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Old discovery could bring new cancer therapies

How tumor cells use sugar may be key to their ability to grow

(Dr. Annick D. Van Den Abbeele, Dana-Farber Cancer Institute)
By Carolyn Y. Johnson
Globe Staff / December 21, 2009

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An 80-year-old discovery about the way cancer cells generate energy is fueling a new wave of research into how cancers proliferate - and how to stop them.

In the 1920s, the German scientist Otto Warburg first observed that cancer cells burn sugar differently than normal cells do. Today, doctors exploit the phenomenon to capture images of tumors using PET-CT scans, which identify areas of the body that are metabolically active.

Still, the reason for cancer cells’ peculiar metabolism - and the question of whether it plays a key role in driving cancer - remained largely mysterious to scientists. Over the past few years, however, biochemistry research has led to a resurgence of interest in cancer cell metabolism - the ways in which cancer cells generate energy to function and grow.

A study led by Harvard Medical School researchers last year found that the seemingly inefficient way cancer cells use sugar may be the key to their ability to grow out of control. Normal cells burn sugar to create energy that fuels the rest of the cell. But rapidly dividing cancer cells use a different process that makes less chemical energy, but produces a pool of resources involved in building new cells.

Other studies revealed that a key part of what cancer-causing genes and mutations do is change a cell’s metabolism. And emerging evidence indicates that tracking whether a tumor is metabolically active may be helpful in predicting whether a therapy is working well before the tumor itself shows signs of shrinking - or not.

The research has led to excitement that it may be possible to starve cancer cells by crippling the enzymes they depend on.

“That’s the optimism - that we can identify the right enzymes the cancer cell is addicted to’’ as a target for a drug, said Lewis C. Cantley, director of the cancer center at Beth Israel Deaconess Medical Center.

He compares it to the difference between a city that depends on a variety of power sources - gas, wind power, and hydropower - versus a city that has only a single source and is vulnerable if its generator conks out.

“Most tissues have multiple ways to get anything made - but tumors tend to get addicted to one particular pathway,’’ he said.

Finding ways to disrupt metabolism is the idea behind Agios Pharmaceuticals, a Cambridge company cofounded by Cantley that last year raised $33 million. And in September, the American Association for Cancer Research hosted a four-day meeting focusing on cancer and metabolism. Last week, the journal Science named cancer metabolism an area to watch in 2010.

“There aren’t too many things you can point to shared by so many cancers. That’s one of the reasons for the enthusiasm in targeting it,’’ said Dr. Gregg L. Semenza, director of the vascular program at the Institute for Cell Engineering at Johns Hopkins University School of Medicine.

In a paper published in Nature last year, Cantley and colleagues found that the enzyme PKM2 played a role in cancer cells’ unusual metabolic processes. Because the enzyme is found in fetal tissues and not in normal adult cells, the discovery raised the prospect of developing a drug that would target the enzyme without harming other tissues - a strategy being pursued by Agios.

Other groups are looking at ways cancer-causing genes can affect metabolism. A study published last week in the journal Science Signaling found that blocking the synthesis of fatty acids needed for building cell membranes may be a therapeutic target for about half of the cases of deadly brain tumors called glioblastomas.

It has proven difficult to find a way to shut down a particular overactive receptor protein known to be involved in many glioblastomas and other cancers. But scientists discovered that one of the things the overactive receptor protein, called EGFR, does is to activate a genetic switch that triggers the synthesis of fatty acids.

So researchers shut off the fatty acid synthesis in tumors with overactive EGFR in mice, and found that it caused massive cell death. “Cancer cells, it appears, become very dependent on that molecular circuitry to provide those building blocks,’’ said Dr. Paul Mischel, a professor of pathology and laboratory medicine at the University of California, Los Angeles, and senior author of the paper.

It is not clear that disrupting a particular metabolic pathway will be a linchpin for stopping cancer, but what is clear is that better understanding cancer cell metabolism will help scientists develop drugs or diagnostic tools.

“A ton of evidence is mounting in this direction,’’ said Dr. Matthew Vander Heiden, a member of the David H. Koch Institute for Integrative Cancer Research at MIT, and a scientific adviser for Agios. “Many of the genetic changes very clearly involved in driving cancer seem in one way or another to change metabolism.’’

Carolyn Y. Johnson can be reached at cjohnson@globe.com.

The tumors (T) are highlighted in this PET-CT scan image because of their unusual metabolism, which causes the cancer cells to consume more of a sugar compound than normal cells. The
kidneys (K) also light up because they
excrete the substance.
After treatment, the tumors are dark, no longer taking in excess nutrients. The kidneys and bladder (B) light up because the substance is being excreted. New evidence suggests that tumors’ metabolic activity, as detected on such scans, might be an early sign of whether a treatment is effective.