Enzyme activation for metabolism modification
New study reveals activation of pyruvate kinase form PKM2 in cancer cells can slow tumor growth
BETHESDA, Md.—A collaborative study by researchers fromseveral organizations has resulted in new data regarding glucose use and thepossibility of affecting metabolism in cancer cells.
The study was led by a team from the Koch Institute forIntegrative Cancer Research at the Massachusetts Institute of Technology (MIT),with researchers from the National Institutes of Health's new National Centerfor Advancing Translational Sciences (NCATS) also taking part. Researchers fromthe Structural Genomics Consortium at the University of Toronto and HarvardMedical School joined NCATS members for the authoring of the paper, whichappeared Aug. 26 in the advance online publication of Nature ChemicalBiology.
Glucose usage is one of the methods by which cancer enablestumor growth, as cancer cells use more glucose than healthy cells. All cellsmake use of the enzyme pyruvate kinase in order to obtain energy from glucose,but cancer cells predominately use one form, PKM2, while healthy cellspredominately use PKM1. PKM2 is present in all types of cancer cells, andutilizes glucose for the creation of new cancer cells rather than energy.
Craig Thomas, Ph.D., a chemist at NCATS and one of thepaper's authors, notes that PKM2 is not a mutated form of the PK gene but "asplice isoform that is present in some types of healthy cells as well as incancer cells."
"It is, however, interesting that all cancer cells revert toexpressing PKM2 over PKM1," he adds. "But this is part of the difference instudying the altered metabolic needs of a cancer cell which is a universalcancer trait as opposed to the genomic drivers of survival and proliferationwhich a varied and unique to various cancer forms."
Matthew Vander Heiden, M.D., Ph.D., an MIT researcher andsenior author of the paper, is a medical oncologist whose lab investigatescancer metabolism, and previous work by Vander Heiden, as well as DimitriosAnastasiou and Lewis Cantley of Harvard Medical School, implied that theactivation of PKM2 might represent an effective method of returning cancer cellmetabolism to a normal state.
MIT and the NIH established a collaboration in 2008 to testthat hypothesis by identifying compounds capable of activating PKM2, apartnership that laid the groundwork for this most recent study. NCATS used ahigh-throughput screening robotic system to discover the compounds, which werethen optimized to produce molecules with the requisite pharmacological activityand physical properties. This study focused on how the derived compoundsactivated PKM2 and what effects activation had on tumors. With the help ofresearchers from Agios Pharmaceuticals, TEPP-46, a PKM2 activator, was foundfor use in a mouse study, and proved to obstruct tumor development and reducetumor size.
"All cancers have PKM2, and learning about the basicsof cancer cell metabolism and proliferation is essential to targeting humantumors," said Vander Heiden in a press release. "I am cautiouslyoptimistic that as we learn more about cancer cell metabolism, we may be ableto identify drugs that act on PKM2 or other metabolic enzymes that could betested against human cancers."
Though a great deal more research is needed before it can bedetermined what, if any, impact this might have for humans in terms of possibletreatments, the researchers were able to identify molecular compounds thatcould activate PKM2, correcting how cancer cells use glucose, impeding tumordevelopment and decreasing tumor size in mice.
"Previous work (much of it from the Cantley and VanderHeiden labs) has demonstrated that the switch from the active PKM1 to thevirtually inactive PKM2 is a means to allow glycolytic intermediates to beshunted toward alternate metabolic pathways associated with amino acid, lipidand nucleic acid synthesis," notes Thomas. "Rapidly dividing cells requirethese building blocks during new cell construction. Thus, the inactivity ofPKM2 is highly advantageous to cell proliferation, and pharmacologicalactivation, as we have shown in this study, impairs that process."
"I think this has taught us something about pyruvate kinasebiology, and I think it lends itself to the hypothesis that intervening inmetabolism to shift it away from an anabolic state, be it with PKM2 activatorsor with something else, could be beneficial to put cancers in a state thatmakes them more difficult to grow," says Vander Heiden.
Moving forward, Vander Heiden notes that his lab will befocusing primarily on understanding how metabolism is regulated to enableanabolic metabolism and cell growth, noting that "it's still not entirely clearwhy pyruvate kinase activity has such a profound effect on anabolic versuscatabolic metabolism in cells." From a more translational perspective, he says,the researchers will seek to determine what effects PKM2 activators might haveon genetically engineered models of tumors versus xenografts, and "what is theright context for this inhibition." Thomas adds that "PK/PD and toxicityoptimizations have yet to be pursued for these agents," and that "from atranslational standpoint, much is yet to be done to see if PKM2 activation is atherapeutically 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 ifthat's the case or not," says Vander Heiden. "The two big questions are reallyhow well will it slow the growth of established tumors as well as which tumorsare most likely to respond to pyruvate kinase activation."