How can we improve the likelihood of a cure for men with high-risk and locally advanced prostate cancer? Radiation oncologist Phuoc T. Tran, M.D., Ph.D., the Irene and Bernard L. Schwartz Scholar, believes the answer lies in making prostate cancer cells more vulnerable to radiation. "More than 30 to 40 percent of men with high-risk and locally advanced prostate cancer who are treated with definitive radiation therapy experience biochemical failure." In response to this, scientists have made radiation therapy more effective in high-risk men by increasing the dose – which has helped, to a certain extent. But the radiation dose can only be bumped up so high before it causes side effects, damaging nearby rectal and urinary tract tissue.
Special, tumor-specific agents
may make the cancer more
sensitive to radiation – so that
each dose of radiation packs more
of a punch.
So, how to protect normal tissue but make the radiation more effective? Special, tumor-specific agents called radiosensitizers may be able to make the cancer more sensitive to the radiation – so that each dose of radiation packs more of a punch. One such class of agents targets HSP90. "HSP90 is a molecule that’s present in abnormally high amounts in prostate cancer cells," Tran notes. "It helps stabilize proteins that are necessary to keep prostate cancer cells alive, and also makes them resistant to radiation."
In early tests, HSP90-targeting drugs worked well in the laboratory and in phase I and II clinical trials, but were not very well tolerated by patients. A next-generation drug, ganetespib, looks much more promising. "In the laboratory, ganetespib exhibits potent activity in a broad range of human cancer cells, including prostate cancer," says Tran. "In addition, we showed that nextgeneration HSP90 inhibitors are potent radiosensitizers of prostate cancer cells. Moreover, ganetespib displayed superior pharmacological and safety properties compared to the earlier drugs and is currently undergoing clinical evaluation in multiple cancer Phase I and II trials," although it is not being tested against prostate cancer.
Because ganetespib is performing so well, Tran believes it will be a potent, tumor-specific radiosensitizer for prostate cancer. With support from the Patrick C. Walsh Prostate Cancer Research Fund, he will begin a Phase I clinical trial of ganetespib along with temporary hormonal therapy in men with high-risk or locally advanced prostate cancer. Currently, hormonal therapy is given to these men for a long period because it makes radiation therapy more successful. Tran believes adding the radiosensitizer will prove an effective triple-threat. "We expect to find the appropriate dose of ganetespib to be used in combination with radiation and hormonal therapy, and lay the groundwork for future Phase II and III trials," he says. "It is exciting that we will be targeting critical pathways that prostate cancer needs to survive and become resistant to radiation."