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Slaying Cancer At Its Roots Revival of classic hypothesis opens auspicious avenues to treatments Volume 88, Number 7, pp. 46 - 47

By Carmen Drahl, Assistant Editor February 15, 2010

James Inglese knew he had to choose carefully. cells, in contrast, go the oxygen-free route no matter Courtesy of Bum-Soo Hong It was 2004, and Inglese, deputy director of the how much oxygen is around. Warburg, who would Speeding to Health NIH’s National Institutes of Health’s Chemical Genomics later become a Nobel Laureate, surmised that this new activator (red) helps a natural activator (black) Center (NCGC), had a plan that could save time and difference gives cancer cells advantages in the lock four copies of a rogue resources for scientists screening large chemical growth department, a hypothesis that today bears kinase together so that libraries for enzyme inhibitors or activators. But his name. it acts like its speedier, he needed just the right protein to test the idea. healthy form. In ensuing decades, the sugar biochemistry of the It had to be something familiar, something well Warburg hypothesis took a backseat to other ideas. understood, but something that wasn’t such a hot In the clinic, agents that interfered with nucleotide target that it would steal the spotlight from the biochemistry, such as 5-fluorouracil, became screening method itself. A colleague, Douglas Auld, popular chemotherapeutics. And the molecular suggested pyruvate kinase, an enzyme that helps biology revolution shifted the cancer research break down glucose. That seemed to fit the bill just spotlight away from metabolism to the myriad fine, Inglese recalls. gene mutations that occur in scores of different Because of its screening efforts, Inglese’s team cancers. Today, though, advances in several areas is poised to make some big contributions to a are helping researchers understand the implications promising area of cancer research, one in which of Warburg’s hypothesis as never before and might the altered metabolic state all cancer cells lead to new cancer treatments. INSPIRATION Warburg in his lab at the Max share—rather than gene mutations specific to In the 1920s, Warburg and his contemporaries Planck Institute for Cell certain cancers—could be the key to finding new answered many fundamental questions about Physiology, in Berlin, in the treatments (C&EN, Oct. 26, 2009, page 20). 1960s. biochemistry, but they never figured out how Coincidentally, pyruvate kinase has emerged as a normal cells and cancer cells regulate their nutrient key player in maintaining the altered metabolism of uptake, how the cells know that they have enough cancer cells and is thus a potential target for cancer resources to grow and divide, explains Craig B. drugs; the enzyme is a scene stealer after all. Thompson, a cancer researcher at the University of The inspiration for this research movement goes Pennsylvania. The renaissance of the Warburg effect back nearly 100 years. In the 1920s, German and studies of cancer and metabolism are about biochemist Otto Heinrich Warburg learned that answering those questions, about understanding the Contact: cancer cells and healthy cells metabolize glucose, fundamental growth defects all cancer cells have Robert G. Urban and ultimately obtain energy, in different ways. in common. “This is about attacking cancer at its Executive Director Normal human cells use an oxygen-demanding roots,” Thompson says. And it just so happens that MIT Koch Institute pathway to break down glucose but can switch to one of those roots might be pyruvate kinase. [email protected] an oxygen-free route when oxygen runs low. Tumor 617.324.2169 Page 2.

The body can make several forms of pyruvate From a drug development perspective, Cantley’s kinase, and tumor cells harbor the same type that results got other cancer researchers excited shows up in other rapidly dividing cells, such as because the subversive pyruvate kinase M2 in those in an embryo, explains Lewis C. Cantley, a tumors isn’t present in most healthy adult tissues. biochemist at Harvard Medical School. Cantley’s Thus, it might be possible to target the enzyme with team has found that this rogue form, called a cancer drug, says Matthew G. Vander Heiden, pyruvate kinase M2, is critical for rapid growth in a former postdoctoral fellow in the Cantley group cancer cells (Nature 2008, 452, 181 and 230). who has since started his own laboratory studying cancer metabolism at Massachusetts Institute of “The goal of a cancer cell is to grow and survive,” Technology. [David H. Koch Institute for Integrative Cantley says. And one thing a growing cell needs Cancer Research]. is chemical building blocks such as nucleic acids, amino acids, and lipids. Pyruvate kinase M2 works At a 2008 conference in Australia, after presenting more slowly than its counterpart in healthy cells, his group’s pyruvate kinase findings, Cantley heard but it is better at helping to generate lots of those about a team that had just the type of screening necessary metabolites. expertise he’d need to target pyruvate kinase M2 with a drug. A few phone calls “I like to picture a conveyor later, Cantley was in touch belt,” says Matthew B. Boxer, with Inglese and his NCGC a chemistry team leader Pyruvate kinase has colleagues, including Auld, who who works with Inglese emerged as a key is the group leader for genomic at NCGC. If glycolysis, the assay technologies. “It all just process that breaks glucose player in maintaining came together for us,” Auld down to form pyruvate, is the altered metabolism says, as the excitement around a series of conveyor belts, of cancer cells and is Cantley’s pyruvate kinase pyruvate kinase sits at the results melded with the NCGC end of the line. If the last thus a potential target team’s screening expertise, belt in a series is slow, “you for cancer drugs. which had serendipitously been get a pileup in the middle,” optimized for that very enzyme Boxer explains. The buildup (Proc. Natl. Acad. Sci. USA of glycolysis intermediates 2006, 103, 11473). can then spill over into other metabolic pathways that The collaborative effort is build whatever the cancer cell needs, he says. well under way. By screening nearly 300,000 molecules in NIH’s Molecular Libraries Small Access to building blocks might not be the only Molecule Repository and optimizing the hits they reason that cancer cells’ metabolism differs from found, the NCGC researchers identified a set normal cells’, says Benjamin F. Cravatt, a chemical of diarylsulfonamide activators that are highly biologist at Scripps Research Institute. The pileup selective for the rogue kinase in tumors (J. Med. of glycolysis intermediates might also be signaling Chem. 2010, 53, 1048). The molecules boost the molecules that direct cancer cells’ behavior and sluggish kinase’s activity so it behaves more like the that could even instruct the cells to become more faster-acting form found in healthy adult cells. The aggressive. Cantley’s work shows that “there is team is now exploring other classes of molecules probably tremendous cross-talk between signaling that do the same. pathways and metabolic pathways,” Cravatt says. Page 3.

What’s really intriguing is how the new never know where you’ll find more targets.At the activators seem to work, says Hee-Won Park, a molecular level, the new activators coax pyruvate collaborator who belongs to both the Structural kinase M2 into its active state, which contains Genomics Consortium (SGC) and the University four copies of the enzyme locked together. The of Toronto’s pharmacology department. Park, molecules complement fructose bisphosphate, SGC research associate Bum-Soo Hong, and a metabolite that is a natural activator of the colleagues determined the X-ray crystal structure enzyme, by binding to sites that the metabolite of pyruvate kinase M2 bound to several of the does not occupy. Together, the compounds confer diarylsulfonamides. They have deposited their superstability to the kinase’s active state, Park data into the publicly available Protein Data Bank. says, perhaps preventing the buildup of metabolic building blocks that sustain cancer cells. At the molecular level, the new activators coax pyruvate kinase M2 into its active state, which As interesting as the structures seem, “we want contains four copies of the enzyme locked to know if that’s how things really work in cancer together. The molecules complement fructose cells,” Park says. Now, Vander Heiden’s lab at MIT bisphosphate, a metabolite that is a natural is testing the best of the diarylsulfonamides to activator of the enzyme, by binding to sites that find out. the metabolite does not occupy. Together, the It’s likely that other enzymes throughout humans’ compounds confer superstability to the kinase’s vast metabolic network also have rogue forms active state, Park says, perhaps preventing the that might be tackled in a similar way, Vander buildup of metabolic building blocks that sustain Heiden says. Already in 2007, Cantley, Thompson, cancer cells. and fellow cancer researcher Tak W. Mak of the As interesting as the structures seem, “we want University of Toronto cofounded a biotechnology to know if that’s how things really work in cancer company inspired by that idea: Agios cells,” Park says. Now, Vander Heiden’s lab at MIT Pharmaceuticals, in Cambridge, Mass. Vander is testing the best of the diarylsulfonamides to Heiden was one of several people who signed on find out. as a consultant for the company, which derives its name from a Greek word meaning “holy” or It’s likely that other enzymes throughout humans’ “saint.” In mid-2008, privately held Agios landed vast metabolic network also have rogue forms $33 million in venture capital funding. that might be tackled in a similar way, Vander Heiden says. Already in 2007, Cantley, Thompson, The pyruvate kinase M2 story is just one piece of and fellow cancer researcher Tak W. Mak of the the complicated puzzle that is metabolism and University of Toronto cofounded a biotechnology cancer, and it’s too early to tell how it will end. But company inspired by that idea: Agios as Inglese and his colleagues can attest, you never Pharmaceuticals, in Cambridge, Mass. Vander know where you’ll find more targets. Heiden was one of several people who signed on as a consultant for the company, which derives its name from a Greek word meaning “holy” or “saint.” In mid-2008, privately held Agios landed $33 million in venture capital funding.

The pyruvate kinase M2 story is just one piece of the complicated puzzle that is metabolism and cancer, and it’s too early to tell how it will end. But as Inglese and his colleagues can attest, you