Inhibiting B-Raf reduces melanoma development

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Related tags: Cancer

A study suggesting combination therapy could stop the spread and
halt the growth of skin melanomas could pave the way for a better
understanding of the disease, and thus, the development of more
effective long-term treatment options for patients.

Of the major types of skin cancer, melanoma is the most lethal form. It is currently the seventh most common cancer in the US, with about 52,000 cases diagnosed annually. Furthermore, it is the cancer with the second fastest growth rate.

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 the UK, more than 7,300 cases of malignant melanoma are diagnosed each year in Britain and 1,700 people die of the disease. About 133,000 new cases of the disease are diagnosed worldwide each year.

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

The study, which specifically identifies proteins that 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.

"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 tumour growth for those melanomas containing the B-Raf mutation,"​ said Gavin Robertson, assistant professor of pharmacology, pathology, and dermatology, Penn State College.

"With cases of melanoma increasing at about 4 per cent 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."

Normal non-mutated B-Raf relays signals from the cell membrane to the nucleus. 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 per cent, but the exact role mutant B-Raf plays in causing melanoma tumours remains 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.

He commented: "Reducing B-Raf activity in melanoma cells before tumours had formed significantly decreased the growth potential of the melanoma cells and, in effect, prevented tumour development."

"In contrast, reducing B-Raf activity in existing tumours in a mouse model did not shrink the tumours 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 tumours and more importantly prevent development of metastatic tumours at secondary sites."

The study shows that in existing melanoma tumours, inhibiting V599EB-Raf activity reduced vascular development, which is essential for tumour growth. Without vascular support the tumours 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 tumours remained the same size, siRNA or BAY 43-9006 would have to be paired with another therapeutic agent to cause the tumours to shrink or disappear,"​ Robertson said.

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

Related topics: Downstream Processing

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