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The Dark Side of the Sun

Skin cancer is on the rise, and Stanford researchers are finding new ways to evaluate and treat it—by studying everything from hair regeneration to a rare genetic condition.

Philippe Weisbecker

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By Sara Solovitch

Their parents call them “butterfly children,” but though the words conjure up a sense of poetry and whimsy, the reality is in harsh contrast. These are children whose every step is an act of blistering pain, whose skin is so fragile that it can fall off in shreds within moments after a parent picks them up. Doctors liken them to burn victims: their wounds require daily salves, gauze and bandages. Like burn victims, they need huge numbers of calories to aid in healing. The more severe among them often are afflicted inside their mouths as well as on their skin: the disease makes their teeth fall out, and blisters and scars the esophagus, making it painful to eat and hard to swallow.

Recessive dystrophic epidermolysis bullosa, or RDEB, is one of the rarest of genetic skin disorders, a true orphan disease that afflicts fewer than 500 people in the United States. And yet—as with many orphan diseases—its secrets, once unlocked, yield medical clues to some of the most common conditions. In this case: skin cancer.

“Nature shows us her mysteries through her errors,” says dermatology professor Paul Khavari. “When you have a genetic error that leads to disease, it has a lot to teach you.”

Khavari, ’84, PhD ’94, is one of 15 or so Stanford scientists converging on the research and treatment of EB (literally, the breakdown and blistering of the epidermis; RDEB is one type), with the additional goal of using it as a gateway to a greater understanding of skin cancer.

As it happens, Stanford is a national leader in the field. Its EB clinic employs a multidisciplinary team of dermatologists, gastroenterologists, nutritionists, geneticists and oncologists. Together, they diagnose, evaluate and oversee the treatment of several dozen patients a year. Although some of those with RDEB live into their 30s, most succumb to an aggressive form of squamous cell carcinoma.

It is this terrible fate that appears to offer an important key about one of the most common skin cancers. Squamous cell, with more than 250,000 new cases reported in the United States each year, is not, typically, a deadly disease.

Khavari’s early research suggested that it turns deadly due to the presence of Type VII collagen, a protein that acts as a glue, anchoring the outer layer of skin to the inner layer and creating a necessary ingredient to the spread of skin cancer. RDEB patients have either an altered version of collagen VII, or a complete absence of the protein. In 2005, Khavari demonstrated that he could trigger squamous cell carcinoma in sloughed-off skin samples from children with RDEB who had a fragment of Type VII collagen, but not in those that lacked the protein entirely.

Newly published studies suggest that the involvement of Type VII collagen in squamous cell may be more complex than first thought. But that doesn’t seem to disappoint Khavari. “The truth is beautiful,” he says. “God forbid we should sit on a lie.”

These days, Khavari has turned his attention to gene therapy. (He triggered squamous cell carcinoma in the 2005 study by flipping the switch on two genes.) Gene therapy is particularly well suited to treating skin diseases, mostly because skin—the largest organ in the human body—is much more accessible than internal organs. In 2002, Khavari successfully performed gene therapy on human skin grafted onto immunodeficient mice.

Khavari and associate professor of dermatology M. Peter Marinkovich are building on this work to transfer new genes into the intact skin of living patients. They are applying to the Food and Drug Administration for approval to begin gene therapy on children with RDEB within the next year. “We’re finally at the stage where we expect to have it in the clinic,” says Marinkovich, who’s been working on EB research for the past 16 years.

This is how they do it:

“We take skin cells and introduce normal collagen Type VII, grow them up a little, then graft the cells back onto the patients in one of their blistered areas. Then, we’ll evaluate how long those grafts last. We expect them to last a long time. Maybe permanently.”

Their work could lead to advancements in vaccine delivery—imagine a doctor inoculating your child by dabbing his wrist—and treatments for other skin disorders. Marinkovich cautions that gene therapy for skin cancer is a long way away: “It doesn’t hinge on the success or failure of our gene therapy.

“The challenge right now is the delivery of the gene. The magic bullet is to inject the gene into the body and have it delivered to all the different cells where they’re required. We’re not there yet.”

When University dermatologists offered free skin cancer screening at Community Day in April, 15 percent of the 200 or so people who took advantage of the offer learned that they did, in fact, have either a squamous cell or basal cell cancer. In Caucasians, basal cell carcinoma is, by far, the most common of cancers, numbering about 900,000 new cases a year.

“It’s scary,” concedes Sabine Kohler, a professor of dermatology and pathology who is considered one of the most respected experts in her field. (The two disciplines have spawned a new specialty, called dermatopathology.) “But by and large, it’s not that big a deal. You take it out and you’re done with it. It’s very, very treatable.”

Far rarer, melanoma—the most deadly of skin cancers—is growing at an alarming rate. The National Cancer Institute reports an increase of 619 percent in melanoma between 1950 and 2000, with a corresponding rise in mortality of 165 percent.

In 2007, an estimated 59,940 Americans will receive a diagnosis of melanoma; 8,110 will die from the disease. Many of the new cases will be in young women; melanoma is the most common cancer among women 20 to 29 years old. A disproportionate number of these will come from California; the aptly and prophetically named Golden State has the highest incidence of melanoma in the country. In 2003, it reported 5,200 new cases.

Although more and better screening is picking up some of the cases, most experts agree that the increase is genuine. One in 1,500 Americans born in 1935 had a risk of developing melanoma; for people born in 2007, the risk is one in 60.

“Melanoma is the only preventable cancer that’s growing and where the mortality rate is actually increasing,” says Susan Swetter, associate professor of dermatology and director of Stanford’s Pigmented Lesion & Cutaneous Melanoma Clinic. “This is believed to be due to increased ultraviolet radiation reaching the Earth’s surface as well as increased sun exposure through outdoor and indoor tanning, and occupational and recreational activities.”

Swetter has been studying the sociology of melanoma. She is part of a national, multicenter study looking at the role wives and girlfriends of older men play in alerting their partners—the very ones most at risk of dying from the disease—to the presence of an “ugly duckling,” a mole on the back, perhaps, that no one else may ever see, one whose shape or color has suddenly begun to morph or grow.

“Where we’re missing the boat, when you look at the mortality rate, is in these older men,” says Swetter, referring to studies showing the mortality rate for men 65 and older grew by 157 percent between 1969 and 1999. “By reaching out to this older male population, we hope to see how the patterns of discovery took place. How medical awareness affects treatment, the importance of social networks, the role that wives play. It’s going to be an important means of changing our educational outreach.”

Swetter also is studying the dirty little secret of melanoma in the United States: the fact that it is grossly underreported, by as much as 35 percent, according to one recent survey in Southern California. Despite federal regulations requiring that all cases of melanoma be reported to a national registry, many dermatologists don’t heed that mandate.

That’s because they can effectively diagnose and treat thin melanomas—those malignancies that measure 1 mm or less in thickness—almost entirely in their offices, explains Swetter, who is working with the California Cancer Registry on a study of dermatologists in the Bay Area.

If melanoma is caught early, patients have an excellent prognosis. “The beauty of melanoma is that it’s right there to see,” says Kohler. “So there’s an excellent chance of recognition and treatment—as opposed to pancreatic cancer, where the patient doesn’t have symptoms until very late. Melanoma is right out there.”

A dermatologist can walk into an examining room and, with 90 percent accuracy, diagnose a lesion as a mole, basal cell carcinoma, squamous cell carcinoma or melanoma. That degree of precision drops below 60 percent for doctors and other health professionals untrained in dermatology.

Most cases of melanoma are still in the thin stage when diagnosed. A tumor that is less than 1 mm thick is less likely to have metastasized into the lymph nodes, at which stage it becomes far more deadly.

But 15 percent of melanomas less than 1 mm ultimately metastasize, while some patients with thick melanomas will live and thrive. Soheil Sam Dadras, a young dermatopathologist, is frustrated by the lack of accurate prognosis. Breslow Depth has been the standard for decades, used by dermatopathologists to measure how thick a melanoma is from top to bottom. They use the results, along with the Clark Level, which interprets skin thickness, to determine severity and prognosis of the cancer.

“It’s inconclusive,” the assistant professor says. “I just saw a 24-year old woman who has a very thin melanoma on her calf, which is the most common place for women to get it. She’s already developed a metastasis in her lymph nodes and I don’t think she’s going to do well.

“There’s a big problem understanding which melanomas are going to act badly. So I’m trying to develop the Stanford Melanoma Index. It’s based on tumor thickness, how rapidly the cells divide, and the number of lymphatic vessels that are involved,” Dadras says. “The idea is that this index will predict how patients with melanoma will fare.”

He is planning to work with Swetter and Andrew Fire, the molecular geneticist who last year won the Nobel Prize for his discovery of how double-stranded RNA can switch off genes one at a time.

Dadras has chosen not to work with animal models, partly because they’re so expensive (a genetically engineered mouse colony can run between $30,000 and $40,000 a year), partly because mice simply make poor hosts for studying melanoma. Mice are nocturnal animals; even after being given the disease, they never go on to actually develop lymphatic, systemwide cancer. In other words, melanoma can’t kill a mouse.

So Dadras plans to tackle the disease in humans—by going back to the stacks, the warehouses storing hundreds of thousands of small paraffin blocks with human archival tissues from biopsies done at Stanford Hospital over the past 30 years. They look like little pieces of sandy meat embedded in wax, but to Dadras they represent a gold mine.

“Tumor samples,” says Dadras. “That’s where we hope to make a difference. I’m starting with actual human disease. Fresh frozen melanoma is very difficult to find, because we need most of the lesion to make the diagnosis. But we’re trying to change that. I’m working with Denise Johnson, our melanoma surgeon, and hopefully a couple others, to get more material.

“If we can extract RNA from the paraffin blocks and then follow these patients and see how [the tissue samples] correlated with clinical behavior, we might see a pattern that tells us about how it metastasizes. My goal is to make it simple, easy and reproducible so that it can be available as a clinical test.

“Melanoma is one of the least understood of all tumors,” he continues. “If you think about a lung tumor, it can grow from the size of a golf ball to literally the size of a melon. Melanoma is small by comparison.”

There aren’t a lot of effective treatments for metastatic melanoma. A personalized cancer vaccine showed some early promise in extending survival for late-stage melanoma patients, but the results have ultimately disappointed.

There is new hope that that may change. In May, a small study by associate professor Peter Lee, a hematologist whose research focuses on the biology of immune response to cancer, shed new light on why the human immune system isn’t able to stop melanoma in its tracks.

Lee’s group found that the immune cells in most people with melanoma fail to respond to interferon, the molecule that normally activates the immune system. Without the ability to respond to interferon, the cells are less able to fend off the cancer.

Lee’s study has been cited as the first real explanation behind a decade of research showing that people with cancer often have dysfunctional immune systems. Finding the disruption in the cancer cells’ interferon response may help in the development of vaccines to treat cancers.

A number of interventions already exist for squamous and basal cell carcinoma. But surgery—the gold standard—can be disfiguring to patients with multiple lesions. Stanford researchers have conducted early studies that suggest cosmetic treatments for wrinkles, such as laser facial resurfacing, chemical peels and topical creams, could be beneficial.

These treatments resulted in an 83 percent to 92 percent decrease in actinic keratoses, rough patches of skin that appear on sun-exposed areas and are considered precursors to cancer. All, according to a 2006 Stanford study, may reduce precancerous lesions and lower the risk of skin cancer.

If the spa treatments don’t pan out, there’s always the Rogaine-style solution. Associate professor of dermatology Anthony Oro and colleagues are at work on additional topical treatments for basal cell, partly inspired by his work on hair regeneration. “These basal cell carcinomas are basically hair cells that try to make a hair and keep growing,” Oro explains.

Like several brain tumors, basal cell carcinoma carries a mutation in a signaling pathway called hedgehog—so called because it resembles a protein in the fruit fly gene that looks like a hedgehog.

“There’s a group of us working on it at Stanford,” says Oro, ’85. “It has given us some very interesting leads—both how to kill the tumor by blocking the pathway and changing the ‘soil’ in which it grows, as well as stopping the growth signals in the tissue around it.”

The study of basal cell carcinoma is rich because of its relationship to other, more lethal cancers. To understand why, Oro says, think of the skin as a sheet of cells—much like the lung, gut and intestine.

“It’s surprising, but it’s really quite similar to the way the lungs and pancreas develop,” says Oro. “They don’t look the same, but they have very common strategies in the ways they develop and are maintained.”

“At first it seems so different,” says Howard Chang, an assistant professor of dermatology whose lab has been studying the phenomenon of wound healing. “But it turns out the same genes and same pathways are used in different organs and what you learn from one is useful in learning about another.”

As a wound heals, hitherto inactive cells respond and move into position, bypassing the normal rules of biologic behavior to begin the work of repairing the body. When cancer metastasizes, it takes advantage of that same repair process and usurps it to its own end. Which is why Chang describes cancer as a wound gone wild.

In many cases, cancer even looks like healing tissue—while never ultimately healing. In fact, Chang notes, a chronic ulcer or wound can actually turn cancerous.

The best example of that, he says, is a little-known disease characterized by wounds: RDEB.

“You might think you want to understand one problem,” Chang says, “but it turns out that by understanding research in general, the rare disease shows you some aspect of biology in a spectacular way.

SARA SOLOVITCH is a writer in Santa Cruz, Calif.

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