Findings from a University of North Carolina study could help predict which advanced prostate cancers will develop a key driver of resistance 鈥� a discovery that could lead to new therapeutic strategies.
In the journal聽, researchers describe the role of a protein variant called androgen receptor variant 7 (AR-V7), which is an alternative form of the androgen receptor that plays a key role in prostate cancer development and treatment. While scientists have known about AR-V7 as a driver of resistance, the new study reveals previously unknown mechanisms of action for it.
鈥淭his is one of the unexposed transformation pathways that scientists have not understood before in prostate cancer,鈥� said 黑料网 Lineberger鈥檚聽, associate professor in the 黑料网 Department of Biochemistry & Biophysics. 鈥淧rior to our study, scientists thought that AR-V7 binds to where the regular androgen receptor binds to in the cancer cell, but we found that鈥檚 not the case. We found that it goes to a new set of targets.鈥�
The American Cancer Society estimates that 164,000 men will be diagnosed with prostate cancer in the United States this year, making it the most commonly diagnosed cancer in men, and more than 29,400 men are expected to die from the disease. More than 90 percent of prostate cancers are diagnosed at the local or regional stage, when they are highly treatable, which contributes to a five-year survival rate of nearly 100 percent. However, the 5-year survival for advanced disease is 30 percent.
Wang said the androgen receptor is a 鈥渕aster regulator鈥� of prostate cancer. It is an intracellular receptor that鈥檚 triggered by signals from hormones like testosterone. It can then pass into the nucleus to act directly on the DNA to activate genes linked to cell growth. AR-V7 is created when the instructions for its DNA construction are spliced differently in a process known as 鈥渁lternative splicing.鈥�
The researchers found this receptor does not need to be bound to signals like testosterone to be active. Instead, it is always active. Furthermore, in addition to binding the same gene targets as the androgen receptor, they determined AR-V7 binds a new set of targets, working with a crucial protein partner called ZFX and other proteins.
鈥淲e鈥檝e discovered 聽an entirely 聽different array of genes that this aberrantly spliced 聽androgen receptor activates that the normal 聽receptor does not; several of these may 聽help trigger cancerous growth,鈥� said 黑料网 Lineberger Director聽, the Lineberger Professor of Cancer Research and a study co-author.
鈥淭hese findings reveal a set of partner proteins and downstream targets that could potentially be druggable,鈥� Wang said.
In cell studies in the laboratory, researchers used investigational compounds to try to block ZFX and another protein that works with AR-V7 in activating this new set of genes. They discovered this approach could suppress prostate cancer cell division.
Wang and Earp believe the study has dual implications: they used the findings to develop a gene signature associated with AR-V7 expression that could be used to identify patients that develop this mechanism of resistance, and the findings could lead to new therapeutic strategies.
鈥淲e have another set of potential targets to look at in castration-resistant prostate cancer, and we鈥檙e develop a gene signature that may help us indicate who鈥檚 going to develop this,鈥� Earp said.
In addition to Earp and Wang, other authors include Ling Cai; Yi-Hsuan Tsai; Ping Wang; Yilin Zhao; Rui Lu; Young Whang; Deyou Zheng; Joel Parker; Dongxi Li; Huitao Fan; Jun Wang; Rohan Bareja; Andrew Sboner and Elizabeth M. Wilson.
The research was supported by the National Institute of Health, the Lineberger Professorship, a Kimmel Scholar Award, the V Foundation for Cancer Research V Scholar award, and a Concern Foundation for Cancer Research grant. Individual researchers were supported by the U.S. Department of Defense Prostate Cancer Research Program, a Lymphoma Research Foundation fellowship, the American Cancer Society and the Leukemia and Lymphoma Society.