A Possible Cause of Resistance to Antiandrogen Treatment for Advanced Prostate Cancer Identified

Analysis of androgen receptor patterns also uncovers a new therapeutic target for advanced disease

A team of researchers in the USA and China led by Dr. Dean Tang at New York State’s Roswell Park Comprehensive Cancer Center has examined androgen receptor (AR) expression patterns in 89 patients with castration-resistant prostate cancer.  Dr. Tang’s team has linked the development of castration-resistant prostate cancer and treatment resistance to a lack of androgen receptor (AR) expression in prostate cancer cells.

The team has also identified a new therapeutic target for advanced prostate cancer. Results of their study appeared September 6 in the journal Nature Communications.

Further research confirmed that cells lacking AR did not respond to treatment with enzalutamide (brand name Xtandi). The researchers report 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. Roswell Park’s Dr. Dean Tang has initiated a phase Ib/II clinical trial based on these findings.

The new findings identify 3 distinct patterns of androgen receptor (AR) expression. AR, a key driver of prostate cancer, is a protein that binds to male hormones. As a way to overcome treatment resistance, the team investigated targeting the protein BCL-2.

Dr. Dean Tang
Dean Tang, MD PhD, Roswell Park researcher.

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 (CRPC), an aggressive and treatment-resistant form of the disease.

Castrate-resistant prostate cancer (CRPC) is defined by disease progression despite androgen depletion therapy (ADT) and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases.

Androgen Receptor (AR)
Androgen Receptor (AR)

In an effort to uncover the mechanisms of treatment resistance and progression in prostate cancer, Dr. Tang’s research pathology lab  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
  • AR partly or totally absent 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 sequencing analysis, the research scientists identified BCL-2, a stem-cell-enriched pro-survival 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,” Dr. Dean Tang explains. “Our study offers new proof-of-principle therapeutic strategies to not only treat advanced and metastatic prostate cancer but also prevent castration resistance.”

The study 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 begun a phase Ib/II clinical trial based on these findings, working 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.

PSA Rising– September 7, 2018. Source, Roswell Park, Buffalo, NY. Edited J. Strax

Sources & Links

Their article 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 and the U.S. Department of Defense, as well as the Cancer Prevention Research Institute of Texas, Chinese Ministry of Science and Technology and National Natural Science Foundation of China.

Enzalutamide (Xtandi), a non-steroidal antiandrogen, is FDA approved in the USA by the Food and Drug Administration (FDA) for the treatment of patients with castration-resistant prostate cancer (CRPC).

Venetoclax  (Venclexta®)  is approved by the Food and Drug Administration (FDA) for the treatment of CLL with 17p deletion in patients who have received at least one prior treatment. There are currently research studies underway to evaluate other uses for this agent.

Roswell Park Comprehensive Cancer Center,  founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York.  View map of the NCCN Network:

Learn more at www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or ASKRoswell@roswellpark.org.