A new study reported at the 2017 American Association for Cancer Research (AACR) Annual Meeting identified new mechanisms and treatment approach for an aggressive subtype of AR-therapy resistant prostate cancer. Prostate cancers are fueled by male hormones called androgens. These growth signals are transmitted to cancer cells through the androgen receptor (AR). Because of this, AR is the primary target for prostate cancer therapy. However, tumors can eventually develop resistance to AR-targeted therapies and progress to lethal disease. At the 2017 AACR Annual Meeting, PCF Young Investigator Dr. Alastair Davies described the identification of one of the biological processes that prostate tumors use to grow without the need for androgens.
Dr. Davies found that blocking AR causes some prostate cancer cells to commit identify fraud – that is, they take on appearances and activities of other cell types, namely neuroendocrine cells (cells that receive neuronal input and produce hormones in response) and stem cells. The biological pathway that was enabling this cellular “face-off” was found to be driven by abnormal activity of EZH2, a protein that controls gene expression by rearranging the structure of DNA and altering access of gene regulators to different genes. This essentially changes which genes a cell can make into proteins, and is a hijacking of the normal processes that cells use to keep their cellular identities (i.e. remain a brain cell as opposed to a skin cell). Importantly, Davies found that inhibition of EZH2 forced the prostate cancer cells to forget their false identities and switch back to once again relying on AR for survival – causing them to be susceptible to AR-targeted therapy.
The types of prostate cancers examined in this study are of a highly aggressive and quickly lethal subtype often referred to as neuroendocrine or anaplastic. Currently there are no standard of care treatment options for these patients. This study provides a path forward for developing new treatment strategies for patients with what has otherwise been a lethal form of prostate cancer.