December 16, 2010

Study examines melanoma drug resistance

Jeffrey A. Sosman Jeffrey Sosman (Vanderbilt)

Study examines melanoma drug resistance

Patients with metastatic melanoma being treated with the new investigational cancer drug PLX4032 are showing strong responses, with an 80 percent anti-tumor response rate among patients whose tumors are positive for the B-RAF (V600E) gene mutation.

However, in all too many cases, patients are developing resistance to the drug and their cancer is beginning to grow again.

Jeffrey Sosman, M.D., professor of Medicine at Vanderbilt-Ingram Cancer Center, and researchers from two other academic medical centers have now identified some of the molecular pathways that allow the tumors to develop drug resistance. The study was published in a recent online issue of Nature.

Jeffrey Sosman, M.D.

Jeffrey Sosman, M.D.

Researchers are actively searching for factors that influence resistance to drugs that treat the B-RAF mutation because the mutation is found in about 50 percent of all melanomas, which are the mostly deadly form of skin cancer.

Investigators had speculated that a secondary B-RAF mutation developed in patient tumors after treatment with the drug, but this hypothesis did not prove to be true.

Instead, they found that some tumors acquired resistance to the drug's mechanism when cancer cells began overexpressing a cell surface protein. In other cases, a second oncogene, N-RAS, was mutated, allowing the cancer to get around the blockade put up by B-RAF drugs.

“We found that drug resistance develops through at least two different molecular mechanisms that activate survival pathways for the cancer cells,” said Sosman, leader of the Vanderbilt Melanoma Program.

“By focusing on these pathways, we can begin the search for additional drugs that may provide therapeutic strategies for melanoma patients who develop resistance to the B-RAF drugs.”

Cancer research is increasingly focused on finding the specific molecular signaling pathways that help cancer cells grow. Mutations in each patient's tumor can influence these signaling pathways. That is why VICC is testing all melanoma patients for specific tumor mutations as part of its new Personalized Cancer Medicine Initiative.

“We have discovered that we need to know more about the genetic fingerprint of each patient's tumor so that we can match the patient with the right drug, though now we know that the story does not end there and we must understand how the tumor adapts to the targeted cancer drugs,” explained Sosman.

The study was led by investigators from the UCLA Johnsson Comprehensive Cancer Center, and included investigators at the Peter MacCallum Cancer Center, East Melbourne, Australia.