New research may show why some prostate cancer recurs after treatment

Cancer researchers have long worked to understand 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.

New research has now detected that androgen-synthesizing proteins are present within cancer cells, which suggests that cancer cells may develop the capacity to produce their own androgens.

The presence of these proteins may explain why some prostate cancers become resistant to these widely-used therapies, and offers new directions for research into future treatments that could block the development of androgens in the cancer cells. The study, funded by the Prostate Cancer Foundation and the National Cancer Institute, was presented today at the Foundation's annual Scientific Retreat.

Androgen-deprivation therapy is routinely used in the treatment of advanced (metastatic) 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 a lethal form of the disease, with most patients dying 18 to 24 months after becoming resistant to hormone suppression. Research in the field has focused on understanding the mechanisms used by these cancer cells to become “castration resistant”.

Investigators Peter Nelson, M.D., Elahe Mostaghel, M.D., Ph.D., and Bruce Montgomery, M.D. from the Fred Hutchinson Cancer Research Center and University of Washington, 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,” explained Nelson. “While this study does not prove that the cancer cells act in this way, it does show it is possible.”

The work of Nelson and Montgomery was inspired, they say, by the work of Jack Geller in the 1980's, which demonstrated that testosterone and potent metabolites could still be found in prostate tumors at levels exceeding those found in the blood, which suggested the cancer could develop its own testosterone. Recent research by Jim Mohler, M.D., Stephanie Page, M.D., Ph.D., and other investigators has also revisited 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,” noted Nelson, “and biopsies of the prostate following testosterone suppression in men who have prostate cancer have shown similar results.”

The research by the Hutchinson Center/University of Washington team now offers a plausible explanation and mechanism of action for these findings. In the study, researchers removed entire metastases, or tumors, from deceased prostate cancer patients who had agreed to be part of a “rapid autopsy” research program. At least three tumors were removed from each patient, and examined for androgen levels and the presence of the enzymes responsible for androgen metabolism.

Nelson noted that the study offers directions for future research in this area. “The next phase will be to determine the source of androgen precursors. These are likely to be derived from andrenal androgens, or possibly from cholesterol. A key experiment will be to follow these precursor molecules in the cancer cells to see if they are converted to testosterone,” said Nelson, “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. Abiraterone, for example, seeks to inhibit the enzymes in the metabolic pathways that convert cholesterol to androgens, and work by blocking androgen synthesis in both the adrenal gland and possibly in the tumors themselves. Other classes of drugs being tested attempt to more completely block interactions with the receptor for androgens within the tumor cells, or alter the degradation of androgens. Rather than continuous treatment which is associated with side-effects, a strategy of maximally inhibiting the androgen axis for a short-time or on an intermittent basis could have the effect of destroying or suppressing cancer cell growth for long time periods. Investigators leading these trials also discussed initial findings in the session at PCF's annual Scientific Retreat.

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,” emphasized Nelson.