- Team identified 3 distinct patterns of androgen receptor expression
- This key driver of prostate cancer is a protein that binds to male hormones
- The protein BCL-2 can be targeted to overcome treatment resistance
Prostate cancer is one of the most common and treatable types of cancer in men. Most patients respond well to hormone therapy or chemotherapy, and five-year survival rates have reached nearly 100% thanks to advances in detection and treatment. However, prostate cancer remains the second-leading cause of male cancer deaths, because those with more advanced or aggressive forms of the disease eventually experience progression or recurrence despite treatment.
For men with advanced disease and tumors that cannot be surgically removed, standard therapy involves drugs that target and block AR, a protein that binds to androgens (male hormones). AR-targeted therapies stop or inhibit the growth of prostate cancer cells, but for unknown reasons, their effectiveness is usually short-lived. Within a year or two of antiandrogen therapy, many patients will develop castration-resistant prostate cancer, an aggressive and treatment-resistant form of the disease.
In an effort to uncover the mechanisms of treatment resistance and progression in prostate cancer, a team of scientists led by Dean Tang, PhD, Chair of Pharmacology and Therapeutics at Roswell Park Comprehensive Cancer Center, in collaboration with scientists at other cancer centers and research institutions in the United States and China, examined AR expression patterns in 89 patients with castration-resistant prostate cancer and found three distinct types: AR in the nucleus of the cancer cell, AR in both the nucleus and cytoplasm, and near or complete absence of AR from all parts of the cell.
Further research confirmed that cells lacking AR did not respond to treatment with enzalutamide (brand name Xtandi), an AR blocker commonly used to treat patients with castration-resistant prostate cancer. These prostate cancer cells were also more likely than AR-containing cells to grow, regenerate and proliferate. Through deep RNA-Seq analysis, the team identified BCL-2, a stem-cell-enriched prosurvival molecule, as a critical regulator and important therapeutic target in castration-resistant prostate cancer cells.
“In order to survive the pressure of chemical castration and antiandrogen therapy, prostate cancer cells overexpress, redistribute or lose androgen receptor,” explains Dr. Tang, the senior author of the study. “Our study offers new proof-of-principle therapeutic strategies to not only treat advanced and metastatic prostate cancer but also prevent castration resistance.”The research team also reports new evidence that combination treatment with enzalutamide and ABT-199 (brand name Venetoclax), a newly FDA-approved BCL-2 inhibitor, markedly inhibits experimental castrate-resistant prostate cancer. Dr. Tang has initiated a phase Ib/II clinical trial based on these findings, in collaboration three Roswell Park clinical colleagues: Gurkamal Chatta, MD, James Mohler, MD, and Igor Puzanov, MD, MSCI, FACP, who are also co-authors on the newly published research.
The study, “Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses,” is available at nature.com. This research was supported by grants from the National Cancer Institute (project numbers R01CA155693, P30CA016056 and P01CA77739) and the U.S. Department of Defense (W81XWH-13-1-0352, W81XWH-14-1-0575 and W81XWH-16-1- 0575), as well as the Cancer Prevention Research Institute of Texas, Chinese Ministry of Science and Technology and National Natural Science Foundation of China.