Finding valuable therapeutic interventions for prostate cancer has long guided research in Dr. Feng Yang at Baylor College of Medicine. In a study published in the Proceedings of the National Academy of Sciences, Yang’s team took a closer look at what drives the growth of advanced tumors that have become resistant to standard castration therapy. Working with cells in the laboratory and in animal models, they discovered an approach that suppresses the growth of therapy-resistant tumors.
“Advanced prostate cancer is usually treated by blocking the actions of androgens, the male hormone that helps it grow,” said Yang, an assistant professor of molecular and cell biology and a member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “Although initially effective, this treatment, called castration therapy, often becomes ineffective as tumors develop resistance to it and can continue to grow, a lethal condition.”
Looking for ways to suppress the growth of these tumors, Yang and his colleagues studied the signals that tumor cells use to drive cell proliferation. They knew that androgen receptor activation remained a key driver of castration-resistant tumor growth, so they focused on GATA2, a factor known to promote androgen receptor expression and activation .
“Although direct inhibition of GATA2 activity remains a challenge, enhancing GATA2 degradation to prevent androgen receptor activation seemed a plausible therapeutic strategy,” Yang said. “We found that the COP1 enzyme drives GATA2 degradation and that this was followed by a striking inhibition of androgen receptor expression and activation. Importantly, when we promoted GATA2 degradation in our models animals, tumor growth and castration resistance were markedly suppressed.”
“Prostate cancer is the second leading cause of death in male cancer patients in the United States and the fifth leading cause of death among men worldwide,” Yang said. “Our study has established a new path that may lead to improved treatments for castration-resistant prostate cancer, supporting further studies to translate this strategy into the clinic.”
Tao Shen, Bingning Dong and Yanling Meng at Baylor College of Medicine and David D. Moore now at the University of California, Berkeley also contributed to this work.
This research was supported by grants from the Department of Defense Congressionally Directed Medical Research Programs (W81XWH17-1-0043), the Cancer Prevention Research Institute of Texas (RP130651), and the RP Science Chair Doherty Jr.-Welch (Q-0022) .
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