Puzzle of Prostate Cancer Resistance to Androgen-Deprivation Therapy Solved

A collaborative study has uncovered what may be helpful in discerning how prostate tumours eventually become resistant to androgen-deprivation therapy - the suppression of circulating

Androgen-deprivation therapy is the suppression of circulating testosterone via surgical castration or medical castration. This therapy is used in prostate cancer, but the tumor eventually becomes resistant to it. A new study has now uncovered the mechanism of this resistance.

Testosterone is the hormone that fuels prostate-cancer growth.

"We found that despite the suppression of circulating androgen levels to very low or castrate levels, metastatic prostate tumours are themselves able to maintain significant levels of testosterone, which fuels the growth of the cancer," said Dr. Elahe Mostaghel, a clinical-research associate in Peter Nelson's laboratory at Fred Hutchinson Cancer Research Centre.

According to the researchers, the study showed testosterone levels to be 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).

Describing their work in the journal Cancer Research, the researchers said that their findings might allow the development of better medicines to treat metastatic cancer that had 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. What these findings suggest is that we really need to target the metastatic prostate-tumor tissue itself as the source of tumour androgens," Mostaghel said.

Besides measuring androgen levels in distant tumor sites, the research team analysed gene-expression patterns in the metastatic tissue to confirm the presence of genetic pathways that control testosterone production.

Their effort showed within metastatic tissue, the presence of the genetic transcripts necessary for making the proteins that produce testosterone and other androgen hormones.

"We not only found that metastatic-tumour tissues have high enough androgen levels within them to support continued growth of the tumour 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 tumour 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 tumour 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 tumour itself," she added.

According to her, doing so might help improve treatment for patients with all stages of prostate cancer, from men with metastatic disease to men with high-risk.

The researchers are of the opioion that the most promising drug targets will be inhibitors of CYP17 enzymes, which disrupt the conversion of progesterone to testosterone precursors, and inhibitors of enzymes that perform subsequent steps in testosterone production: AKR1C3 and 17BHSD3.

During the course of 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, they 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.

The team further examined metastatic human prostate-cancer cells, obtained from androgen-deprived men, which had been engrafted and allowed to grow in both castrated and non-castrated mice, a process called xenografting.

It was observed that androgen levels in the xenograft tumors in the castrated mice, which had no circulating androgen, were actually higher than in the xenograft tumours in the mice that had not been castrated.

The researchers found a particularly striking difference in levels of DHT.

"We found DHT levels to be twice as high in the castrated mice. That tells us that the tumour is making testosterone and hanging on to it somehow and is further evidence that metastatic tissue has the capacity to make its own testosterone," Mostaghel said.

Source-ANI
RAS/L