How advanced prostate cancer becomes resistant to androgen-deprivation therapy

In addition to measuring androgen levels in distant tumor sites, the researchers analyzed gene-expression patterns in the metastatic tissue to confirm the presence of genetic pathways that control testosterone production. The researchers indeed found within the metastatic tissue the genetic transcripts necessary for making the proteins that produce testosterone and other androgen hormones.

“We not only found that metastatic-tumor tissues have high enough androgen levels within them to support continued growth of the tumor cells, but also a critically important reason behind why those androgens are there – the discovery that the gene pathways for synthesizing androgens from cholesterol appear to be present in the distant tumor sites. This finding will allow us to start honing in on the specific source of those androgens and how we can eliminate them,” Mostaghel said. “As we develop new drug targets, we will need to focus on enzymes that seem to be active in the tumor tissue itself. This offers a new way of looking at hormone suppression. In addition to systemic suppression, it suggests we also need to target hormone suppression much more specifically, inside the tumor itself.” Doing so could improve treatment for patients with all stages of prostate cancer, she said, from men with metastatic disease to men with high-risk, localized tumors in which there is concern that small amounts of cancer may have escaped the prostate.

Mostaghel and colleagues feel the most promising drug targets will be inhibitors of CYP17 enzymes, which disrupt the conversion of progesterone to testosterone precursors, as well as inhibitors of enzymes that perform subsequent steps in testosterone production: AKR1C3 and 17BHSD3.

For the study, the researchers examined soft-tissue prostate-cancer metastases obtained from eight medically or surgically castrated men via the University of Washington rapid-autopsy program, one of a handful of such programs in the nation. For control purposes, the researchers also examined benign and cancerous prostate tissue from eight men who underwent radical prostatectomy for early-stage, localized prostate cancer, and prostate tissue from two men whose prostates were removed for reasons unrelated to prostate cancer.