Gene Therapy Gives Hope in Virulent Form of Cancer

Photo: New drug known as RO5185426, is designed to hit the ?Achilles? heel? of a melanoma tumor

Melanoma researchers are known to be a jaded bunch.

Despite years of research, the last significant new treatment for the severe form of skin cancer came out in 1992 -- and only 5 percent to 10 percent of cancer patients get any lasting results with that treatment.

The best doctors have been able to offer patients has been experimental medicine, "because there are no right answers," on how to treat melanoma that has spread to other organs, Dr. Anna Pavlik, director of the melanoma program at the New York University Cancer Institute.

But in 2008, patients enrolled in a clinical trial of an experimental drug called PLX4032 started to get better. Much better.

"I've never seen anything like this," said Dr. Jeffry Sosman, principle investigator of the recently completed phase II study the new drug. "I had patients who were in extreme pain and within a week or so, came to the office off of pain medicine."

Sosman said that drug, which is now known as RO5185426 is designed to hit the "Achilles' heel" of a tumor. The drug works by blocking the effects of the so-called BRAF genetic mutation discovered to be in melanoma tumors through the human genome project. Turn off the gene, and it will stop sending signals to the cells to grow uncontrollably.

About 70 percent to 80 percent of patients with the mutation saw their tumors regress, often by about 50 percent within months of trying the medicine, Sosman said. And unlike chemotherapy, which often works for six months or so before tumors grow again, most of the patients who tried RO5185426 are still waiting for the other shoe to drop.

Although the drug needs one more round of rigorous testing in a phase III trial before it could be approved for commercial use, the promise of new drug has caught the attention of the media and of melanoma researchers nation-wide. The New York Times first reported on the promising results of the drug trials.

Stephen Dixon, of Nashville, Tenn., said RO5185426 literally changed his view on life.

Melanoma Patient: 'From Six Months, to I Don't Know How Long'

"I was getting my things together -- I thought I didn't have a long to live. I thought that I was going to start getting sick," said Dixon, 57, who was diagnosed with melanoma twice in his life.

Dixon didn't even have a mole to warn him the second time.

Twelve years earlier doctors removed malignant mole on his neck along with a section of his skin. For a decade, check-ups showed no sign of cancer and Dixon was told he go on without appointments, cancer-free. Then somewhere from that area, the cancer grew again under his skin.

"I was having night sweats, and I didn't understand why," said Dixon. "And rather than going to my primary care doctor, I went to my oncologist and he found it."

When he started RO5185426 10 months ago, the melanoma in his neck had spread to his lymph nodes and attacked his one of his adrenal glands.

Dixon said he already knew the prognosis for this type of cancer. Only 16 percent of people with his diagnosis survive for 5 years. So Dixon retired from his job at a wholesale distributor for heat and cooling supply products and began waiting.

"They gave me the medicine for five or six months and it became toxic to me," said Dixon, who began to suffer from excruciating headaches and lost 30 pounds.

But the medicine was working. Dixon watched his tumor regress, or shrink, "by 50-60 percent" in volume on CT scans.

"Now they say my adrenal gland is almost normal size," said Dixon. "At my last check-up they said it's holding steady."

His doctors have since lowered his dosage and he's since gained back the weight. There have been no improvements on his condition, but Dixon is surprised the results have held out this long. Now the only side effects seem to be a case of numb feet.

"The big picture is that people think this is a very exciting drug," said Dr. Henry Koon, an oncologist who specializes in melanoma care at the University Hospitals Case Medical Center in Cleveland. "This is something that can impact two-thirds of melanoma patients."

Not All Melanoma Patients Have BRAF Mutation

The other third of melanoma patients do not carry the BRAF mutation, Koon noted. And RO5185426 comes with side effects but Koon, who is not involved in the clinical trials, pointed out that administering it in pill form is much less intrusive than administering the immunotherapy, Interleukin-2.

"You actually have to come in the hospital for two out of three weeks (for immunotherapy)," said Koon. "It requires almost ICU level care."

Not to say RO5185426 is free from the typical harsh side effects of cancer treatment.

Scott Kehne, of Knoxville, Tenn., has had more severe side effects from RO5185426.

"Fluid retention. Rashes. It actually causes, for many of us, the formation of squamous cell carcinomas; another form of skin cancer," said Kehne, who had to have squamous cell carcinoma growths removed from his skin after starting the drug.

Sosman said the drug also puts people at risk for squamous cell carcinomas in their mouths, on their genitals, and anus as well. But compared to melanoma, squamous cell cancer is easier to treat.

"I also have joint soreness. Of course I have never experienced arthritis, but I'm guessing that's what it feels like," said Kehne.

Kehne, 63, is still well enough to work fulltime. But his frequent 14 mile hikes in the nearby Smokey Mountains have been cut short.

"Of course the alternative's worse," said Kehne.

Kehne's cancer started with a mole on his chest that he developed in junior high school. He remembers spending summers at the local swimming pool -- "it was my baby sitter," he joked -- but he never used, or even heard about, sunscreen.

Although Kehne went into doctors to get his mole checked throughout his life, "no one ever suggested to remove it," said Kehne. Then, in 2006, he bumped the mole while "doing something physical" and felt a pang. Doctors soon diagnosed him with Stage IV cancer.

"Immediately upon taking the drug within the first couple weeks I had something like a 30-40 percent regression. That's not unusual at all from what the doctors tell me," said Kehne, whose condition has stabilized in the seven months he has been taking the drug.

Drug May Be Part of New 'Targeted' Medications

"If it [the cancer] continued to progress at the way it was going, I was going to be a very short-timer," he said.

Such success stories have made Sosman feel like there is finally some traction "a first base" in melanoma research. But he and his colleagues who cooperated across the country to study RO5185426 know it won't be a cure.

While many of the patients have kept up their success, Sosman and Pavlik point out that a few have regressed and their cancer has come back. A few patients in the first clinical trial have died.

"While the results have been astonishing in many ways, it's also been disappointing to see patients regress after such a great response," said Sosman, who is also a professor of medicine at the Vanderbilt-Ingram Cancer Center in Nashville, Tenn.

But the success rate for the new drug makes it the first hope in a long series of therapies that target mutated genes.

"It's one of many. When it comes to melanoma we believe there are many (gene) targets that we need to turn off. The other targets that we are looking at are the MEK pathway AKT pathway," said Pavlik, who is running one of the sites for the phase III clinical trial of the drug.

"As we learn to target these mutations we may need to target more than one to get complete success. This is clearly the right step in the right direction," she said.

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