Abstract
Researchers have developed a compound, SR9243, that kills cancer cells by inhibiting lipid production and the Warburg effect. The drug induces cell death in multiple types of cancer and does not cause the side effects that have derailed previous attempts to target these processes.
Researchers have developed a drug that kills cancer cells by inhibiting lipid production and the Warburg effect, the tendency for tumors to rely heavily on glycolysis even when a more efficient way of metabolizing glucose is available. The drug induces cell death in multiple cancer types and does not cause the side effects that have derailed previous attempts to target these processes.
“It's hitting two of the major metabolic pathways that cancer cells like to use,” says senior author Tom Burris, PhD, chair of the pharmacology and physiology department at the St. Louis University School of Medicine in Missouri.
Researchers do not fully understand how the Warburg effect helps cancer cells, but it may aid cellular proliferation—and thus give tumors a growth advantage—by increasing production of metabolites that can be converted to lipids, amino acids, and nucleotides. Scientists have tried to design drugs to target specific enzymes in glycolysis or lipogenesis. However, most glycolysis inhibitors have been ineffective or killed normal cells, and lipogenesis inhibitors have caused side effects, such as anorexia and weight loss.
The agent developed by Burris's team, SR9243, targets the nuclear receptors LXRα and LXRβ. These receptors activate expression of glycolysis and lipogenesis enzymes. The drug prompts the receptors to bind co-repressor proteins that reduce expression of those enzymes instead.
The drug killed colorectal, lung, and prostate cancer cells in cell culture but did not affect healthy cells, the team reports (Cancer Cell 2015;28:42–56). Expression of glycolysis and lipogenesis genes dropped, as did levels of glycolysis metabolites and lipids. In mice with xenografts of these cancers, the drug slowed tumor growth and did not cause weight loss, liver toxicity, or inflammation of normal tissue.
That the drug worked in different types of cancer cells is encouraging, says Ralph DeBerardinis, MD, PhD, chief of the division of pediatric genetics and metabolism at The University of Texas Southwestern Medical Center in Dallas, who wasn't involved in the study. “It means that if the therapy turned out to be effective, it wouldn't be tied to a small subset of human cancers. It could potentially be fairly general.”
Burris's team found some limitations, however. SR9243 was less potent in pancreatic and ovarian cancers and had no effect on breast tumor cell lines, says Burris. He and his colleagues are investigating why these cancers don't respond well to the treatment.
DeBerardinis also cautions that scientists still know little about which metabolic pathways are active in a human tumor. “The metabolism of an actual tumor in a person is a black box,” he says. He would like to see the drug tested in mice with tumors that arise spontaneously rather than from an injected cell line, because their metabolism may be more similar to that of a human patient's tumor than tumors established from xenografts.
For more news on cancer research, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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