Drug kills cancer cells building blocks

Targeting cancer cell metabolism is recognized as a promising area for the development of cancer chemotherapeutics. Discoveries by Drs. Bingham, Zachar and colleagues at Stony Brook University led to a technology for the design of drugs that disrupt cancer metabolism. In collaboration with Cornerstone Pharmaceuticals, they are evaluating the basic mechanisms of actions behind this class of agents. The relationship with Cornerstone has its roots within Stony Brook's Center for Biotechnology, an organization that helps translate basic research discoveries into technologies that have commercial and clinical value. Cornerstone has licensed the technology from The Research Foundation of the State University of New York, on behalf of Stony Brook University.

In 2008, initial stage (phase I) Food and Drug Administration (FDA)-approved clinical trials of anti-cancer compounds began. As the exclusive licensee, Cornerstone is sponsoring the clinical trials, which have now moved into phase II. The latest research findings in the paper, titled "A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process," highlights the results of cultured cell studies by the research team in support of the phase II clinical trials.

"We discovered that CPI-613 acts as a 'cocktail of one,' meaning the single agent kills cancer cells selectively by simultaneously attacking two crucial metabolic enzymes in cancer cells, and each by a different mechanism," said Dr. Bingham, Associate Professor in the Department of Biochemistry and Cell Biology. "The critical clinical implication of this duel mechanism of action is that unlike other current anti-cancer agents, CPI-613 has the capacity to attack tumor metabolism more robustly than single-target agents and be less vulnerable to evolved drug resistance."

Dr. Bingham added that CPI-613's two-pronged attack on this cancer cell cycle efficiently and selectively induces cancer cell death in a variety of cancers, including solid tumors and also in leukemia and lymphoma.

The agent attacks and deactivates two lipoate-using enzymes that are major entry points for energy and carbon into the mitochondrial citric acid cycle of the cancer cell. These enzymes are known as the alpha-ketoglutarate complex (KGDH) and the pyruvate dehydrogenase complex (PDH).

Previously, the researchers showed that CPI-613 attacked PDH by activation of regulatory kinases. In contrast, KGDH is auto-regulated by oxidation-reduction (redox) processes. The new study reveals that CPI-613 shuts down KGDH completely by way of an artificial hyper-stimulation of this redox autoregulatory process, destroying the energy producing capacity of the cells.

"Since KDGH and PDH control flux of metabolites through the mitochondrion, the effects of drug treatment are to shut down tumor cell mitochondrial metabolism completely, resulting in cancer cell death," explained Dr. Bingham.

The research team hopes that by CPI-613's mechanisms of action to attack at least two cancer metabolic targets, this class of anti-cancer agents will form the foundation for the development of effective treatment of many cancers by way of shutting down multiple cancer cell metabolic regulation targets.