DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

High dose testosterone causes DNA damage and suppresses prostate cancer growth

Posted July 28, 2020

Michael Schweizer, M.D., University of Washington

 Dr. Michael Schweizer
Dr. Michael Schweizer

Since the discovery that blocking hormones can slow the growth of cancer cells in the 1960s, androgen deprivation therapy has been the standard treatment for prostate cancer. This mode of therapy seeks to either stop the production or the activity of androgens, such as testosterone, in the body to treat the disease - a process termed castration. This depletion of testosterone is associated with many debilitating side effects for men that lessen the quality of life, such as lower energy and diminished libido. Eventually, prostate cancer cells often mutate to increase sensitivity towards low concentrations of testosterone to trigger tumor growth leading to castration resistance. This increasing arms race is difficult to control and often progresses to metastatic disease and death.

Curiously, there have been observations that exposure to higher than natural doses of androgens can kill the sensitized castration-resistant prostate cancer cells. Supported by a FY15 Physician Research Training Award, Dr. Michael Schweizer at the University of Washington conducted mechanistic studies aimed at understanding how high doses of testosterone affects prostate cancer and causes cell death. Understanding why some prostate cancers regress when exposed to high doses of testosterone would help identify which patients are most likely to respond to this form of treatment, and identify combination therapies that might further enhance the treatment. Their group found that excess androgens induced markers of DNA damage in the prostate cancer cells and could suppress key genes involved with DNA repair. Both the accumulation of DNA damage and the inability to fix that damage activated self-destruction signals within the cancer cells and drove positive therapeutic response in preclinical models. Analyzing tumor samples from prostate cancer patients, they found that mutations in DNA repair genes were also associated with improved responses in men receiving high dose testosterone in the clinic. These lines of evidence suggest that blockade of important DNA repair mechanisms could bolster the efficacy of other treatments.

Based on their investigation, they have launched a Phase II clinical trial testing the combination of high dose testosterone with Olaparib, a drug that inhibits DNA damage repair and has recently received FDA approval for the treatment of prostate cancer. Importantly, the increase of testosterone associated with this treatment helps patients feel more active during treatment, improving their quality of life. They hope that combining these therapies will be synergistically effective for treating castration-resistant prostate cancer.

Micahel Schweizer Figure
Prostate cancer cells (blue) show signs of DNA damage (green) when exposed to synthetic androgen (R1881).

Publications:

Schweizer MT, Hancock ML, Getzenberg RH, et al. 2018. Hormone levels following surgical and medical castration: defining optimal androgen suppression. Asian journal of andrology 20(4): 405-406. doi: 10.4103/aja.aja_38_17.

Schweizer MT, Cheng HH, Tretiakova MS, et al. 2016. Mismatch repair deficiency may be common in ductal adenocarcinoma of the prostate. Oncotarget 7(50): 82504-82510. doi: 10.18632/oncotarget.12697.

Schweizer MT, Antonarakis ES, and Denmeade SR. 2017. Bipolar androgen therapy: a paradoxical approach for the treatment of castration-resistant prostate cancer. European urology 72(3): 323-325. doi: 10.1016/j.eururo.2017.03.022

Schweizer MT and Yu EY. 2017. AR-Signaling in Human Malignancies: Prostate Cancer and Beyond. Cancers 9(1): 7. doi: 10.3390/cancers9010007.

Mohammad OS, Nyquist MD, Schweizer MT, et al. 2017. Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions. Cancers 9(12). doi: 10.3390/cancers9120166.

Teply BA, Wang H, Luber B, et al. 2018. Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study. The Lancet. Oncology 19(1): 76-86. doi: 10.1016/S1470-2045(17)30906-3.

Link:

Pharmacologic Dose Testosterone to Treat Castration-Resistant Prostate Cancer: Mechanisms of Action and Drivers of Response  

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Last updated Tuesday, July 28, 2020