DeWeese and Yegnasubramanian: Giving testosterone after a period
of hormonal therapy is "a radicalnotion that... would represent a
paradigm shift for treatment of high-risk prostate cancer."
An unusual observation by Hopkins scientists about how testosterone affects prostate cancer cells may lead to more effective radiation therapy in men with high-risk disease.
Currently, the standard of care for men with prostate cancer that is likely to recur or spread beyond the prostate is to combine hormonal therapy with radiation therapy – a powerful combined approach that has been shown to improve control of cancer in the pelvis, reduce the likelihood of metastasis, and prolong life. "Typically, we treat men with hormonal therapy for two months, followed by radiation plus hormonal therapy," says Theodore DeWeese, M.D., Chairman of the Department of Radiation Oncology and Molecular Radiation Science. "In some men, the hormonal therapy continues for 24 months after the radiation. Despite this, some 30 to 50 percent of men still have a recurrence of their high-risk cancer. New approaches to improve these outcomes are critically needed."
DeWeese, with research scientist Vasan Yegnasubramanian, M.D., Ph.D., and their team, may have found a better way to control the cancer. "Recently, some members of our team found that testosterone stimulation of prostate cancer cells can result in breaks of the DNA ," says DeWeese. "This was a novel finding, and in some ways, it’s very similar to what we already knew about how radiation also causes breaks in DNA ." Putting the two ideas together led DeWeese and Yegnasubramanian to wonder whether they could take advantage of this. Could they coordinate hormonal therapy and radiation in a way that could exploit the DNA breaks, and achieve better results?
"We believe our results may have
significant implications for altering
current clinical management of men
with high-risk prostate cancer."
"These data led us to consider," DeWeese adds, "that testosterone stimulation after an initial period of testosterone deprivation, when appropriately timed with radiation therapy, might lead to particularly effective control of high-risk prostate cancer – a radical notion that, if proven, would represent a paradigm shift for treatment of high-risk prostate cancer."
DeWeese and Yegnasubramanian began to explore this possibility in the laboratory. First, their team treated human prostate cancer cells growing in a dish with testosterone and radiation. They found that "indeed, the combination of the two treatments resulted in more harmful breaks to the DNA than either one alone." But did the extra DNA damage kill more cancer cells? To answer this question, they treated mice with human prostate tumors "in the same way we treat men with prostate cancer," DeWeese explains. "That is, we first reduced their testosterone level, then delivered radiation to their tumors while the testosterone levels were still low." Just as it does in humans, this treatment helped control the growth of aggressive prostate tumors. But some of the tumors regrew quickly. Next, they tried their alternate timing strategy with testosterone and radiation. "In this experiment, we deprived mice of their testosterone, and once the testosterone was very low, we gave testosterone back to the mice and then irradiated the tumors. As we hypothesized, the mice treated in this way had tumors that were far better controlled than with the standard treatment."
These results suggest that treating prostate tumors with radiation while a jolt of testosterone is simultaneously breaking the cancer’s DNA provides better tumor control. "We believe our results may have significant implications for altering current clinical management of men with high-risk prostate cancer," says DeWeese. The next step is to determine the best timing and radiation dosage to get the maximal effect.