Research

Androgen Receptor in Prostate Cancer

Extensive clinical and basic research has shown that Androgen Receptor (AR)-mediated transcription drives the proliferation and growth of almost all prostate cancers. A better understanding of this critical transcription factor is needed to more effectively treat prostate cancer patients. Our laboratory currently studies a diverse group of problems related to AR signalling in an effort to develop new therapeutics to treat late-stage prostate cancer.

Development of new Functional Genomic Techniques to study AR

Following activation, the AR translocates from the cytoplasm to the nucleus where it binds to several thousand chromosomal sites. The vast majority of these sites act as cis-regulatory enhancers and can interact with specific distal promoters via chromatin looping which subsequently induces gene transcription. This not a simple process and multiple enhancers can potentially interact with the same promoter. With such complexity it is extremely challenging to understand how one AR binding site can impact transcription of a specific gene. Therefore, we are working to develop novel functional genomic techniques using CRISPR/Cas9 to characterize the role of specific AR binding sites. In addition to these approaches, we are also characterizing publicly available whole genome sequencing data to better understand how specific enhancers impact gene transcription.

Characterization of constitutively active AR variants

Inhibiting AR-mediated transcription is one of the most effective treatments against prostate cancer. Yet, while initially effective at slowing the disease most cancers eventually recur. There is extensive evidence that AR signalling still drives prostate cancer growth even in castrate conditions. How AR signalling occurs in the absence of androgens has been extensively studied and demonstrated to occur through several mechanisms including the expression of constitutively active AR variants (ARV). These splice variants do not require androgen to initiate signalling and are therefore intrinsically resistant to all FDA-approved therapeutics that target the AR. While these constitutively active variants allow the cancer to grow in castrate conditions, they also induce extremely high levels of AR-mediated transcription. Our laboratory demonstrated that similar to supraphysiological concentrations of androgens, ARVs can induce cellular senesce and permanently inhibit the proliferation of the cancer. We demonstrated that before a cancer can utilize ARVs they must first develop resistance to this variant induced senescence. Currently, we are working to understand how this resistance arises.

Identification of novel AR antagonists

Combining computational screening and high-throughput testing we are working to developing novel inhibitors of the AR that target critical co-activators required for transcriptional activation. We have identified several potent compounds that show excellent efficacy against both prostate cancer cell lines and animal models. Similar to other disease indications, we believe that having multiple drugs which can target the AR will dramatically slow the development of resistance. In addition, these compounds provide a powerful chemical probe to better understand the basic mechanism of androgen receptor activation.

Characterization of Lysine Demethylases in Prostate Cancer

Post-translation modification of histones can dramatically alter gene-transcription and cellular function. Those proteins that “read”, “write” or “erase” these modifications can therefore be thought to determine the very nature of the cell. Given such a role, there is increasing evidence that disregulation of these epigenetic modifying enzymes is involved in both the development and continued proliferation of prostate cancer. In an effort to better understand these critical enzymes in prostate cancer our group has studied lysine demethylase (KDM), a family of enzymes that remove both repressive and activating methyl marks. We have identified several KDM enzymes that are required for prostate cancer cell proliferation and now working to understand their mechanism of action and utility as a pharmacological target.