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Cancer researchers have long worked at unraveling the mystery of why some prostate cancers recur after the use of therapies designed to stop the production of testosterone and other androgens that fuel cancer-cell growth. Now a team from the Hutchinson Center and the University of Washington are knitting pieces of knowledge back together into a form that offers a plausible explanation and new directions for study.
Drs. Pete Nelson and Elahe Mostaghel, of the Human Biology Division, and Dr. Bruce Montgomery, UW, have detected that androgen-synthesizing proteins are present within cancer cells. This suggests cancer cells may develop the capacity to produce their own androgens.
The presence of androgen-synthesizing proteins may explain why some prostate cancers become resistant to these widely used therapies. It also offers new directions for research into future treatments that could block the development of androgens in the cancer cells. The Prostate Cancer Foundation and the National Cancer Institute funded the study, and the Foundation's recent annual scientific retreat featured the results.
Androgen-deprivation therapy is routinely used in the treatment of advanced prostate cancer, in order to deprive cancer cells of these hormones that fuel their growth. However, over time cancer cells can become "androgen independent," and grow even in the presence of these medications. This type of the cancer is lethal, with most patients dying 18 to 24 months after becoming resistant to hormone suppression. Researchers in the field have focused on understanding the mechanisms by which these cancer cells become "castration resistant."
Nelson's team conducted tests on tumors removed and preserved from deceased prostate-cancer patients during "rapid autopsies" immediately after death. All the patients had received androgen-blocking therapies during the course of treatment to suppress tumor growth.
The researchers were able to detect in the tumors the key proteins, or enzymes, needed for a cell to produce its own testosterone from cholesterol present in the cell. "This study, along with other research in the field, suggests that cancer cells may have the ability to adapt and produce their own androgens that permit these cancer cells to survive," Nelson said. "While this study does not prove that the cancer cells act in this way, it does show it is possible."
The work of Nelson's team builds on a 1980s study that suggested cancer could develop its own testosterone and work by other investigators revisiting these ideas.
"In other studies, men without prostate cancer who received androgen-suppressing drugs also showed surprisingly high levels of androgen in their prostates even with low levels in their blood, and biopsies of the prostate following testosterone suppression in men who have prostate cancer have shown similar results," Nelson said.
In addition to offering a possible explanation of past findings, Nelson's findings show a mechanism of action and offer directions for future research in the area.
"The next phase will be to determine the source of androgen precursors. These are likely to be derived from adrenal androgens, or possibly from cholesterol," he said. "A key experiment will be to follow these precursors molecules in the cancer cells to see if they are converted to testosterone, hence proving these tumor cells are actually capable of such a conversion."
New medications are being tested in the early stages of clinical trials with the goals of blocking androgen synthesis.
Nelson lauded the Prostate Cancer Foundation for their leadership role in funding research in the field. "What PCF has allowed is exploration of innovative and high-risk ideas, instrumental in allowing us to pursue this area of investigation," Nelson said.
[From a Prostate Cancer Foundation news release.]