Aug. 27, 2012 Scientists have known for decades that cancer cells use more glucose than healthy cells, feeding the growth of some types of tumors. Now, a team that includes researchers from the National Institutes of Health's new National Center for Advancing Translational Sciences (NCATS) has identified compounds that delay the formation of tumors in mice, by targeting a key enzyme that governs how cancer cells use glucose and its metabolites.
The study, published August 26 in the advance online publication of Nature Chemical Biology, was led by researchers from the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT), Cambridge. Researchers from the Structural Genomics Consortium at the University of Toronto and Harvard Medical School, Boston, also joined NCATS scientists to author the paper.
All cells use an enzyme called pyruvate kinase to derive energy from glucose. Recent studies have shown that cancer cells preferentially use one form of pyruvate kinase, called PKM2, which uses glucose to make additional cancer cells 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.
In the study report, the researchers describe the identification of molecular compounds that activate PKM2, correct the way human cancer cells use glucose, and delay tumor development and decrease tumor size in mice. The results support PKM2 activation as a potential therapeutic strategy for cancer. However, the researchers emphasized there is much more work needed to understand the implications of their findings for humans, such as determining what types of tumors might be sensitive to PKM2 activation.
"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 Division of Pre-Clinical Innovation 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."
NIH Common Fund's Molecular Libraries Program supported this research, as well as the prior development of the PKM2 activators. Additional support was provided by NCATS.
"It is gratifying to see such important scientific discoveries made possible in part by the Molecular Libraries Program," said James M. Anderson, M.D., Ph.D., director of the Division of Program Coordination, Planning, and Strategic Initiatives that guides the NIH Common Fund's programs. "This collaboration paired experts from two different scientific disciplines and transformed our understanding of cancer cell metabolism."
The study of cancer cell metabolism, pioneered by Nobel Laureate Otto Warburg in the early part of the 20th century, has witnessed a resurgence in research activity in recent years. New compound tools will be critical to dissecting the complex pathways that govern how cancer cells utilize nutrients such as glucose that provide the molecular building blocks to support rampant cell growth. The PKM2 activators detailed in the paper are among the first pharmacological compounds identified that will enable researchers to dig deeper into this key problem.
MIT researcher Matthew Vander Heiden, M.D., Ph.D., senior author of the paper and a medical oncologist whose lab studies cancer metabolism, has been a leading advocate of the idea that metabolic reprogramming provides cancer cells with an ability to prosper and grow. Previous work pioneered by Vander Heiden with Dimitrios Anastasiou and Lewis Cantley, both of Harvard Medical School, suggested that activating PKM2 might restore cancer cell metabolism to a normal state.
To test that theory, MIT researchers and the NIH formed a collaboration in 2008 to identify PKM2 activators, laying the foundation for the current study. NCATS researchers discovered the compounds, using a high-throughput screening robotic system. Researchers optimized the compounds in order to yield molecules with the needed pharmacological activity and the required physical properties for experimentation.
In the new study, the researchers focused their attention on how the compounds activate PKM2 and the effect this activation has on the formation of tumors. Hints as to the consequences of PKM2 activation were derived from experiments involving PKM1, a highly related enzyme of PKM2 that is found in healthy cells in an active state.
The unique mechanism of PKM2 activators prompted the research team to dig deeper into the metabolic consequences of activating PKM2. The researchers looked at the ability of the activators to mimic the results associating PKM1 expression with delayed tumor development. Aided by researchers at Agios Pharmaceuticals, Cambridge, Mass., they determined that one PKM2 activator, TEPP-46, could be used in a mouse study. The mice were given the compound, and it hindered tumor development and reduced tumor size.
"All cancers have PKM2, and learning about the basics of cancer cell metabolism and proliferation is essential to targeting human tumors," Vander Heiden said. "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."
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The above story is reprinted from materials provided by National Center for Advancing Translational Sciences.
- Dimitrios Anastasiou, Yimin Yu, William J Israelsen, Jian-Kang Jiang, Matthew B Boxer, Bum Soo Hong, Wolfram Tempel, Svetoslav Dimov, Min Shen, Abhishek Jha, Hua Yang, Katherine R Mattaini, Christian M Metallo, Brian P Fiske, Kevin D Courtney, Scott Malstrom, Tahsin M Khan, Charles Kung, Amanda P Skoumbourdis, Henrike Veith, Noel Southall, Martin J Walsh, Kyle R Brimacombe, William Leister, Sophia Y Lunt, Zachary R Johnson, Katharine E Yen, Kaiko Kunii, Shawn M Davidson, Heather R Christofk, Christopher P Austin, James Inglese, Marian H Harris, John M Asara, Gregory Stephanopoulos, Francesco G Salituro, Shengfang Jin, Lenny Dang, Douglas S Auld, Hee-Won Park, Lewis C Cantley, Craig J Thomas, Matthew G Vander Heiden. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nature Chemical Biology, 2012; DOI: 10.1038/nchembio.1060
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