Signaling proteins may represent biomarkers for melanoma

WASHINGTON, D.C. For the first time, researchers studying patients with abnormal moles have identified proteins that could help predict whether such moles will progress into melanoma, the deadliest form of skin cancer. The study provides promising evidence that the proteins may represent potential biomarkers for prevention therapy. The results were announced today at the annual meeting of the American Association for Cancer Research (AACR), at the Washington Convention Center in Washington, D.C. The study, abstract number 5742, also looked at the effect of a common treatment for melanoma, interferon, on the levels of these biomarker proteins.

While investigating the mechanisms of action of interferon treatment on patients at high risk for melanoma recurrence who had multiple abnormal moles, investigators found that two intracellular signaling proteins called signal transducers and activators of transcription, STAT1 and STAT3, were correlated with the degree of mole abnormality when examined under a microscope. The researchers also found that interferon regulated the proteins in a manner that was dependent on its dose.

"While abnormal moles are a major risk factor for new primary melanoma development, it is difficult to know who among these patients will eventually develop the disease," said principal investigator John Kirkwood, M.D., professor of medicine at the University of Pittsburgh and director of the Melanoma Center at the University of Pittsburgh Cancer Institute (UPCI). "Rather than aggressively treating all of these patients, our hope with further study is to potentially test for these proteins and select those patients most likely to benefit from specific doses of interferon therapy."

In the study, researchers treated 40 patients at various levels of risk for recurrence of melanoma with interferon administered at either high or low doses. They then examined changes in the appearance of the patients' moles under a microscope and used molecular markers to determine the expression levels of STAT1, a protein associated with anti-tumor effects, and STAT3, a protein linked to melanoma progression. They found that the more severe the pathologic abnormality of the mole, the greater the level of STAT3 expression. Results also indicated that after high-dose interferon the level of STAT 1 increased 7.8 times and after low-dose interferon it increased 1.4 times over pretreatment levels. In contrast, STAT3 was reduced by 55 percent with high doses of interferon and by 39 percent with low doses. The ratio of STAT1 to STAT3 best represented the impact of interferon, increasing 23 times with high dose interferon and 2.6 times with low doses.

"Our study found that interferon regulates expression of STAT1 and STAT3 in a dose-dependent manner and provides a useful biomarker of interferon impact on these well- established precursor lesions, which have the potential to become cancerous," said Dr. Kirkwood. "This suggests that these markers will be important to follow in our efforts to prevent the new development of melanoma in the skin of our patients, as well as melanoma recurrence."

According to American Cancer Society predictions, an estimated 62,190 new cases of melanoma are expected in 2006 and 7,910 deaths are expected to occur.

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Lead author of the study was Wenjun Wang, M.D., Ph.D., Melanoma Center, University of Pittsburgh Cancer Institute. Coauthors include Howard Edington, M.D., Uma N. Rao, Ph.D., Drazen Jukic, M.D., Hong Wong, Ruth Mascari and Cindy Sander, all of the Melanoma Center of University of Pittsburgh Cancer Institute. The study is funded by grants from the Grant Channell Memorial, Roche Pharmaceuticals and Schering Plough Research Institute.


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