How advanced prostate cancer becomes resistant to androgen-deprivation therapy

Findings suggest androgen production occurs within metastatic prostate tumors

SEATTLE – For the past 70 years the treatment of choice for advanced, metastatic prostate cancer has been androgen-deprivation therapy. That is, the suppression of circulating testosterone – the hormone that fuels prostate-cancer growth – via surgical castration (orchiectomy) or medical castration with testosterone-blocking drugs. While such therapy buys time for patients, it is not a cure, as inevitably the cancer becomes resistant to the androgen deprivation and continues to grow.

A team of researchers led by Peter Nelson, M.D., and Elahe (pronounced EL-ah-hay) Mostaghel, M.D., Ph.D., of Fred Hutchinson Cancer Research Center; and R. Bruce Montgomery, M.D., and Paul Lange, M.D., of the University of Washington School of Medicine, in collaboration with other colleagues at UW and Oregon Health Sciences University, has uncovered what may be the key to understanding how prostate tumors eventually become resistant to androgen-deprivation therapy.

“We found that despite the suppression of circulating androgen levels to very low or castrate levels, metastatic prostate tumors are themselves able to maintain significant levels of testosterone, which fuels the growth of the cancer,” said Mostaghel, a clinical-research associate in Nelson’s laboratory, which is based in the Human Biology Division of the Hutchinson Center.

The researchers found that testosterone levels were four times higher in metastatic tumors from castrate men (collected immediately after death via rapid autopsy) than in benign and cancerous prostate tissue in men with normal circulating androgen levels (collected at the time of prostate surgery).

This finding, reported in the June 1 issue of Cancer Research, could lead to the development of better drugs to treat metastatic disease – cancer that has spread beyond the prostate to distant sites throughout the body, such as bone, lymph nodes and internal organs.

“So far we’ve targeted systemic, or circulating, androgens in men with advanced prostate cancer,” Mostaghel said. “What these findings suggest is that we really need to target the metastatic prostate-tumor tissue itself as the source of tumor androgens.”