A team that includes scientists from the National Institutes of Health's new National Centre for Advancing Translational Sciences (NCATS) have identified compounds that delay the formation of tumours in mice, by targeting a key enzyme that governs how cancer cells use glucose and its metabolites.
The study was published in 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 tumour development and decrease tumour 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 tumours 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, MD, 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 Programme 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 Programme," said James M Anderson, MD, PhD, director of the Division of Programme Coordination, Planning, and Strategic Initiatives that guides the NIH Common Fund’s programmes. "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, MD, PhD, 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 tumours. 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 tumour development. Aided by researchers at Agios Pharmaceuticals, Cambridge, Massachusetts, they determined that one PKM2 activator, TEPP-46, could be used in a mouse study. The mice were given the compound, and it hindered tumour development and reduced tumour size.
"All cancers have PKM2, and learning about the basics of cancer cell metabolism and proliferation is essential to targeting human tumours," 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."
The National Centre for Advancing Translational Sciences (NCATS) aims to catalyse the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions.
The NIH Common Fund supports a series of exceptionally high-impact research programmes that are broadly relevant to health and disease. Common Fund programmes are designed to overcome major research barriers and pursue emerging opportunities for the benefit of the biomedical research community at large. The research products of Common Fund programs are expected to catalyze disease-specific research supported by the NIH Institutes and Centres.
NIH, the nation's medical research agency, and is a component of the US Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases.