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Research Explains How Advanced Prostate Cancer Becomes Resistant to Androgen-Deprivation Therapy

Monday, June 2, 2008 General News J E 4
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SEATTLE, June 2 For the past 70 years the treatment ofchoice for advanced, metastatic prostate cancer has been androgen-deprivationtherapy. That is, the suppression of circulating testosterone -- the hormonethat fuels prostate-cancer growth -- via surgical castration (orchiectomy) ormedical castration with testosterone-blocking drugs. While such therapy buystime for patients, it is not a cure, as inevitably the cancer becomesresistant to the androgen deprivation and continues to grow.

A team of researchers led by Peter Nelson, M.D., and Elahe (pronouncedEL-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 ofWashington School of Medicine, in collaboration with other colleagues at UWand Oregon Health Sciences University, has uncovered what may be the key tounderstanding how prostate tumors eventually become resistant toandrogen-deprivation therapy.

"We found that despite the suppression of circulating androgen levels tovery low or castrate levels, metastatic prostate tumors are themselves able tomaintain significant levels of testosterone, which fuels the growth of thecancer," 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 inmetastatic tumors from castrate men (collected immediately after death viarapid autopsy) than in benign and cancerous prostate tissue in men with normalcirculating androgen levels (collected at the time of prostate surgery).

This finding, reported in the June 1 issue of Cancer Research, could leadto the development of better drugs to treat metastatic disease -- cancer thathas spread beyond the prostate to distant sites throughout the body, such asbone, lymph nodes and internal organs.

"So far we've targeted systemic, or circulating, androgens in men withadvanced prostate cancer," Mostaghel said. "What these findings suggest isthat we really need to target the metastatic prostate-tumor tissue itself asthe source of tumor androgens."

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

"We not only found that metastatic-tumor tissues have high enough androgenlevels within them to support continued growth of the tumor cells, but also acritically important reason behind why those androgens are there -- thediscovery that the gene pathways for synthesizing androgens from cholesterolappear to be present in the distant tumor sites. This finding will allow us tostart honing in on the specific source of those androgens and how we caneliminate them," Mostaghel said. "As we develop new drug targets, we will needto focus on enzymes that seem to be active in the tumor tissue itself. Thisoffers a new way of looking at hormone suppression. In addition to systemicsuppression, it suggests we also need to target hormone suppression much morespecifically, inside the tumor itself." Doing so could improve treatment forpatients with all stages of prostate cancer, she said, from men withmetastatic disease to men with high-risk, localized tumors in which there isconcern that small amounts of cancer may have escaped the prostate.

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

For the study
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