Cancer Connections Everywhere

In the 1920s, German biochemist Otto Heinrich Warburg noticed a metabolic quirk in cancer cells—they break down glucose via an oxygen-free metabolic pathway, regardless of whether oxygen is available.

Today, a reinvigoration of Warburg's ideas is afoot, and it is a harbinger of a larger effort to determine the relationships between metabolism and cancer. Indeed, that multifaceted relationship will be the topic of an upcoming Keystone symposium in March. And just last week, pharmaceutical giant AstraZeneca announced a partnership with Cancer Research Technology, the commercial arm of the U.K.'s largest independent cancer research funder, to develop cancer metabolism drugs (see Business Concentrates, page 28). Growing interest in this area of research is also evident in recently published studies.

A case in point is work at Agios Pharmaceuticals, a privately held cancer therapeutics company in Cambridge, Mass. Agios researchers are looking at several metabolic enzyme targets. For example, they have found a surprising effect for brain-cancer-associated mutations in the enzyme isocitrate dehydrogenase 1. Rather than halting the enzyme's dehydrogenase activity, the mutations cause it to catalyze a reduction, the researchers find (Nature 2009, 462, 739). The product of that reduction, a metabolite called 2-hydroxyglutarate, is over 100 times more abundant in tumors with the cancer-associated mutation. So the compound could be a useful marker in tests of a patient's blood, urine, or cerebrospinal fluid to determine whether their tumor has the mutation. It could even be an indicator of whether certain experimental cancer drugs are working, says Joshua D. Rabinowitz, a coauthor of the work and consultant for Agios who studies metabolism at Princeton University.

Other researchers are learning that fatty acid biochemistry could be another important factor in cancer's development (C&EN, June 23, 2008, page 35). For instance, Benjamin F. Cravatt's team at Scripps Research Institute has shown that monoacylglycerol lipase, an enzyme that breaks down lipids, is a metabolic hub that might be boosting signals that lead to greater aggressiveness in cancer cells (Cell 2010, 140, 49).

Still other researchers are looking at amino acid biochemistry for connections. Since the 1950s, it has been clear that tumors consume large amounts of the amino acid glutamine, says Craig B. Thompson, a cancer biologist at the University of Pennsylvania. The breakdown of glutamine to lactate, a process called glutaminolysis, is a hallmark of tumor cell metabolism. Recent work in Thompson's and other groups suggests that in cancer cells, glutaminolysis complements the out-of-whack glucose metabolism described in Warburg's hypothesis, helping cells obtain high-energy cofactors and other materials they need to make more cellular building blocks (Proc. Natl. Acad. Sci. USA 2007, 104, 19345).

Meanwhile, chemical biologist Stuart L. Schreiber and coworkers at the Broad Institute, in Cambridge, Mass., are taking a global approach to metabolism and cancer. They're trying to map how a cancer cell's genetics determine what its metabolic Achilles heel might be. The researchers laid the foundation for that work in 2005, when they treated cancer cell lines with small molecules that perturb specific metabolic pathways while monitoring a slew of metabolic responses such as oxygen consumption. Sure enough, Schreiber's team found that the cancer cells' genetic makeup influences their vulnerability to the small molecules. In particular, a mutation to a well-known cancer gene called Ras leads to heightened vulnerability to a glycolysis inhibitor (Proc. Natl. Acad. Sci. USA 2005, 102, 5992).

Schreiber's lab is continuing this work under the auspices of a new network at the National Cancer Institute: the Cancer Technology Discovery & Development Network (CTD²). The network aims to decode relationships between metabolism, genetics, and cancer while also finding small-molecule drug leads. Schreiber leads the Broad Institute's center within the network. "This is an extremely exciting and promising area of cancer research, especially when viewed from the broader perspective," Schreiber says.

Chemical & Engineering News

ISSN 0009-2347

Copyright © 2011 American Chemical Society