Genetically Engineered Mouse Model to Boost Studies on Melanoma

Cancer researchers have created a line of genetically engineered mice that closely mimics the conditions found in about 30% of human melanomas and that will serve as a model system for the study of the disease.

Activation of the human BRAF gene by mutation is one of the earliest and most common of genetic alterations in human melanoma. The BRAF (murine sarcoma viral oncogene homolog B1) gene makes a protein called B-RAF, which is involved in sending signals in cells, and in cell growth. This gene may be mutated in many types of cancer, which causes a change in the B-RAF protein. This can increase the growth and spread of cancer cells.

Investigators from the University of California, San Francisco (USA) genetically engineered a line of mice to possess human BRAF in their skin melanocyte cells. When activated, the gene caused the melanocytes to form benign lesions that failed to progress to melanoma after 15-20 months. To complete the melanoma model the investigators silenced the activity of the Pten tumor-suppressor gene. They reported in the March 12, 2009, online edition of the journal Nature Genetics that silencing of Pten-elicited development of melanoma with 100% penetrance, short latency, and with metastases observed in lymph nodes and lungs.

Inhibitors of the mTorc1 gene (rapamycin) or MEK1/2 (PD325901) prevented melanoma formation but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Combined treatment with rapamycin and PD325901 caused shrinkage of established melanomas.

"There has not been a major advance in the treatment of metastatic melanoma in the last 25 years,” said contributing author Dr. Martin McMahon, professor of cancer biology at the University of California, San Francisco. "While other cancers are more common, it is the rate of increase and the often aggressive course of the disease that worries people who study melanoma.”

"This study indicates that the mouse model we have built, based on the cardinal genetic features of the human disease, can be used to test responses to targeted therapeutics,” said Dr. McMahon. "The signal failure to improve the prognosis of metastatic melanoma patients is likely to be improved on in years to come by the use of agents that target specific genetic mutations in the disease. Nevertheless I believe it will up be three to five years before the types of preclinical experiments we are doing right now will result in improved prognosis for patients with metastatic melanoma.”

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