Finding may 'restart the survival clock' for prostate cancer patients

In a surprising finding that may radically change in the way prostate cancer is managed, researchers at the University have shown in laboratory experiments that the male hormone testosterone, which fuels prostate cancers early in their growth, can in later stages cause tumors to stop growing or even shrink.

The finding is reported in the Oct. 15 issue of the Proceedings of the National Academy of Sciences.

Doctors have routinely used surgical or chemical castration to slow the growth of cancer that has spread beyond the gland. This technique has been used since 1941, when urologist Charles Huggins, a University faculty member and now the William B. Ogden Distinguished Service Professor Emeritus, showed that prostate cancers require testosterone for growth and demonstrated the effectiveness of removing the hormone. Huggins received the Nobel Prize for this work in 1966.

Men treated with anti-hormone therapy often show dramatic improvement. But within a few years, the tumors regrow because the cells lose their dependency on testosterone and are able to thrive without it.

Now a researcher who was a colleague of Huggins for more than 30 years has shown that those tumors that no longer depend on testosterone may in fact be sensitive to it.

Shutsung Liao, Professor in the Ben May Institute for Cancer Research, and his co-workers showed in laboratory mice that testosterone can shrink experimental human prostate tumors that no longer depend on the hormone.

The finding suggests that testosterone supplementation, perhaps delivered by a patch, may be beneficial for certain types of prostate cancer, and that prolonged use of anti-hormone drugs, like Lupron, Zoladex and Proscar should no longer be routine.

"This is an interesting preliminary finding that may make us rethink our approach to therapy," said Glenn Gerber, Assistant Professor in Surgery, about Liao's study.

Prostate cancer is the most commonly diagnosed cancer in American men, with 317,000 new cases and 41,400 deaths expected in 1996. Although several treatment options are available for cancers confined to the gland, only anti-hormone therapy has been effective for slowing the growth of distant tumors.

"Although three-quarters of prostate cancer patients can have their tumors shrunk by castration or anti-hormone drug therapy, most of these cancers recur in one to three years and are then no longer dependent on hormones," Liao said. "Currently, once the tumor becomes independent of testosterone, there is no way to treat it."

Standard chemotherapy agents are not very effective against prostate cancer. The goal, according to Gerber, is to improve long-term management of the disease.

"While this new approach is not likely to cure anyone," said Gerber, "it suggests that we may be able to restart the survival clock, perhaps several times, not just by starving cells that need testosterone but also by feeding it to cells that gag on it."

To simulate the recurrence of hormone-independent cancer, John Kokontis, Research Associate in the Ben May Institute, grew human prostate cancer cells in the laboratory and weaned them off testosterone, a process that required repeated reculturing of the cells over a two-year period. These cells, capable of growing testosterone-free, were used to seed tumors in laboratory mice. The mice with these tumors were compared to mice implanted with tumors that need testosterone.

The researchers found that adding even low levels of testosterone could shrink established tumors of hormone-independent cells. Removing the added testosterone, or adding testosterone-lowering drugs, caused the tumors to regrow.

The researchers dedicated the report to Huggins, who turned 95 last month and has been in ill health. The work was funded by the National Institutes of Health.

Authors of the report in addition to Liao and Kokontis are visiting professor Richard Hiipakka, Senior Research Associate in the Ben May Institute, and Yoshihisa Umekita.