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Publications of the Week

Bypassing Drug-Resistance Mechanisms of Prostate Cancer with Small-Molecules That Target Androgen Receptor Chromatin Interactions

By August 25, 2017No Comments

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 This week we profile a recent publication in Molecular Cancer Therapeutics
from the laboratory of Dr. Paul Rennie (pictured) at the Vancouver Prostate Centre

Can you provide a brief overview of your lab’s current research focus?

My lab has had a long history of studying androgen regulation of prostate cancer and has contributed much of the experimental groundwork for the development of widely used, cost-efficient treatments for advanced prostate cancer and for providing the mechanistic basis for many treatment protocols. Our current translational research focus is to develop new drugs for inhibition and/or extinction of the androgen receptor (AR), the central target in the treatment of advanced prostate cancer. In partnership with Dr. Artem Cherkasov’s drug design team, our approach is to use in silico computer-aided drug design to identify new small molecules, which can inhibit the activity of the AR through direct binding to novel sites within the receptor. One such site resides in the AR DNA Binding Domain (DBD), which is distinct from the androgen-binding site normally targeted by all clinically used anti-androgens.

What is the significance of the findings in this publication?

In this publication, we tested our lead anti-AR DBD inhibitor, VPC-14449, on a panel of anti-androgen resistant prostate cancer cell lines that had AR mutations or expressed constitutively active, truncated AR isoforms. VPC-14449 was rationally designed to block DNA binding based on the X-ray structure of the AR. VPC-14449 reduced AR transcriptional activity, cell growth, and target gene expression in every model system tested; demonstrating the utility of this targeting modality against cancer cells that no longer respond to clinically used anti-androgens. Mechanistically, VPC-14449 reduced the ability of full-length AR as well as AR variants to interact with chromatin. Furthermore, we also demonstrate increased cell killing when our inhibitor was used in combination with Enzalutamide, the main anti-AR drug currently used in the clinic. Collectively, these findings highlight the potential for AR DBD–specific inhibition to overcome drug resistance in castration-resistant prostate cancer.

What are the next steps for this research?

These studies confirm that alternative AR-targeting approaches are a viable option for drug-resistant prostate cancer. The potential synergy seen in the combinatorial studies are particularly interesting to follow up on because a dual targeting strategy of simultaneously shutting down both ends of the AR signaling cascade could reduce or even eliminate the emergence anti-androgen resistance. Through a licensing and collaborative agreement with Roche Pharmaceuticals, we are working to improve pharmcokinetic and drug properties of our current anti-AR DBD inhibitors for eventual inclusion in phase I/I clinical trials.

This research was funded by:

This research was primarily supported by grants from Prostate Cancer Canada and CIHR.

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