Study suggests combination therapy could stop spread, halt growth of melanomas

Researchers at Penn State College of Medicine have identified the mechanism by which the most mutated gene in melanoma, called v599EB-Raf, aids melanoma tumor development demonstrating its importance as a therapeutic target.

"Our studies suggest that using therapies to target and inhibit the function of mutant v599EB-Raf protein could prevent the spread of melanoma and halt tumor growth for those melanomas containing the B-Raf mutation," said Gavin P. Robertson, Ph.D., assistant professor of pharmacology, pathology, and dermatology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center. "With cases of melanoma increasing at about 4 percent per year and no effective treatments available for advanced-stage disease, it's imperative that we continue to look for important proteins that could be targeted therapeutically. Studies like this one that identify how inhibiting important melanoma regulating proteins reduce melanoma development will lead to a better understanding of the disease, and thus, the development of more effective long-term treatment options for patients."

The study, titled "Mutant V599EB-Raf Regulates Growth and Vascular Development of Malignant Melanoma Tumors," appeared in the March 15, 2005, issue of Cancer Research.

The job of normal non-mutated B-Raf is to relay signals from the cell membrane, which is the boundary of the cell receiving the signals, to the nucleus, which contains genetic material and controls many of the cell's activities. B-Raf is one member of the chain that relays signals playing an important role in cell signaling. The protein is usually only active when needed to relay signals.

In contrast, mutant B-Raf is active all the time, which disrupts the chain's normal function. Previous studies have shown B-Raf is the most mutated gene in melanomas, present in about 60 percent of human melanomas, but the role mutant B-Raf plays in causing melanoma tumors remained unknown.

Robertson used human melanoma cells, applying siRNA, small interfering ribonucleic acids, or BAY 43-9006, a general Raf inhibitor, to show that lowering mutant B-Raf protein reduced melanoma development.

"Reducing B-Raf activity in melanoma cells before tumors had formed significantly decreased the growth potential of the melanoma cells and, in effect, prevented tumor development," Robertson said. "In contrast, reducing B-Raf activity in existing tumors in a mouse model did not shrink the tumors but did prevent them from getting bigger. These discoveries are important for the treatment of metastatic melanoma since therapeutically inhibiting mutant B-Raf could prevent growth of existing tumors and more importantly prevent development of metastatic tumors at secondary sites."

The study shows that in existing melanoma tumors, inhibiting V599EB-Raf activity reduced vascular development, which is essential for tumor growth. Without vascular support the tumors remained the same size. This process occurs by reducing the secretion of VEGF, a factor downstream of B-Raf promoting vascular development, from melanoma cells.

"Because the tumors remained the same size, siRNA or BAY 43-9006 would have to be paired with another therapeutic agent to cause the tumors to shrink or disappear," Robertson said.

Of the major types of skin cancer, melanoma is the most metastatic and lethal form. It is currently the seventh most common cancer in the U.S., with about 52,000 cases diagnosed annually. Furthermore, it is the cancer with the second fastest growth rate. In 2004, an American's lifetime risk of developing melanoma was one in 63 and at the current rate of increase will be one in 50 by 2010. As a direct result of a lack of effective therapeutics, the 2005 prognosis for patients in the metastatic stages of the disease remains very poor with average survival ranging from six to 10 months.

In addition to Robertson, the study team included: Arati Sharma, Nishit R. Trivedi, Melissa A. Zimmerman and Charles D. Smith, Department of Pharmacology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, and David A. Tuveson, University of Pennsylvania.