Melanoma Update: Recent Advances in Research
Skin cancer is increasingly common around the world, and patients with the most aggressive form of the disease, melanoma, have few treatment options. Nonetheless, two recent reports suggest progress in treating patients at different stages of the disease, while a third offers insights into the nature of melanoma tumors that spread, or metastasize.
In April, a clinical trial led by Dr. Steven Rosenberg, chief of NCI's Surgery Branch, reported that half of its 38 patients responded to an experimental treatment for refractory metastatic melanoma. The treatment, called adoptive cell transfer, involves harvesting immune cells from a patient, stimulating their ability to attack tumor cells, and returning them to the body.
A few weeks later at the ASCO annual meeting, researchers announced that for some patients whose melanoma has spread to the lymph nodes, detecting and removing the nodes early in treatment may reduce the chances of recurrence and increase survival, particularly for patients with intermediate-stage disease.
While presenting the findings from the Multicenter Selective Lymphadenectomy Trial, Dr. Donald Morton of the John Wayne Cancer Institute noted that, in the future, diagnostic and prognostic decisions will likely involve molecular information in the form of biomarkers, as has happened with other cancers.
A major challenge for researchers trying to identify melanoma biomarkers has been obtaining tumor tissue. Often a patient's entire primary tumor is removed at a community clinic and used by pathologists for diagnosis.
But that may be changing. Dr. Haqq and his colleagues recently assembled sufficient material to profile gene activity across the spectrum of melanoma progression. They found two subtypes of melanoma metastases in the study, each with characteristic patterns of gene activity.
Indeed, the various stages of tumor development - benign mole, primary tumor, metastasis - can be recognized by unique patterns of gene activity. This suggests that melanoma progression can be viewed as a series of distinct molecular events, the researchers reported in the April 26 Proceedings of the National Academies of Science.
"The study produced a lot of different leads and right now we're trying to follow up and validate them with more samples and in different models systems," says Dr. Mohammed Kashani-Sabet of UCSF. "The hope is to prove that by identifying and suppressing some of these genes, you can prevent the melanoma from spreading."
The entire field is struggling to identify biomarkers with clinical utility, notes Dr. Michael Bittner of the Translational Genomics Research Institute in Phoenix, who also studies gene activity in melanoma tumors.
"This paper shows a lot of interesting things, but so much is happening that it's hard to get a handle on which markers might be reliable for prognostic studies," says Dr. Bittner, adding that melanomas are diverse and other biomarker studies have had similar troubles.
The results represent a starting point for investigating questions about the behavior of melanoma tumors from the perspective of the genes involved, suggests Dr. Haqq.
For instance, the researchers will now try to understand whether some patients in the radial growth phase - when a tumor spreads outward rather than downward into skin - are at risk for metastasis and should be monitored more closely than in the past.
The question was raised by the discovery that some metastatic tumors and some tumors in the radial growth phase shared the same gene signature.
"This study certainly challenges researchers to further evaluate these lesions and understand the types of genetic changes associated with melanoma metastasis," says Dr. Martin Mihm, a professor of pathology at Massachusetts General Hospital. By early next year, melanoma researchers will have a new tool. NCI's Cancer Diagnosis Program (CDP), in collaboration with the melanoma research community, is developing a melanoma tissue microarray with tissue samples from approximately 250 specimens representing various stages of melanoma progression, including melanocytic nevi, primary melanomas, and samples from metastatic lesions.
"We hope this resource will be useful for comparing genetic alterations and the expression of various proteins to identify changes where they appear in the different stages," says Dr. Magdalena Thurin of CDP. "Understanding the molecular basis of melanoma could be exploited to find biomarkers and targets for therapy."
The project grew out of a 2003 meeting sponsored by CDP and the Melanoma Research Foundation to discuss ways to increase the availability of melanoma tissue.
By Edward R. Winstead