A team of Scripps, 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.
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.