Prostate Cancer Resource Center

Finding the Possible Cause of Resistance to Prostate Cancer Treatment


A collaborative research team has linked the development of castration-resistant prostate cancer and resistance to treatment to a lack of androgen receptor (AR) expression in prostate cancer cells, identifying a new therapeutic target for one of the deadliest forms of cancer among men. Results of this research, which was led by scientists at Roswell Park Comprehensive Cancer Center, were published in Nature Communications (2018;9(3600)).

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 U.S. 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, 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,” explained 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, a newly FDA-approved BCL-2 inhibitor, markedly inhibits experimental castrate-resistant prostate cancer. Tang has initiated a phase Ib/II clinical trial based on these findings, in collaboration with three Roswell Park clinical colleagues: Gurkamal Chatta, MD, James Mohler, MD, and Igor Puzanov, MD, MSCI, FACP, who are also co-authors on the new published research.


 

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