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Capturing Biomarkers of Melanoma's Progression

Skin cancers are the most common of all cancers. One in five Americans will develop skin cancer in their lifetime - about a million of us each year. More than 95 percent of these are basal cell or squamous cell carcinomas - nonmalignant moles or nevi - which can easily be removed by surgery or treatment.

Melanoma, the most deadly form of skin cancer, evolves through various stages from a benign mole, to a primary tumor, and eventually to a metastatic lesion. These stages can be recognized by unique patterns of gene activity, suggesting that melanoma progression can be studied and staged as a series of distinct molecular events.

Increasingly, molecular profiling data are collected for solid tumors such as those associated with breast and colon cancers to identify biomarkers that will be helpful in early detection. Similar approaches for the field of skin cancer research are lagging behind. There is a need for human skin cancer biopsies because the lesions are small and often removed in a setting outside an oncology practice - in a dermatologist's or family physician's office.

This barrier to biomarker research in melanoma was discussed in mid-January at a conference in Santa Fe, N.M. The "Markers of Tumor Progression, Diagnosis and Prognosis" session highlighted the need for tissue samples from melanoma patients.

Biomarker issues also were on the minds of more than 50 prominent melanoma researchers last October, when they met in Gaithersburg, Md., for the "Resources for Melanoma Research Workshop," according to Dr. Magdalena Thurin, program director in NCI's Cancer Diagnosis Program (CDP). The conclusions from this meeting urged the research community to establish a high-quality melanoma tissue sample resource to support discovery and development research. "Without a more reliable source of well-characterized human melanoma tumor tissue for systematic and meaningful studies, we can't pursue the most urgent issues in melanoma research," says Dr. Thurin.

CDP and the Specialized Programs of Research Excellence (SPORE) skin program at NCI addressed this issue by arranging for more active collection of the tissues that would be needed to build tissue micorarrays (TMAs) that will contribute to the discovery of biomarkers for melanoma. The Tissue Array Research Program (TARP), within NCI's Center for Cancer Research (CCR) began to assemble TMA slides consisting of a systematic grid of paraffin-embedded tissue taken from tumors in a number of different patients.

Scientists use TMAs to determine whether an immunohistochemical assay or antibody for their candidate biomarker is present. TMAs provide researchers "a high-throughput laboratory platform to explore the molecular features of the progression pathway, from a nevus all the way to metastatic melanoma," says Dr. Stephen Hewitt, TARP's manager.

"We saw a chance to bring some rational order to the process of supplying quality tissue to foster melanoma research," he says. "From NCI's point of view, everyone is on the same team." A second melanoma TMA was produced as a SPORE-sponsored effort.

"Newly improved high-throughput genomic and proteomic approaches are beginning to make inroads into the molecular characterization of this disease," says Dr. Dorothea Becker, a member of the University of Pittsburgh Melanoma Center and co-chair of the October workshop. "A number of promising genes, proteins, and other candidate biomarkers have emerged in the last few years that may help to predict and assess the risk of developing melanoma, serve to identify melanoma at an early stage, and become good targets for much-needed new therapies for advanced-stage melanomas."

The NCI-supported first-generation TMAs "are only a good beginning," says Dr. Hewitt. "This resource should help move things forward, but what we really need to do is partner with private practitioners, dermatologists, local oncologists, and melanoma patients to develop a strategy to obtain high-quality, well-annotated tissue samples that can be used for basic and discovery research."

The October 2005 workshop produced a list of the 33 most promising biomarker candidates. Each has shown some promise as a way to detect or treat melanoma, or to provide insights into progression or an early warning of metastasis.

By Addison Greenwood