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Yale Researchers Devise A One-Two Punch Against Melanoma

7:06 p.m. EDT, July 18, 2012


Although awareness of skin cancer has increased considerably in the past few decades, about 70,000 people were diagnosed with melanoma in 2011, and 8,720 people died from advanced melanoma. The American Cancer Society expects both those numbers to go up this year.

But a number of drug developments in the past few years have bolstered doctors’ arsenal in the fight against melanoma, the deadliest form of skin cancer. Last year, the U.S. Food and Drug Administration approved theBristol-Myers Squibb drug Yervoy, a drug that boosts the immune system‘s ability to fight melanoma tumors. The FDA also approved vemurafenib, developed by the California biotech company Roche and Plexxikon, which inhibits the growth of melanoma tumors. Both drugs have been shown to extend the lives of people suffering advanced melanoma by months and, in some cases, years.

New developments continue to emerge at an impressive pace. Earlier this month, scientists at Brigham and Women’s Hospital published research about a newly identified molecule that would help the immune system fight melanomas. And last month, researchers in Germany reported that their drug, dabrafenib, slowed tumors in patients with a common gene mutation.
At Yale University, Tarek M. Fahmy and a group of researchers have taken a different tack. Rather than develop new drugs, they’ve taken existing, widely used drugs and found a new way to deliver them to the tumors they are designed to attack.

“What we’re interested in doing is taking the basic science and creating delivery systems, said Fahmy, a bioengineer.

For all the new drugs that have been developed, he said, none has consistently proven to substantially extend the life of someone with melanoma.

“Part of the reason that the average survival rates are low is because of the aggressiveness of the tumor,” he said. “If [the drug] does reach it, it’s such a low dose that it doesn’t do its job.”

Fahmy said melanoma has proven particularly resistant to immunotherapy — a means of fighting cancer by boosting the patient’s immune system to attack cancer cells — because the tumor has so many ways of attacking the patient’s immune system.

This week Fahmy and a team of researchers published a study in Nature Materials about a new therapy that makes it possible to simultaneously hit a melanoma tumor with two previously incompatible drugs.

“In essence, it’s a one-two punch strategy that seems to work well for melanoma and may work even better with other cancers,” said Fahmy, an associate professor of biomedical engineering and chemical and environmental engineering.

One of the two drugs, known as Interleukin-2, helps strengthen the body’s immune system. In the past, this drug has had limited efficacy because metastatic melanoma tumors emit a protein — known as transforming growth factor b — that disrupts the immune system.

Enter the second half of the one-two punch: a small-molecule drug called Sb505124 that inhibits transforming growth factor b.

“That is a new idea which hasn’t been tried before,” Fahmy said, “that is, to do both together in a special delivery system.”

What made it complicated is that the inhibitor drug is a small molecule agent, while the immune booster is about 1,000 times bigger.

“You have two things doing two different things, and they need to be in the same place,” he said.

The researchers were able to get around this problem by developing a drug delivery system known as a nanolipogel, which uses biodegradable nanoparticles that can simultaneously hold the chemically diverse drugs and gradually release them into the tumor. Fahmy compares the nanoparticle to a bus small enough to make its way through the body, but big enough that it gets stuck in the capillaries leading into the tumor. Once stuck, it dissolves and releases its contents.

The treatment was administered to mice with melanoma tumors, both intravenously and directly into the tumors. The researchers found that it significantly delayed tumor growth and increased the mice’s survival.

“I think this is a good kind of approach,” said Dr. Upendra Hegde, an oncologist with the University of Connecticut, who was not part of the study. “I think it seems to be very promising. You cannot cure melanoma, but you can control it by making the immune system more resistant to the tumor.”