The androgen receptor (AR) is a hormonal receptor and transcription factor which drives uncontrolled proliferation of cancerous cells in prostate cancer. Drugs targeting AR have been instrumental in increasing survival and quality of life for patients with prostate cancer. However, in some patients, the cancer eventually develops resistance to the AR antagonists and leads to castration resistant prostate cancer. When this occurs, treatments options are limited, and new therapies are needed for these patients.
AR contains three domains: an unstructured N terminal domain, a DNA-binding domain, and a ligand-binding domain. All of the FDA approved drugs currently target the ligand binding domain of AR, where they compete for binding with androgens. In this ASPIRE award, Denes Hnisz will examine the understudied N-terminal domain. This domain is necessary for the oncogenic properties of AR, and Hnisz’s group has preliminary data showing that the N-terminal domain is responsible for liquid-liquid phase separation of AR, and they have also shown that phase separation is necessary for its function.
Now, they will examine how the disordered N-terminal domain of the androgen receptor (AR) influences phase separation in vitro through biophysical assays and mutagenesis based on computational predictions. They will mutate AR to identify constructs that have different phase separation properties in cells and study their modulation of AR target genes. Finally, they will construct a phase diagram for AR phase separation, to be used eventually for a small molecule screen to find chemical matter which can affect phase separation and act as leads for therapeutic compounds. Although the androgen receptor has been intensely studied, its phase separation behavior is not well understood, and this project will help shed light on new aspects of its biology and set the stage for developing novel therapeutic modalities for prostate resistant prostate cancer.