The idea has been in use since the 1940s: Take away testosterone, which prostate cancer cells need to survive and grow, and the cancer will shrink. “When testosterone in the blood circulation is lowered by surgical castration or by drugs such as Lupron or Zoladex, many of the prostate cancer cells within a patient die off,” explains Samuel Denmeade, M.D., The Carolyn and Bill Stutt Scholar. “But some of the cells survive, because they adapt to the new environment of low testosterone,” and eventually prostate cancer continues to grow.
Autopsy studies of men who died from prostate cancer have shown that the cells stopped being resistant to to the hormonal therapy because they stopped making the testosterone’s main target – the androgen receptor. But other studies have found that some prostate cancer cells adapt to the lowtestosterone environment by making even more of the androgen receptor. Denmeade believes that this marked increase in the androgen receptor may be the reason why hormone-depriving therapies stop working.
In laboratory experiments, Denmeade and colleagues found that prostate cancer cells that are not killed by hormonal therapy can paradoxically be killed if they get the opposite treatment: high levels of testosterone. “Based on this, we performed a small pilot clinical trial, in which we learned that men with metastatic castrate-resistant prostate cancer could tolerate high doses of testosterone without worsening of side effects or disease.” Quality of life improved for these men, and some men had “significant therapeutic responses lasting up to a year or more,” Denmeade says. These results were so promising that Denmeade is planning another clinical study “to test whether rapid alteration between low and high levels of testosterone would produce a beneficial response in men with prostate cancer. We believe that rapid cycling between high and low levels does not allow time for the prostate cancer cells to adapt to the ever-changing environment.”
Quality of life improved for these men,
and some men had “significant therapeutic
responses lasting up to a year or more.”
In this next trial, men with very little or no metastatic disease will receive initial treatment to lower testosterone for six months. Then they will receive three monthly injections of testosterone to raise their blood testosterone to high levels; then they will go back to low hormone levels for three months. This cycle will be repeated twice.
Denmeade hopes that in addition to killing more cancer cells, this treatment plan will improve quality of life by reducing many of the serious side effects of hormone therapy; these can include weight gain, osteoporosis, loss of muscle strength, loss of libido, fatigue, and mood changes.