Prostate cancer cells depend on androgens to grow and thrive. Because of this dependency, hormone therapy – the blockade of androgens and the androgen receptor (AR) – has been the cornerstone of prostate cancer treatment for decades. As science has progressed, therapies that are better and better at blocking these male hormones and slowing the growth of prostate cancer have been developed.
Cancer however, is a slippery beast, and one way that prostate cancer adapts to these treatments, is to switch and become a different “cell type” – one that doesn’t need androgens to keep going. Prostate cancers that continue to progress after treatment with the stronger AR-inhibiting treatments enzalutamide and abiraterone, have sometimes lost prostate cell characteristics and taken on features of neuronal cells. This form of prostate cancer, often referred to as neuroendocrine prostate cancer (NEPC), is rapidly lethal, and novel treatments are urgently needed.
At the 2018 American Association for Cancer Research (AACR) Annual Meeting, a study led by PCF Young Investigator Dr. Amina Zoubeidi, of the Vancouver Prostate Centre, reported progress on the development of a highly promising new treatment strategy for NEPC. Dr. Zoubeidi and team found that BRN2, a protein that regulates gene expression in neuronal cells, is found at high levels on NEPC. The team hypothesized that turning on BRN2 may be a tactic that prostate cancer cells use to switch to the NEPC form, and that blocking BRN2 may effectively treat NEPC or prevent it from developing.
Dr. Zoubeidi and team developed a new drug that inhibits the activity of BRN2. The BRN2-inhibitor blocked the ability of prostate cancer cells to switch to the NEPC form when being treated with enzalutamide. Instead, prostate cancer cells treated with the BRN2-inhibitor remained sensitive to enzalutamide and were unable to grow in the presence of this treatment combination. Overall, these studies suggest that combining enzalutamide with the BRN2-inhibitor may be a highly effective new treatment strategy for prostate cancer.
“We are now editing the chemical scaffold of this BRN2-inhibitor atom by atom, and over the last 6 months have improved stability almost 20-fold while maintaining specificity,” said Daksh Thaper, a PhD student in Dr. Zoubeidi’s lab who presented the study at AACR. “Moving forward, we will continue to improve the molecule for stability and potency, as well as begin testing our current lead candidate in preclinical human prostate cancer models.”
“While we are continuing to optimize our BRN2 tool compound to a clinical trial ready drug, we have gained valuable insight into potential combination therapies as well as rational patient selection that will help ensure the success of an ensuing clinical trial,” said Dr. Zoubeidi.
This study is supported by a 2017 PCF Challenge Award to Dr. Zoubeidi and team to develop a clinical trial-ready BRN2-inhibitor for the treatment of NEPC.
The 2018 AACR Annual Meeting was held from April 14-18, 2018, in Chicago, IL.