BACK IN HIGH SCHOOL, Heather Schulte used to tan before special events like homecoming. She didn't know then that her blond hair, blue eyes and fair skin put her in a high-risk group for skin cancers — and that basking under sunlamps put her at even greater risk through intensive exposure to ultraviolet (UV) rays.

As a freshman in college, she noticed an odd- looking mole on her back. She went to her doctor, not thinking that the mole was anything serious, and was shocked when a biopsy indicated that she had melanoma, the most dangerous type of skin cancer.

"I didn't even know what melanoma was," recalls Schulte, now 20 years old. "They called me back for more surgery after they removed the mole, and they told me the diagnosis. It was very scary."

Lynn A. Cornelius, MD, associate professor of medicine and chief of the division of dermatology, is now Schulte's physician.

"Over the past 40 years, our ultraviolet exposure as a population has increased," Cornelius says. "During that same period, the number of melanoma diagnoses also has risen." There is most likely a causal relationship.

During the 1970s, the number of melanomas diagnosed in the United States grew by about 6 percent each year. The number of cases continues to rise, although the rate has slowed to about 3 percent per year. Nearly 60,000 cases of melanoma were diagnosed in 2005.

The correlation between UV exposure and melanoma reflects basic facts about skin. The UV energy of the sun can easily penetrate the thin layer of skin cells that lies over the pigment cells where melanoma originates. The pigment cells, or melanocytes, are sensitive to DNA damage caused by ultraviolet light. So the more sun or sunlamp exposure, the more damage to skin cells. If a person is at increased risk (easily sunburned, freckled, history of excess sun exposure, family history of melanoma, increased number of moles, or atypical moles), the likelihood of melanoma is higher.

"Over the past 40 years, our ultraviolet exposure as a population has increased. During that same period, the number of melanoma diagnoses also has risen."   LYNN A. CORNELIUS, MD

Compared to more common forms of skin cancer — basal cell and squamous cell cancers — invasive melanoma can quickly advance to a metastatic disease with a very poor prognosis. The best hope for a good outcome is to catch a melanoma early, as Schulte did, and have the growth and the surrounding skin surgically removed.

For most patients with thin, early melanomas, such surgery leaves them free of the disease for the rest of their lives, but with the continued need for routine skin exams to monitor for potential spread and the development of a second melanoma. But about one quarter of patients will develop metastatic melanoma after removal of the original lesion, and this is highly dependent on the depth of penetration of the original tumor into the skin.

In metastatic melanoma, tumor cells may spread from the skin to lymph nodes and, in the most serious cases, through the blood to internal organs. With lymph node involvement, doctors remove the cancerous and surrounding lymph nodes and may administer interferon. Internal tumors may be removed and chemotherapeutic drugs such as dacarbazine given.

"Unfortunately, systemic chemotherapy is effective in only about 10 to 20 percent of advanced melanoma patients," Cornelius says. "So there's an urgent need for additional treatment regimens."

Cornelius has teamed with medical oncologist Gerald P. Linette, MD, PhD, assistant professor of medicine, on clinical trials to test new protocols for advanced melanoma. These patients often are managed in a multidisciplinary approach — the melanoma team also includes dedicated surgical oncologists, dermatologic surgeons, radiologists and radiation oncologists.

One of the current clinical trials tests a relatively new drug called sorafenib in patients with stage IV melanoma, the most advanced form of the disease in which the cancer has spread to the lungs or liver. Sorafenib already has FDA approval as a therapy for advanced renal cancer and has been shown to inhibit two proteins implicated in the progression of melanoma.

In this study, patients receive sorafenib along with traditional chemotherapy. The trial has demonstrated that sorafenib is well-tolerated and elicits few side effects.

"Sorafenib shows a lot of potential; we've seen encouraging results in our patients," Linette says.

Hope for treating metastatic melanoma also lies in the body's own defenses. Instead of injecting drugs to inhibit or kill metastatic cells, alternate approaches make use of the body's immune system to ferret them out.

Before he came to the School of Medicine, Linette and his colleagues investigated a treatment that isolated specialized immune cells called dendritic cells from each patient and "taught" the cells to recognize melanoma after tissue culture in the lab. These dendritic cells were then returned to the patients to do their work and activate the killer T cells of the immune system.

"This therapy increases the immune response to specific proteins involved in pigment production and enhances the immune system's ability to attack malignant melanocytes," Linette explains.

All the patients in the study developed a melanoma-specific immune response. And while the average patient with advanced melanoma survives less than a year, most patients in this trial survived well over two years. Linette has initiated the process to repeat this promising study on a larger scale at the School of Medicine.

At present, he is conducting a trial of a different immunotherapy method. It investigates an antibody (CTLA4) that encourages the immune system's destroyer cells (T cells) to proliferate and fight melanoma tumors.

"The immune system inherently responds to melanoma cells," Linette says. "So on their own, about 10 percent of melanoma patients will have a modest immune response that can reduce tumors. But giving this antibody generates a significant immune response in about 15 to 20 percent of melanoma patients."

Medical oncologist Gerald P. Linette, MD, PhD, is conducting melanoma research that focuses on immunotherapy methods.

Further new melanoma treatments are likely to arise from research on the genetic foundations of melanoma. Cornelius and colleagues have embarked on a project investigating a gene that becomes overactive in melanoma tumors and produces a protein that helps increase the growth rate of tumor cells. This gene could provide researchers with a potential new target for therapeutic medications. In addition, because about one-tenth of melanoma patients have a genetic predisposition to the disease, Cornelius has been involved in a project that analyzes DNA from melanoma patients to identify the genetic variations associated with melanoma in the hope of identifying patients at increased risk of disease.

Although advances in research may eventually reduce the mortality rate of metastatic melanoma, prevention remains extremely important. And the best prevention is to decrease exposure to ultraviolet light and to have frequent skin examinations if one is at increased risk.

Cornelius would like people to be more aware of what Heather Schulte learned the hard way — going after that "healthy" tan can increase the chance of developing melanoma. Furthermore, unlike many cancers, which are more prevalent in the older population, melanoma has a significant impact in younger age groups.

"It's important for everyone to realize that melanoma can develop at any age," says Cornelius, "and that melanoma in teens and young adults seems to be increasing."

Cornelius has diagnosed enough melanoma in patients in their 20s and 30s to spur her to start an educational program designed to spread the word about the causes and symptoms of the disease. Young adults such as Schulte help Cornelius drive home her points.

"Most young people that I talk to about it haven't heard of melanoma," Schulte says. "They've been told that tanning is bad for you, but they really don't know what that means."

A recent report stated that 30 million people in the United States use tanning booths. "Tanning is ridiculously popular now," says Schulte, who caught her melanoma early and is now free of disease. "A lot of people I know will buy a one-month unlimited package and go every single day so they can get their money's worth."

For her part, Schulte is adamant that her tanning days are over. "I'll never tan again," she says. "Not ever."