Moffitt Cancer Center Uses Innovative Treatment Strategy to Overcome Drug Resistance

December 05, 2017

 

TAMPA, Fla. – Drug resistance has long been an impediment in cancer therapy. But Moffitt Cancer Center is hoping to change that with an innovative new therapeutic strategy called adaptive therapy. Based on evolutionary principles and tested through mathematical models, this strategy uses short bursts of therapy to suppress cancer growth rather than large doses of a therapeutic agent aimed at killing all of a patient’s cancer cells. Now, Moffitt has used the adaptive therapy strategy to treat patients with metastatic prostate cancer. The results were published Nov. 28 in Nature Communications.

Prostate cancer is one of the most common cancers in American men, following skin cancer. One in seven men will be diagnosed with the disease during his lifetime. And nearly half of all prostate cancer patients will develop metastatic disease.

The first line of treatment for patients with metastatic prostate cancer is androgen deprivation therapy, but nearly all men progress to metastatic castrate-resistant prostate cancer. This is often because of resistance caused by increased CYP17A1 expression, an enzyme key to testosterone production. Abiraterone acetate, a CYP17A1 inhibitor, helps reduce prostate-specific antigen (PSA) levels and improve survival, but patients can become resistant to the therapy.

According to Robert Gatenby, M.D., study senior author and co-leader of the Cancer Biology & Evolution Program at Moffitt, “there is a natural tendency to use high-dose therapy based on the assumption that each patient receives maximum benefit by killing as many cancer cells as possible. However,  according to evolutionary principles, high-dose therapy is the least likely to be successful in controlling the tumor for any length of time because it intensely selects for resistant cells and allows them to grow rapidly because the treatment has eliminated all of their competitors. We want to try to work with evolution rather than letting evolution be a source of our defeat.”

Following theoretical analysis and model simulations, our investigators identified a patient-specific strategy for prolonging response to abiraterone. They initiated a pilot study to investigate the adaptive therapy strategy. Study participants take abiraterone and prednisone until their PSA levels decline to less than 50 percent of their baseline level. Once that number is achieved, abiraterone therapy is suspended. Patients are monitored every four weeks. Treatment is reinstated only if a patient’s PSA level is above the pre-abiraterone baseline.

This study is still ongoing. Patients will remain on this treatment strategy unless they develop radiographic progression or ECOG (Eastern Cooperative Oncology Group) performance status deterioration while on abiraterone. Of the 11 patients enrolled in the pilot study, 10 remain on the trial. One has exhibited radiographic progression.

“At the study’s first interim analysis, 10 of our 11 study patients were approaching the two-year mark without evidence of radiographic progression, their outcomes met and exceeded the historical benchmark (median rPFS + 16.5 months) established in the December 2012 phase 3 study that led to expanded FDA approval for abiraterone,” said Jingsong Zhang, M.D., Ph.D., principal investigator of this pilot trial and assistant member of Moffitt’s Genitourinary Oncology Program. “Significantly, this result was achieved with less than half the amount of abiraterone that would have been used for continuous dose therapy, which has an average wholesale price of $9,000 per month.”

This work was supported by grants from the James S. McDonnell Foundation, Moffitt’s internal grant for clinical trial and the National Cancer Institute (R01CA170595, U54CA143970-05, P30-CA07292).

About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 49 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s excellence in research, clinical trials, prevention and cancer control. Moffitt is listed as one of the top 10 cancer hospitals in the nation and has been listed in U.S. News & World Report as one of the “Best Hospitals” for cancer care since 1999. Moffitt devotes more than 2 million square feet to research and patient care. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 5,600 team members, Moffitt has an economic impact in the state of $2.1 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on FacebookTwitter and YouTube

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