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Starve the tumors by blocking the absorption of glutamine

No Jolla, Kalev. – March 19, 2021 – Scientists at the Sanford Burnham Prebis Institute for Medical Discovery have identified a candidate drug that blocks the absorption of glutamine, a major food source for many tumors, and slows the growth of skin cancer. The drug is a small molecule that targets the glutamine transporter, SLC1A5, that pumps nutrients into cancer cells – providing a promising new approach to treating melanoma and other cancers. The study has been published in the journal Molecular cancer treatments.

“While great strides have been made recently in treating skin cancer, the tumors of many patients are becoming resistant to treatment, and this has become a major obstacle in the successful treatment of the disease,” says Ze’ev Ronai, Ph.D., director of the appointed cancer center of the National Cancer Institute in Sanford Burnham Pripes. And senior author of the study. This study describes a promising compound that selectively targets the uptake of glutamine, an amino acid nutrient that tumors rely on for survival. We hope this drug will fulfill the unmet medical need of people living with this deadly cancer. ”

More than 7,000 people die from skin cancer each year in the United States, according to the American Cancer Society, and cases continue to increase annually. In the past decade, immunotherapy and personalized treatments have prolonged survival times for many patients. However, given the high rate of cancer recurrence, scientists are increasingly focusing on treatment strategies to prevent relapse and increase overall survival.

“This is a very important study because many of the targeted drugs for treating skin cancer have been hindered greatly by the rapid development of treatment resistance, sometimes at the same speed within several months. While immunotherapy approaches are promising, they are only effective in a subset of patients, and it can Resistance to treatment also develops in this place, “says M. Celeste Simon, Ph.D., Arthur H. Rubinstein is professor of MBBS in the department. Cell Biology and Growth and Scientific Director of the Abramson Institute for Family Cancer Research at the University of Pennsylvania Perelman School of Medicine. “The candidate drug identified in Dr. Ronai’s study offers an exciting new therapeutic approach to treating glutamine-addicted tumors, which includes a long list of human cancers, and hopefully will extend the amount of time that people with skin cancer respond to available treatments.”

Blocking the nutritional supply of the tumor

Researchers know that fast-growing tumors are able to reprogram their metabolism to generate additional energy for survival and growth. Tumors often achieve this by pumping increased levels of the amino acid glutamine into their cells, primarily through a pump called SLC1A5. As a result, cancer researchers are working to find drugs that block SLC1A5 and reduce glutamine levels.

In the study, Ronai and his team set out to identify drugs that could block the absorption of glutamine. In collaboration with researchers at the institute’s Konrad Priebes Center for Chemical Genomics, the scientists screened 7,000 different compounds for their ability to interfere with SLC1A5. This work identified about 20 outcomes, or promising options, and one was chosen based on its superior ability to prevent SLC1A5 from reaching the cell membrane. This candidate drug, IMD-0354, inhibited tumor growth in both cell culture and in mice with melanoma.

“Our study shows that targeting SLC1A5, which prevents glutamine from entering the cell in the first place, is an effective way to slow the growth of cancer cells,” says Yongme Feng, Ph.D., a scientist at the Runai Lab at Sanford Burnham Prebys and first author of the study. “Since many types of tumors depend on glutamine for survival, this drug may be able to treat many different types of cancer.”

As a next step, Ronai and his team will work to improve IMD-0354, focusing on improving the biophysical properties that will help speed up the preclinical evaluation of the drug candidate.

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Additional study authors include Gaurav Pathria, Susan Heinen Jenelle, Michael Jackson, Brian James, John Yin, and David A. Scott of Sanford Burnham Prebes. Study DOI 10.1158 / 1535-7163.MCT-20-0354.

The research presented in this press release was supported by the National Institutes of Health (NIH) (R35CA197465, P30CA030199), the Department of Defense (DoD) (CA1810216), and the Skin Cancer Research Alliance (509524).

About Sanford Burnham Prebis Medical Discovery Institute

Sanford Burnham Prebys is a prominent, independent biomedical research institute dedicated to understanding human biology and diseases and advancing scientific discoveries to deeply impact human health. For more than 40 years, our research has produced breakthroughs in cancer, neuroscience, immunology, and pediatric disease, anchored in the National Cancer Institute designated cancer center and advanced drug discovery capabilities. For more information, visit us at SBPdiscovery.org, or on Facebook at facebook.com/SBPdiscovery, and on Twitter @SBPdiscovery.

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