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.
“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.”
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.
In animal trials, obese mice treated with these repurposed drugs began to slim down after a few days and continued to shed fat at a precipitous rate until they reached a normal body weight, usually about three weeks later. This process was associated with a dramatic decrease in food consumption. But unlike drugs that cause weight loss by reducing food intake, these compounds seemed to reduce food intake by causing weight loss. As the fat cells shrank, they released free fatty acids that acted as a source of energy for the body, seeming to partially supersede the need for food calories. As soon as the animals reached a healthy weight, their food consumption returned to normal or even elevated levels, even though they continued to receive the drug. Nonetheless, the mice retained their new lean physiques for the remainder of the study–about six months total.
Not only did the mice lose weight, but they also became healthier overall. Their metabolic rate increased, their insulin sensitivity improved, and the fat content of their livers diminished. Within the fat tissue itself, there was a marked change in the number and architecture of blood vessels. Hughes says that all of these changes were highly reminiscent of those seen with extreme calorie restriction, which has long been known to improve health and extend life span in rodents. That makes sense, he says, because while the mice are actively losing weight, their calorie consumption plummets by as much as 80 percent.
Zafgen plans to start clinical trials on an anti-angiogenic molecule later this year, to determine whether the weight loss and health improvements seen in mice will translate to humans. Meanwhile, the company is working to better understand why the drugs it has tested are so potent in mice, and to discover new molecules with similar effects.
The rodent studies suggest that the doses sufficient for fat loss are lower than that required for tumor suppression, which might reduce the potential for side effects.
Hughes emphasizes that Zafgen intends its drugs to be used by the morbidly obese, and not by those trying to shed a pesky 15 pounds. “It’s serious medicine,” he says–not a lifestyle drug.
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