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UCLA scientists uncover mechanism of response to targeted therapy

UCLA researchers knew - based on two clinical trials - that a subset of kidney cancer patients responded well to an experimental targeted therapy, but they didn't know why. If they could determine the mechanism behind the response, they would be able to predict which patients would respond and personalize their treatment accordingly.

Extrapolating from the clinical responses, Jonsson Cancer Center scientists uncovered the cascade of molecular events by which the cancer cells in a subset of patients became sensitized to the experimental drug CCI-779. Armed with this information, UCLA researchers are developing a test to identify which patients will benefit from receiving CCI-779.

The research, published this month in Nature Medicine, takes researchers a step closer to personalized medicine - treating cancer patients not with a one-size-fits-all therapy but with a treatment based on the specific molecular signature of their cancer cells.

"We knew there were certain kidney cancer patients who responded to this drug, but we didn't know the mechanism behind the response," said George Thomas, first author of the study, an assistant professor of pathology and a Jonsson Cancer Center researcher. "We had to determine the mechanism of response so we could identify the responders."

Thomas, with Jonsson Cancer Center researchers Dr. Ingo Mellinghoff and Dr. Charles Sawyers, discovered that human kidney cancer cells that had lost the tumor suppressor gene Von Hippel Lindau (VHL) were more sensitive to the growth inhibitory effects of CCI-779. One of the main functions of VHL is to regulate a protein called hypoxia inducible factor (HIF). When patients lost VHL, they had high levels of HIF. Thomas said the cancer cells became dependent on HIF to grow, so high levels of the protein gave the cancer cells a growth advantage.

CCI-779 had previously been tested at UCLA in prostate cancer patients and researchers knew it targeted the mTOR protein.
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Source:University of California - Los Angeles


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