Potentially potent chemo target in sight

SAN FRANCISCO — Fruit flies don’t get cancer, but a protein first discovered in Drosophila could prove to be a chemotherapy target that may stop even the most aggressive cancers in their tracks.

A protein known as the “seven in absentia homolog,” or SIAH, may help put the brakes on runaway cancers, said Amy Tang, a researcher at the Mayo Clinic in Rochester, Minn., on December 14 at the annual meeting of the American Society for Cell Biology. 

In fruit flies, the protein “seven in absentia” is an enzyme that tags other proteins for destruction. It is also at the end of a chain of chemical reactions — called the RAS pathway — that drives cells to proliferate.

In a majority of human cancers, the RAS pathway gets geared up and sent into overdrive so that cells grow out of control. Many researchers have tried to target a protein on the RAS pathway to slow down or halt the growth of cancer cells. But Tang and her colleagues decided to look farther down the chain than others have looked to see if more effective targets for chemotherapy could be found.

Tang and her colleagues discovered that, in humans, a version of seven in absentia is found in rapidly dividing cells. The team examined tissue samples from more than 100 pancreatic cancer patients and found high amounts of SIAH in cancer cells: the more aggressive the cancer, the more SIAH in the tumor cells.

Pancreatic cancer is one of the deadliest forms of cancer. The National Cancer Institute estimates that almost 38,000 new cases of the disease will be diagnosed in the United States in 2008 and more than 34,000 people will die from pancreatic cancer.

Since the enzyme is abundant in cancer cells, but not in healthy cells, Tang reasoned that attacking SIAH might also knock out cancer cells. The researchers inactivated SIAH in mice with cancer. The therapy had dramatic effects on tumors in the mice.

“I did not see reduced [tumors]. I did not see depressed. I saw abolished,” Tang says. The more aggressive the cancer, the more effective inactivating the enzyme was in melting the tumors. “It was actually shocking to me.”

Disrupting the enzyme also abolished breast and lung tumors as well as pancreatic cancer in the mice. As dramatic as the results were, Tang wasn’t satisfied with merely destroying tumors.

“Tumorigenesis does not kill. Metastasis kills,” she says.

But attacking SIAH also blocked metastasis: Cancer cells did not spread to other parts of a mouse’s body, the researchers found.

Tang’s methods of attacking SIAH are not currently practical for use in humans, but she is hopeful that pharmaceutical companies could develop chemotherapy drugs that would specifically interfere with the enzyme’s activity in cancer cells.

“We’ve given the whole cancer field a new target,” Tang says.

There is no question that Tang has identified a critical molecule for cancer proliferation, but her work is plagued by the same reality as all cancer research, says Mark Kieran, the director of pediatric medical neuro-oncology at the Dana-Farber Cancer Institute in Boston. “The reality check is that turning off a major regulatory pathway is hard,” he says. “If it were easy we would have done it already any number of times.”