Enzyme activation for metabolism modification
BETHESDA, Md.—A collaborative study by researchers from several organizations has resulted in new data regarding glucose use and the possibility of affecting metabolism in cancer cells.
The study was led by a team from the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT), with researchers from the National Institutes of Health's new National Center for Advancing Translational Sciences (NCATS) also taking part. Researchers from the Structural Genomics Consortium at the University of Toronto and Harvard Medical School joined NCATS members for the authoring of the paper, which appeared Aug. 26 in the advance online publication of Nature Chemical Biology.
Glucose usage is one of the methods by which cancer enables tumor growth, as cancer cells use more glucose than healthy cells. All cells make use of the enzyme pyruvate kinase in order to obtain energy from glucose, but cancer cells predominately use one form, PKM2, while healthy cells predominately use PKM1. PKM2 is present in all types of cancer cells, and utilizes glucose for the creation of new cancer cells rather than energy.
Craig Thomas, Ph.D., a chemist at NCATS and one of the paper's authors, notes that PKM2 is not a mutated form of the PK gene but "a splice isoform that is present in some types of healthy cells as well as in cancer cells."
"It is, however, interesting that all cancer cells revert to expressing PKM2 over PKM1," he adds. "But this is part of the difference in studying the altered metabolic needs of a cancer cell which is a universal cancer trait as opposed to the genomic drivers of survival and proliferation which a varied and unique to various cancer forms."
Matthew Vander Heiden, M.D., Ph.D., an MIT researcher and senior author of the paper, is a medical oncologist whose lab investigates cancer metabolism, and previous work by Vander Heiden, as well as Dimitrios Anastasiou and Lewis Cantley of Harvard Medical School, implied that the activation of PKM2 might represent an effective method of returning cancer cell metabolism to a normal state.
MIT and the NIH established a collaboration in 2008 to test that hypothesis by identifying compounds capable of activating PKM2, a partnership that laid the groundwork for this most recent study. NCATS used a high-throughput screening robotic system to discover the compounds, which were then optimized to produce molecules with the requisite pharmacological activity and physical properties. This study focused on how the derived compounds activated PKM2 and what effects activation had on tumors. With the help of researchers from Agios Pharmaceuticals, TEPP-46, a PKM2 activator, was found for use in a mouse study, and proved to obstruct tumor development and reduce tumor size.
"All cancers have PKM2, and learning about the basics of cancer cell metabolism and proliferation is essential to targeting human tumors," said Vander Heiden in a press release. "I am cautiously optimistic that as we learn more about cancer cell metabolism, we may be able to identify drugs that act on PKM2 or other metabolic enzymes that could be tested against human cancers."
Though a great deal more research is needed before it can be determined what, if any, impact this might have for humans in terms of possible treatments, the researchers were able to identify molecular compounds that could activate PKM2, correcting how cancer cells use glucose, impeding tumor development and decreasing tumor size in mice.
"Previous work (much of it from the Cantley and Vander Heiden labs) has demonstrated that the switch from the active PKM1 to the virtually inactive PKM2 is a means to allow glycolytic intermediates to be shunted toward alternate metabolic pathways associated with amino acid, lipid and nucleic acid synthesis," notes Thomas. "Rapidly dividing cells require these building blocks during new cell construction. Thus, the inactivity of PKM2 is highly advantageous to cell proliferation, and pharmacological activation, as we have shown in this study, impairs that process."
"I think this has taught us something about pyruvate kinase biology, and I think it lends itself to the hypothesis that intervening in metabolism to shift it away from an anabolic state, be it with PKM2 activators or with something else, could be beneficial to put cancers in a state that makes them more difficult to grow," says Vander Heiden.
Moving forward, Vander Heiden notes that his lab will be focusing primarily on understanding how metabolism is regulated to enable anabolic metabolism and cell growth, noting that "it's still not entirely clear why pyruvate kinase activity has such a profound effect on anabolic versus catabolic metabolism in cells." From a more translational perspective, he says, the researchers will seek to determine what effects PKM2 activators might have on genetically engineered models of tumors versus xenografts, and "what is the right context for this inhibition." Thomas adds that "PK/PD and toxicity optimizations have yet to be pursued for these agents," and that "from a translational standpoint, much is yet to be done to see if PKM2 activation is a therapeutically relevant strategy for cancer treatment."
"A lot of people are interested in 'oh, is this a new drug', and it's an interesting possibility, but I think more work is needed to know if that's the case or not," says Vander Heiden. "The two big questions are really how well will it slow the growth of established tumors as well as which tumors are most likely to respond to pyruvate kinase activation."