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Scripps Florida Scientists Share $3.85 Million NIH Grant to Develop New Class of Cancer Therapies

Study Will Focus on Inhibiting a Hallmark of Cancer Cell Metabolism

JUPITER, FL, March 6, 2012 – A pair of Scripps Research Institute scientists, one a cancer biologist and the other a chemist, has been awarded $3.85 million from the National Institutes of Health (NIH) to develop a new generation of broad spectrum anti-cancer therapeutics, including breast cancer and lymphoma.

John Cleveland, chair of Scripps Florida’s Department of Cancer Biology, and William Roush, chemistry professor, executive director of Medicinal Chemistry, and associate dean of graduate studies at Scripps Florida, are co-principal investigators for the new five-year project.

The focus of the research is on two proteins considered high priority targets for cancer therapeutics, Mct1 and Mct4. These “transmembrane transporters,” which specifically transport lactic acid, a byproduct of cancer cell metabolism, out of cancer cells, are expressed at low levels in normal tissues but at high levels in most malignancies.

“This project represents the culmination of three years of collaboration between our two laboratories to design, develop, and validate novel anti-cancer therapeutics targeting these transporters,” Cleveland said. “They are a new and unexploited avenue for cancer therapy, a potential Achilles’ heel to attack a broad spectrum of tumor types. A lot of malignancies express Mct1 and we think we can tailor these inhibitors to treat afflicted patients.”

Mct1 and Mct4 come into play during a process called “aerobic glycolysis,” a pathway used by cancer cells to generate energy from glucose and to produce essential building blocks. In cancer cells, this process produces an excess of lactate or lactic acid, which is a predictor of malignancy and even metastasis—the spread of cancer. Cleveland and Roush have shown that targeting Mct1 and Mct4 not only disrupts lactate homeostasis in certain types of lymphoma, but also disables tumor cell metabolism and proliferation.

So far, Cleveland and Roush have developed more than 190 small molecules to inhibit Mct1. With the new grant, the scientists plan to optimize these Mct1 inhibitors, synthesize new small molecule inhibitors of Mct4, and to devise new approaches to selectively deliver these agents to cancer cells.

“This is an example of the very best kind of collaboration at Scripps Research,” Roush said, “leading from discoveries in cancer biology to the development of novel compounds through the work of the Medicinal Chemistry and the Pharmacokinetics groups to produce an entirely new generation of cancer therapeutics.”

In the new project, the scientists will also explore the roles played by Mct1 and Mct4 in lymphomas and breast cancer driven by the Myc oncoprotein, which is activated in approximately 70 percent of all human cancers.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

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