. We are working to understand how these pathways control AR activity, and more importantly, use that information to find new ways to treat PCa
(Project 2). We are also using our cell-based AR conformation change assay to identify tissue-selective AR modulators to develop novel PCa drugs that have fewer side-effects, as well as new classes of SARMs to treat other diseases associated with AR activity
(Project 3). We are developing a rodent model to assess the tissue-selective activity of these potential SARMs
(Project 3). In the process, we hope to learn more about the distinct mechanisms by which AR is controlled in different tissues. Finally, we are investigating the relationship between age-related decline in serum testosterone levels and prostate disease, and exploring the possibility that testosterone replacement therapy could reduce the incidence of benign prostatic hyperplasia and PCa
(Project 4). Please see the research projects tab for more details.
