Scientists have known for decades that cancer cells use more glucose than healthy cells, which can feed the growth of some tumors. Now, a team that includes researchers from NCATS has identified compounds that delay tumor formation in mice. The compounds target a specific form of pyruvate kinase, called PKM2, which governs how cancer cells use glucose.
The study’s findings were published online in the Aug. 26, 2012, advance issue of Nature Chemical Biology. Biologists from the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT) in Cambridge led the research team, which included scientists from NCATS, the Structural Genomics Consortium at the University of Toronto and Harvard Medical School in Boston.
“The last several years have brought an avalanche of new discoveries that have begun to explain a phenomenon of altered cancer cell metabolism first described almost 90 years ago,” said Christopher P. Austin, M.D., NCATS director and one of the paper’s authors. “This work provides a wonderful example of how molecular compounds can be used as tools to probe and understand biological processes and, at the same time, explore new drug targets in the fight against cancer.”
How It Works
The pyruvate kinase enzyme is involved in a critical energy-producing process known as glycolysis ― a process common in all cell types where glucose is broken down to produce adenosine triphosphate (ATP), the cell’s main energy source. Healthy cells and cancer cells use this process and enzyme differently. Studies have shown that the preferential expression of one form of pyruvate kinase, called PKM2, in cancer cells enables molecules produced through glycolysis to be used for new cell construction instead of energy. This altered metabolic state appears to be a fundamental aspect of many cancers, and reversing the process represents a new opportunity for cancer treatment.
Lead study author Matthew Vander Heiden, M.D., Ph.D., a medical oncologist at MIT, along with colleagues at Harvard University, discovered that PKM2 is one of the main contributors to the altered cancer cell metabolism. The researchers found that replacing PKM2 with another form of pyruvate kinase, PKM1, actually stopped human lung cancer cells from forming tumors in mice. Vander Heiden and researchers from the NCATS Chemical Genomics Center, part of NIH’s Molecular Libraries Program, established a collaboration to test the theory that pharmacological activators of PKM2 would return cancer cells to a healthy metabolic state.
Using high-throughput screening and medicinal chemistry, the team identified molecular compounds that could be used as drugs to activate PKM2. With these small molecules in hand, the team had the compounds they needed to examine whether restoring PKM2 activity would be detrimental to tumor growth ― similar to what they saw when they replaced PKM2 with PKM1 in earlier experiments.
A Strategy for Cancer Therapy?
To test whether activating PKM2 would slow or stop tumor growth, the investigators evaluated the PKM2 activators in mice. The team selected a drug called TEPP-46, which was well-tolerated in mice and provided maximum PKM2 activation. Mice with human tumor cells were divided randomly into two groups that received either the drug or placebo for seven weeks. At the end of the test, researchers found that TEPP-46 did not completely stop tumor development, but it did delay tumor growth and reduce the size of tumors.
“It’s fair to say that perhaps activating pyruvate kinase could have some role in pushing tumors away from a program that allows them to efficiently grow,” Vander Heiden said. “Whether or not it would really be a viable drug in people is an open question.” Nonetheless, he admitted to being “cautiously optimistic.”
The NIH Common Fund’s Molecular Libraries Program supported this research and the prior development of the PKM2 activators. Additional support was provided by NCATS.
Posted September 2012