Co-opting a Cancer Treatment to Spur Fat Loss

Drugs that block blood-vessel growth could tackle obesity.

Both cancer and obesity kill hundreds of thousands of patients each year, but they have more than the Grim Reaper in common. Tumors and excess fat are both unhealthy accumulations of tissue that require elaborate networks of blood vessels to feed them. Now Zafgen, a biopharmaceutical startup based in Cambridge, MA, is attacking obesity the way that cancer researchers have been attacking tumors for decades: using drugs that interfere with its blood supply.

Feed the flab: The fat cells (stained red) that make up adipose tissue can't grow without blood vessels (stained green) to nourish them. Zafgen, a startup based in Cambridge, MA, is developing obesity drugs that starve fat tissue by blocking blood-vessel proliferation. These drugs, which were originally designed to halt tumor growth, cause dramatic weight loss in obese mice. One of them will enter human clinical trials later this year. Credit: David Burk, Pennington Biomedical Research Center

"It's a very interesting and exciting concept," says Rakesh Jain, director of the Edwin L. Steele Laboratory for Tumor Biology, at Massachusetts General Hospital, who has no ties to Zafgen. However, anti-angiogenic drugs such as Avastin, used to treat breast, lung, and colon cancer, have unpleasant side effects--especially when used long term--including problems with the reproductive, cardiovascular, and immune systems. "Their toxicity is manageable, but they are not innocuous agents," says Jain.

Most pharmacological treatments for obesity have focused on controlling food intake. They attack weight gain centrally--in the brain--by trying to reduce appetite or encourage a feeling of satiety. But the neural mechanisms that regulate food intake also influence other physiological processes, says Zafgen president and CEO Thomas Hughes, meaning that this strategy is prone to producing side effects. Past weight-loss drug candidates have been discarded for their unwanted effects on mood, wakefulness, and reproductive function, and because their efficacy can wear off over time. "It's kind of like a whack-a-mole game," says Hughes. "You push down one thing, but something else pops up. That seems to be the nature of the way that circuits are wired in our brain."

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Instead, Zafgen aims to attack weight gain peripherally--in the fat tissue--which researchers hope will circumvent the side effects and rebound associated with more traditional approaches. "Conventional wisdom is that people become obese because they overeat," says Hughes. "But the fact is that in an environment where people are exposed to the same food supply and lifestyle, some will gain weight and others will not." In animals, those discrepancies seem to correlate with genetically determined differences among individuals' fat tissue, he says. Animals with so-called hungry adipose--fat tissue with a strong propensity to expand--show different expression of genes that regulate blood-vessel formation than animals that are naturally lean.

Zafgen aims to alter those natural differences, effectively converting hungry adipose into its more benign cousin, thereby shrinking existing fat stores and preventing the accumulation of new ones. To do so, the company is investigating a class of small molecules originally designed to stop blood-vessel growth in tumors but abandoned due to their low performance. These agents attach to receptors in the lining of blood vessels, preventing the binding of factors that normally spur those vessels to proliferate. While these drugs proved ineffective for treating cancer, they might work for obesity, in which case simply shrinking fat tissue rather than completely eradicating it is sufficient.