New Cancer Drug Gives Patients With Rare Skin Cancer New Hope

June 6, 2012— -- For nearly 50 years, Joe Brindley, 81, has been going to the doctor every few months, getting chunks of cancer removed from the skin all over his body. Doctors removed so much skin from his nose that he needed a skin graft from his forehead to reconstruct it.

"I said at the time, Doc, do you think that will do me any good? I'll have new skin cancer in three years," Brindley said. Sure enough, two years after the painful surgery, the cancer returned.

Stewart Slone, 63, estimates that he's had more than 1,000 skin cancers in his lifetime. Surgeries to remove cancer from the top of his head left it bald and raw. He said people called him lots of names he'd like to forget.

"I've sort of lived as an outcast, all the scars on my face, and no hair and the red color to my head," he said.

Brindley, Sloane and thousands of others have a condition called basal-cell nevus syndrome, or Gorlin syndrome. It's a rare genetic disorder that gives a single person hundreds to thousands of skin cancer tumors during his or her lifetime.

People with the condition usually have surgery every two or three months to remove a cancerous lesion from their skin. They risk losing an ear, an eye or nose, along with having scars and lesions on their faces.

"Surgery was the only treatment, and has been for many years," said Kathlyn Roth, 58, who has had Gorlin syndrome since she was 15. "When you're walking around with a bandage or cotton ball sewn to your face, people look at you very strangely."

However, patients with Gorlin syndrome now have new hope from a drug that treats the disease. The drug, called vismodegib, not only treats patients with Gorlin syndrome but also thousands patients with advanced stages of basal cell carcinoma, the most common form of skin cancer.

Three studies published today in the New England Journal of Medicine describe the success of the drug against basal cell carcinomas. Dr. David Bickers, chairman of dermatology at Columbia University and an author of one of the studies, said for the 2 million people who develop a few small skin cancers, surgery is still the best option. But for people with advanced forms of the disease, the drug will be a major help.

"These patients instead of having one or two basal cells, often develop dozens, even hundreds of them, requiring hundreds of surgeries," Bickers said. "For those patients, taking this drug and reducing the tumor burden is a major advance."

Tracking a Sonic Hedgehog

The quest for a treatment for this type of skin cancer began more than 20 years ago, when scientists discovered a biologic pathway that tells the body's cells when to stop growing. The pathway, called the sonic hedgehog pathway, plays a key role in the growth and development of fertilized eggs, starting and stopping at specifically timed points in development.

"Once you're born, it pretty much shuts off. And that's a good thing," Bickers said.

But the trouble begins when the sonic hedgehog pathway spins out of control.

"When it turns on again in the adult, this drives the cell division that drives the growth of tumors," Bickers said. Decades of research has shown scientists that the pathway is active not only in skin cancer, but also in some childhood cancers, pancreatic cancer and certain types of lung cancer.

In patients with Gorlin syndrome, an error in a gene called PTCH prevents their bodies from putting the brakes on the sonic hedgehog pathway, leading to the unchecked growth of tumors.

Now, nearly 20 years after scientists discovered the role of the pathway in tumor growth, researchers developed vismodegib to target the pathway, basically shutting it off. The drug is manufactured by Genentech.

According to the new results of small clinical trials, the approach works. Researchers studied 104 patients in the most advanced stages of basal cell carcinoma, giving them the drug for a little over a year. Tumors shrank in the majority of the patients, and in some patients, the tumors disappeared completely.

In a study of 41 patients with Gorlin syndrome, the results were similar. In the 26 patients getting the drug, researchers saw only two new tumors develop, compared with 29 new tumors in the 15 patients taking a placebo pill. The size of existing tumors also shrank in patients taking the drug. The drug worked with surprising speed; the researchers wrote that they expected the drug to need at least two months to make noticeable changes, but many patients saw results after about one month on the drug.

"This really is a breakthrough," said Dr. Darrell Rigel, clinical professor of dermatology at NYU-Langone Medical Center, who was not involved in the study. "On a scale of one to 10 in breakthroughs in dermatology, this is probably an eight or a nine."

Rigel has been using vismodegib in his patients with advanced basal cell disease since the U.S. Food and Drug Administration approved it in January. He said the differences for these patients have been dramatic.

"We really had nothing for these patients before. If someone comes in with 30 or 40 of these tumors, you start running out of places to cut people," he said. "To now have something that works so dramatically is very exciting."

Tough Side Effects, But Worth It The drug has some tough side effects, such as hair loss, painful muscle cramps, weight loss and loss of taste. The side effects were enough to drive 54 percent of the Gorlin syndrome patients to drop out of the study. In the study of patients with advanced basal cell carcinoma, seven patients died, though it's not clear if their deaths were directly related to the effects of the drug.

"The side effects were difficult. They take some soldiering," said Julie Breneiser, 54. She lost 50 pounds and had painful cramps in her legs and hands. She said losing her hair, including her eyebrows, was the most difficult thing to accept.

"But every time I felt down about, I thought about what I'm potentially gaining from the drug and for others who could benefit from it in the future," including her two children, both of whom have the disease, she said.

The drug's side effects were also tough for Brindley, who dropped 25 pounds and lost his hair.

"I didn't have much hair to begin with," he said. "The bright side is, I don't have to shave anymore."

But they were worth it in the end. Brindley said nearly all of his skin cancers disappeared after two months on the drug.

"I'm so amazed at what this drug did for me," he said. "My grandmother and mother and uncle and older sister all had it. I am so thankful that someone finally found a cure for this."