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UCLA scientists uncover mechanism of response to targeted therapy

Previous studies also had shown that inhibitors of mTOR also might inhibit HIF.

"We theorized that by inhibiting mTOR, which contributes to HIF levels, we might be able to significantly reduce HIF and remove the growth advantage the cancer cells had," Thomas said. "Because we now know the mechanism that is fueling the growth of the cancer cells, we can identify patients who will respond to this drug."

About 50 to 70 percent of kidney cancer patients have lost VHL, Thomas said. Their tumors, therefore, will have high levels of HIF and likely will respond to the drug. This finding could potentially help about 20,000 kidney cancer patients every year.

Typically, scientists seeking a target for a new cancer therapy start work in cell lines andthen advance to laboratory animals to test their theories. Working backward from responsesin clinical trials is unusual, Thomas said. Responses observed in clinical studies led researchers back to the laboratory. Their laboratory findings will be tested in further clinical studies, bringing the observation full circle, from the patient to the lab and back to the patient again.

In this case, CCI-779 was being tested at UCLA in a Phase I study on patients with a variety of advanced cancers. Researchers noted that patients with kidney cancer seemed to respond better to the drug than patients with other cancer types. That led to a Phase II study solely in kidney cancer patients. That study showed that a subset of patients had a complete response, while a high percentage experienced partial responses or had their disease stabilize, meaning it was no longer growing.

Thomas predicted that CCI-779 would probably be most effective when given in combination with other therapies because it "in kidney cancer, it stops the tumor cells from growing, it doesn't kill them." It could be paired with conventional chemotherapy or with another targeted therapy, such as an angiogenesis inhibitor, which cuts o
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Source:University of California - Los Angeles


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