Medical science is one step closer to a breakthrough in the treatment of melanoma, the deadliest of all skin cancers, and Nashville’s Sarah Cannon Research Institute is right in the thick of things.

 

While melanoma accounts for less than 5 percent of U.S. skin-cancer cases, it causes most skin-cancer deaths. According to the American Cancer Society, 68,720 new melanoma cases were reported in the United States in 2009, and 6,850 Americans died of the disease.

 

SCRI is one of a few sites in a new international trial that compares a new drug from Roche Pharmaceuticals with the melanoma standard of care, which is an older medicine called dacarbazine, a chemotherapy compound. “There are actually four pharmaceutical companies that are competing with drugs in this class,” said Howard “Skip” Burris, MD, SCRI chief medical officer and director of drug development.

 

The drugs are called BRAF inhibitors, and they work to stop spontaneous mutations in a gene known as BRAF. The problem comes when a defective gene then encodes a protein, which “is part of a pathway that enables cells to grow and develop normally,” Burris explained. “So when you have that mutation in a cell, the cell doesn’t turn off, and it grows out of control and thus … by definition … becomes a cancer cell. We’ve found that you could design a pill therapy that would, in fact, block that mutation and turn the cell off.”

 

SCRI was involved in the Phase 1 work with this class of compounds and was selected to participate in the Phase 3 trial of the Roche drug. In fact, SCRI investigators have also been involved in the development of other BRAF inhibitors. SCRI researcher Jeffrey Infante, MD, is scheduled this month to present melanoma research on a competing compound at the annual meeting of the American Society of Clinical Oncology.

 

Burris said there’s been “a lot of buzz of late” in the oncology community about the promise of BRAF inhibitors. That’s because half of melanoma patients have this mutation. “It’s been the first exciting new advance in melanoma in quite some time,” he said, adding, “Now we’re learning that within individual types of cancers, there are percentages of patients who will have a specific DNA problem. They will have something go wrong with a gene, and it makes that an attractive target against which to design a cancer therapy.”

 

Similar breakthroughs have happened in fighting other cancers. For example, once it was found that a translocation of the so-called Philadelphia chromosome was associated with chronic myelogenous leukemia, targeted therapies have dramatically improved survival rates. Another example is the drug Herceptin, which targets the 20 percent of breast cancer patients who suffer an overexpression of the HER2 protein.

 

Burris said the BRAF mutation likely contributes to the growth of some other tumors, particularly those related to the pancreas, colon and lungs; yet with melanoma, the problem is particularly relevant. “We all thought when we started out that it might help 10 or 20 percent of the patients. It was a little surprising that almost half of melanoma patients actually have this mutation,” Burris said. “So the number of patients who might benefit from these treatments is quite large.”

 

SCRI opened enrollment for its Phase 3 trial of the Roche compound in May, which appropriately was “Melanoma Awareness Month.” Trial participants simply take a pill a day, and they avoid some of the traditional toxicities of chemotherapies like hair loss, a low white blood count and anemia. “With these chronic oral medications, we have different toxicities that we have to battle,” Burris said. “The common toxicities that we see with these classes of drugs are skin rash, some diarrhea and fatigue, but compared to traditional chemotherapy, these are very well tolerated.” He added that it’s much easier to halt a daily oral therapy if side effects are intolerable.

 

Burris predicted that the trial, with several hundred patients worldwide, will wrap up in 12 months or so — meaning that, depending on the trial’s findings, the compound could be on the market by 2012. “One thing that is promising when working with therapies like this is that you start with the patients with the most severe form of the disease and already had to come back. If you’re achieving good results in patients like that, then the next step will be to use it earlier,” he said. He explained that “the promise down the line” is that melanoma patients could receive the therapy for a few months after their initial excision, and any remaining cells wouldn’t have a chance to reoccur.

 

“This class of medicines is probably going to be considered revolutionary. These come along every now and then in a disease, and I think this one is going to rank right up there as having one of the more significant impacts that we’ve had for a cancer,” Burris said. “We’ve had some dramatic results to date – doctors showing each other scans of patients where the tumors have gone away completely.”

 

The Sarah Cannon Research Institute motto, Burris said, is for patients to think of a clinical trial as the first treatment option rather than a last one. “We’ve talked about personalized medicine and the best therapy for the right patient,” Burris said. “I think that with the study of these mutations and the drugs that are coming along, we are getting much closer to that being a reality.”