Biology Seminar
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Biology Seminar

Prostate cancer is one of the most commonly diagnosed cancer in men and one of the leading causes of cancer-related death in Europe. If the cancer is diagnosed early, it is frequently curable by surgery or radiotherapy. However, locally advanced, recurrent or metastatic prostate cancer is much more difficult to control and patients are commonly treated with androgen withdrawal therapy. This is designed to either target the production of androgens or their binding to the androgen receptor (AR). While initially successful, the effectiveness of this type of treatment is usually temporary and the surviving tumour cells almost always progress to a “castrate-resistant” state. The treatment options for these patients are very limited and the median patient survival is 1-2 years. While the molecular mechanisms responsible for the progression to castration-resistance are poorly defined, there is strong evidence that in most cases, the inappropriate activation of the AR drives the recurrent growth of the cancer. Inhibiting the AR therefore offers the best validated therapeutic strategy to treat castrate-resistant prostate cancer.

Recent studies have identified a novel site on the AR called the binding function 3 (BF3) that is proposed to induce an allosteric modification that inhibits critical co-activator interactions. In an effort to identify inhibitors that target the BF3, an in silico screen was conducted using a database of ~50 million chemicals. From these results, >600 compounds from several diverse chemical classes were selected and assayed using an eGFP cell-based AR transcription assay. Many potent AR inhibitors were identified some with  similar activity as MDV3100 (IC50 <1 µM). Based on MTS assays and cell morphologies, the majority of these compounds were found to be non-cytotoxic at the concentrations tested. Interestingly, these compounds also effectively inhibited AR transcriptional activation in MDV3100 resistant cell lines. Critically, the mechanism of action of the “hit” compounds were validated by several different biochemical assays including Biolayer Interferometry, AF2 and ligand binding site fluorescence polarization assays and x-ray crystallography. Based on these results several lead compounds were tested in a novel fluorescent preclinical model and were found to inhibit AR activity in vivo. By working through a novel mechanism action these compounds offer a new way of inhibiting AR that may potentially circumvent antiandrogen resistance.

 Short Bio

Dr. Nathan Lack is an Assistant Professor in the School of Medicine at Koç University. He received his DPhil in Pharmacology from the University of Oxford with Professor Edith Sim. In his graduate work he identified and characterized a carbon-carbon hydrolase involved in mycobacterial cholesterol metabolism. Following this, he went on to conduct a Postdoctoral fellowship from 2009-2011 at the Vancouver Prostate Center in the University of British Columbia. In addition, he also worked for the pharmaceutical company AnorMED and was involved in the development of the FDA approved therapeutic Plerixafor. His current research is focused on the development of novel functional genomic techniques to characterize androgen receptor signaling.