In 1964, at age 23, Michael McGillicuddy was diagnosed with melanoma. Doctors told him he had six months to live, typical for late-stage cases, yet he survived another 12 years. In the more than quarter-century since Michael McGillicuddy's death, melanoma is still the most commonly occurring cancer among 20- to 30-year-olds, and its incidence overall is rising.

In fact, in the past 30 years the percentage of melanoma cases has doubled, and among Caucasians that figure has tripled. The situation is particularly acute in Florida, which is second only to California in the total number of melanoma cases. Sarasota also has an incidence rate above the national average. Officials are calling the rise an epidemic and say that without precautions melanoma will become even more prevalent.

Michael McGillicuddy's death, a private story, has had public repercussions. Spurred by his loss, his brothers, former U.S. Sen. Connie Mack and Sarasota philanthropist Dennis McGillicuddy, have played important roles in sponsoring melanoma research. The three brothers, says Mack, were unusually close: "We were fraternity brothers at the University of Florida, we were in high school together, we were in grade school together."

Cancer is a fearsome part of the McGillicuddy heritage. The brothers' parents also died of it. And chillingly, years after Michael's death, both Connie and Dennis developed melanoma, although they are now cancer-free. Connie Mack's wife and daughter have successfully battled breast and cervical cancers, respectively. Mack underwent treatment for the first time in 1989, just as his Senate career was beginning, and had a second, less serious bout in 2003. "I've often said I probably am alive today because of Michael's death," says Mack, "because the rest of the family became extremely sensitive to changes in mole coloration and structure, and we would go and have our semi-annual dermatology exam. As a result of that, I caught it early."

Melanomas develop in melanocytes, the pigment-producing cells in the skin. For that reason, they usually resemble harmless moles in color and size, but they do have a few characteristic distinctions: In contrast to moles and freckles, melanomas have asymmetrical borders and irregular coloring. Detecting those distinctions early is essential to a good prognosis, says Dr. Vernon Sondak, head of Moffitt Cancer Center's cutaneous oncology department.

"If it's picked up early, it's highly curable," he says. "And yet if it progresses just a little bit-and that's one of the real paradoxical things about melanoma-if it just gets a little bit thicker into the skin or just a few cells get out into the lymph nodes, it can suddenly be a very difficult cancer to treat."

For stage-one or stage-two melanomas, when the cancer remains at its origin on the skin, the treatment is simply localized surgery. Things get much more complicated at stage three, when the melanoma spreads to the lymph nodes in quantities that vary from a few cells to tumors large enough to cause a visible lump.

At stage four, the melanoma has spread from the lymph nodes throughout the body, posing an almost intractable problem for current therapies. "Most of our patients [with stage-four melanoma] will die," usually within a year or less, says Sondak.

But researchers are making progress on improving that outcome, and the family has generously supported that research. Just last year Dennis McGillicuddy and his wife, Graci, made a $1 million contribution toward melanoma research at Moffitt, a gift that endowed the Michael McGillicuddy Chair in melanoma research and treatment. The gift honors not only Dennis McGillicuddy's younger brother, but also the energy with which his older brother has promoted medical research as a senator and, more recently, as the chair of Moffitt's board. And it recognizes both Moffitt's excellence in medical research and its "culture of caring and compassion," as Dennis puts it.

The McGillicuddy gift enabled Moffitt to recruit Dr. Jim Mulé, one of the country's top melanoma researchers. Since Mack became chairman, Moffitt has aimed to become the foremost melanoma center in the nation.

Melanoma was the first topic Mack broached with Moffitt director Bill Dalton when Dalton assumed his post, in 2002. "It just seems logical to me from my own personal perspective that I would want to do something with melanoma research, but it also seems logical for the Moffitt Cancer Center-located in Florida-to focus on melanoma research as well," says Mack.

Some of Moffitt's most ambitious melanoma research focuses on the period after lymph nodes have been removed, or, in stage-four cases, the metastatic period.

As a formerly normal cell, the cancer is difficult for the body to detect. And melanoma cells send out immune-suppressive signals. Immunological approaches to melanoma treatment have focused on either stimulating the positive immune response signals or lifting the suppressive environment that melanoma cells can create. There is always a risk, even when the affected lymph nodes have been removed, that the cancer may return. For that reason, adjuvant therapy, a way of stimulating the immune system, is often recommended after surgery to decrease the chance of recurrence.

The only currently approved adjuvant therapy uses a substance called interferon alfa. Doctors debate whether and how it should be used, because the treatment can be toxic. Besides, many patients may be fully cured by surgery, and others will have recurring melanoma despite the interferon.

In other immune-based treatments, modified viruses introduce genetic material; DNA is injected directly into the cell; or an electrical charge is used to open pores in the cell membrane, a technique called electroporation.

But vaccines, once among the most promising immune-based delivery systems, have so far proven ineffective. Vaccines, it was hoped, would be less toxic than other treatments. But within the past year, several nationwide vaccine studies were closed when they failed to show a significant improvement in outcome compared to surgery alone. Sondak says his team is "in an analysis mode," trying to discover why the vaccines failed. Researchers need to determine whether the vaccines themselves simply weren't good enough, whether they were used too late in the game, or whether particular subsets benefited more than others.

This is also, says Sondak, a time to reconsider the biology of both tumors and the immune system in order to develop new therapeutic techniques.

But other immunological approaches are abundant, and researchers have seen some recent success with technologies that disrupt melanoma cells' ability to send negative signals to the immune system. Ultimately, optimum treatments will likely establish a balance between stimulating the immune system and neutralizing melanoma's immune suppression.

The role of genes will be critical in that work; in all of the more than 200 forms of cancer, changes in the genome are what trigger dysfunctional cell growth. The precise reasons these genes go haywire are not known. Nor, necessarily, are the genes themselves; but in melanoma, as in many other forms of cancer, the relevant genetic mechanisms are likely to be numerous.

The complexity of the genome-melanoma relationship is clear when you consider that some people develop the disease after chronic exposure to ultraviolet rays and others after very little exposure. And the consequences may not appear for decades. Dennis McGillicuddy developed his melanoma at the age of 63, after a lifetime in the outdoors. "For years, I've worn not only protective sunscreen but protective clothing," he says. "But my understanding is that scientists can't really tell you; is it only early childhood burns, or is it recent stuff, or a combination?"

Since melanoma probably has a variable genetic basis, no one cure is likely to be effective for all patients. Still, Dr. Sondak feels hopeful. "We're starting to see new technologies and real optimism for each individual component of what we can do, a better understanding of what the positive and negative signals are, new approaches, new vaccines, new ways to deliver the genes, new genes to deliver, new targets to attack, or things to blockade that will be beneficial, and we're seeing each one of those individually have some occasional successes," he says.

"Ultimately, the answer's probably not going to be any one of those things. It's probably going to have to be some of all of those things."

SPOTTING MELANOMA

Melanoma comes in many shapes and places, depending on your ethnicity, skin tone and gender. Because it is a cancer of melanocytes, the cells that produce melanin for skin and hair coloring, it necessarily varies.

Caucasians have the highest incidence rate. In Caucasian males, melanomas often appear on the torso, especially the back, while in females they are often detected on arms and legs. But melanomas can show up any place you have skin.

Caucasians should remember ABCD. In contrast to normal moles, melanomas are 1.) Asymmetrical, 2.) with Borders that are irregular, 3.) have varied and changing Color and 4.) a Diameter usually greater than six millimeters.

African-Americans, Hispanics and Asian-Americans can also develop melanomas, but for those races there appears to be little differentiation by gender, and they tend to develop in places that are less problematic: on the soles of the feet and the palms of the hands, in mucous membranes in the mouth and nasal passages, and on the genitals, among other places.

In all races, melanomas can appear at any age, including childhood. For pictures of melanoma growths, see the self-exam section at www.skincancer.org.

IN THE GENES?

Scientists know that ultraviolet rays can trigger changes in the genome that cause melanocytes to reproduce dysfunctionally, resulting in melanoma. Those rays generally come from either the sun or tanning beds (equipment unequivocally condemned by the National Cancer Institute, the World Health Organization and the Federal Trade Commission).

But the specifics of those changes are less clear. Why do some people develop melanoma after many years of exposure, and some after only a brief time? Does adult melanoma result from childhood exposure, or is the effect cumulative? Further, why is there variation in the amount of time it takes for cancer cells to spread from the skin to the lymph nodes, and from the lymph nodes to the rest of the body? These discrepancies suggest multiple genetic roots.

Documenting the genetic bases of cancers-not only of melanoma-is the next big project in cancer research. That project is being organized by a new initiative, the Cancer Genome Atlas, a collaboration of the National Cancer Institute and the National Human Genome Research Institute, the government organization that "mapped" the human genome. The hope is that making this data available to researchers everywhere will speed the work of finding cures.