For the unlucky 10% of men diagnosed with prostate cancer who have the most aggressive form, the prognosis is grim. The available prostate cancer drugs may initially shrink their tumors, but the remaining cancer cells usually grow out of control again after a couple of years. These drug-resistant cases account for most of the nearly 29,000 annual deaths in the United States from prostate cancer.
Researchers led by Charles Sawyers at Memorial Sloan-Kettering Cancer Center in New York City have now developed a compound that could prevent some of the deaths. This Thursday, they will report online in Science that in mice the compound shrank implanted human prostate tumors untreatable with current drugs and that it showed signs of arresting tumor growth in men with similarly drug-resistant cancer. Although more clinical studies are needed, cancer researchers are excited about the potential drug, which tackles prostate cancer by a mechanism different from that of current drugs. "It's possibly a new and better way of treating prostate cancer," says oncologist Philip Kantoff of the Dana-Farber Cancer Institute in Boston.
In prostate cancer, genetic changes within cells allow testosterone and similar hormones, known as androgens, to fuel unrestrained cell growth. Most patients receive drugs to limit the body's production of androgens. If the tumor continues to grow, physicians prescribe other drugs that bind to the androgen receptor in the prostate cell's cytoplasm so that the hormone cannot land on the receptor and turn it on. But these drugs usually fail after a time.
This problem intrigued Sawyers, who had earlier worked on resistance to Gleevec, a potent leukemia drug he helped develop. In 2003, Sawyers's team showed why cells from advanced prostate tumors eventually thwart standard drugs: The cells produce high levels of the androgen receptor, and this makes them so sensitive to androgens that even the receptor-blocking drugs can stimulate the cells to grow. Sawyers next joined forces with chemist Michael Jung, whose group at the University of California, Los Angeles, synthesized nearly 200 androgen-like compounds. The researchers screened the molecules, selecting ones that bound tightly to the androgen receptor but didn't activate it. Jung's group then tweaked promising candidates to make two potential drugs.
In addition to binding to the androgen receptor, the new compounds seem to hinder it from getting into the cell's nucleus, binding to DNA, and triggering the expression of genes, the team reports. "It's a beautiful story," says cancer pharmacologist Donald McDonnell of Duke University in Durham, North Carolina.
In a clinical study with one of the compounds, dubbed MDV3100, levels of prostate-specific antigen--a marker for prostate tumor growth--dropped by at least 50% in 13 of 30 patients with advanced disease for whom other treatments had failed. "For this group of patients, this is a very impressive result," says Sawyers. Medivation Inc. in San Francisco, California, which collaborated on this work, is now testing the drug at higher doses on more patients. (Sawyers is a consultant for the company and is a co-inventor on a patent for MDV3100.)
Even if MDV3100 extends the lives of men with advanced prostate cancer, their tumors will likely become resistant to it, too. But researchers hope the compound can be combined with another drug candidate, developed by a different team but also in trials, that stops cancer cells from making their own supply of androgens. "A very exciting possibility" is that a cocktail of these drugs will prevent men with early prostate cancer from ever reaching the drug-resistant stage, says Kantoff, who heads one of several centers that are testing MDV3100.