A paradigm shift for targeted cancer therapy

Jul 8 2008

We already know that recycling benefits our planet; and now new research suggests that the cellular version might be useful for battling cancer.

Scientists at Stanford University have identified a molecule that uses this unexpected pathway to selectively kill cancer cells. The research, published by Cell Press in the July 8th issue of the journal Cancer Cell, may drive treatment strategies for cancer in an entirely new direction.

Renal cell carcinoma (RCC), the most common form of kidney cancer, is nearly always caused by mutation of the von Hippel-Lindau (VHL) tumor suppressor gene and often does not respond well to treatment.

"Since RCCs have a poor prognosis and are refractory to standard chemotherapies, there is a need to develop new therapies for kidney cancer," says senior author Dr. Amato J. Giaccia. Dr. Giaccia and colleagues used a sophisticated screening procedure to search for molecules that could selectively destroy VHL-deficient kidney cancer.

"Specifically identifying and targeting the cancer cells, while leaving normal cells intact should have great therapeutic impact. Most side effects people associate with chemotherapy, such as nausea and hair loss, are due to toxic effects of drugs on normal tissues. Exploiting a feature of cancer cells should spare the normal tissue and decrease these awful side effects," explains Dr. Giaccia.

The researchers discovered a compound, STF-62247, that was selectively toxic to RCCs deficient in VHL whereas cells with normal VHL were not affected. Treatment of RCC cells lacking functional VHL induced autophagy, a cellular recycling process that cells normally use to conserve resources during times of stress. "Increasing evidence implicates a role for autophagy in cancer, but it is not well understood how cellular and environmental cues drive autophagic cells down survival or death pathways," explains Dr. Giaccia.

The researchers demonstrated that STF-62247 enhanced autophagy in VHL-deficient cells while inhibition of the autophagy pathway significantly increased the survival of VHL-deficient cells treated with STF-62247. "We have found a small molecule that selectively induces cell death in VHL-deficient cells, such as those that are found in kidney cancer. This represents a paradigm shift for targeted therapy," concludes Dr. Giaccia.