April 05, 2019
Shielding healthy organs from radiotherapy for pancreatic cancer
BY Jill Russell, Ph.D.
Unresectable pancreatic cancer is usually fatal because other treatments, such as radiation therapy, cannot be used. Radiation therapy causes toxicity in the adjacent healthy tissue of important and sensitive organs, such as the small intestine, which can lead to internal bleeding.
In a recently published study in Scientific Reports, a Nature journal, researchers at The University of Texas MD Anderson Cancer Center and Rice University investigated the possibility of using pro-drug WR-2721, also known as amifostine, to protect the intestinal tract during radiation exposure to treat pancreatic cancer.
“Radiation can help improve survival and quality of life by approximating surgery,” says Cullen Taniguchi, M.D., Ph.D., assistant professor in the Department of Radiation Oncology at MD Anderson, “but we had to find a way to protect nearby healthy tissue from potentially lethal doses of radiation.”
WR-2721, approved by the U.S. Food and Drug Administration as a radioprotective agent, is usually administered intravenously before radiation treatments. Enzymes called alkaline phosphatases metabolize WR-2721 into another compound called WR-1065 that reduces radiation damage.
IV drug is too harsh, but oral drug works in mice
However, intravenous WR-2721 is not often used because it causes severe nausea and hypotension in patients. Because the intestinal tract, particularly the duodenum and jejunum of the small intestine, has high levels of alkaline phosphatases, the researchers hypothesized that oral administration of WR-2721 might activate the drug only in the intestines, and not in tumors. This might lead to fewer adverse side effects.
Using both healthy mice and a mouse model of spontaneous pancreatic cancer, the researchers found that WR-2721 was converted to the protective WR-1065 form of the drug in the intestines, but not tumors. Using a specialized technique called in vivo mass spectrometry, the researchers found that mice that received oral WR-2721 had up to 12 times higher protective WR-1065 levels in the duodenum and jejunum compared to the liver and up to 30 times higher levels in the small intestine than in tumor tissue.
Taniguchi’s team also found that oral WR-2721 was fairly well-tolerated by mice, with only modest decreases in food consumption and body weight, which models severe nausea in humans. Once the oral drug was stopped, the animals rapidly recovered within 2 days of stopping treatment; however, mice that received intravenous WR-2721 had to be sacrificed after 4 days because of dramatically reduced food consumption and body weight.
Importantly, oral WR-2721 protected the intestinal tract from radiation doses that would normally be lethal. This allowed researchers to give ultra-high doses of focused radiation (12.5 Gy x 5 doses) to mice with pancreatic cancer to try to destroy their tumors. This treatment with WR-2721 and radiation tripled the median survival compared to control mice.
The possible benefit of an oral version of WR-2721 came from previous research by Rice University chemist James Tour and colleagues, along with Kathryn Mason of MD Anderson, now retired from the Department of Experimental Radiation Oncology. While testing the radioprotective potential of antioxidant particles, they found the control mice in their experiment, treated with an oral version of WR-2721, actually did better than those treated with the particles.
Mason shared the data with Taniguchi and a collaboration began. Mason and Tour are co-authors on the present study.
Clinical trials planned
Because WR-2721 has already been approved by the FDA, Taniguchi is optimistic that MD Anderson will be able to offer clinical trials in the next year or two and quickly obtain approval for using oral WR-2721 with radiation therapy to treat unresectable pancreatic cancer.
WR-2721 likely will also enable radiation therapy for other abdominal or pelvic cancers, such as hepatobiliary tumors or even metastatic disease in the abdomen.
Taniguchi’s laboratory is currently researching other radioprotective agents, including FG4592 in an article recently accepted by Cancer Research and GC4419 in a current clinical trial at MD Anderson.
“We hope to give oncologists an array of different radioprotective options to make radiation therapy possible for unresectable abdominal tumors and late stages of disease,” Taniguchi says.
Co-author Tour noted the original goal of his research. “It is exciting to see that work that was originally intended to mitigate against the effects of terrorist nuclear attacks holds such promise for the treatment of those suffering from pancreas cancer,” Tour said.
This research was funded by grants from the National Cancer Institute of the National Institutes of Health (R01CA207236, T32CA186892, F31CA210631, P30CA016672), the Cancer Prevention & Research Institute of Texas, V Foundation, Kimmel Foundation, Sabin Family Foundation Fellowship and the McNair Foundation.