GIST patients help researchers zero in on the origins of cancer

Oregon Health Sciences University seeks patent on possible advance

By Joe Rojas-Burke
The Oregonian

By studying a rare abdominal tumor, researchers in Portland, Oregon, have zeroed in on a likely new target for treating cancer: a protein that acts like a broken switch to spur cells into runaway growth mode.

The discovery raises hopes for finding another drug like Gleevec — the pill that targets an aberrant signaling protein to fight cancer without the brutal side effects of chemotherapy. Researchers at Oregon Health Sciences University have filed for patent protection on the new findings and said they have signed a contract with an undisclosed drug company to pursue new treatments.

“We predict these mutations will be found in other cancers,” said lead investigator Dr. Mike Heinrich, an associate professor at OHSU and the Portland Veterans Administration Medical Center. The study was published Jan. 9 on the Web site of the journal Science.

“I think they are probably right,” said Julie Cherrington, a scientist and vice president at Sugen, a biotechnology firm in South San Francisco that has developed a drug for GIST now in early clinical trials. She said the study will probably spark an all-out hunt for the mutations in other tumor types. Sugen was not involved in the new study, but the company has an ongoing relationship with Heinrich and colleagues at OHSU.

The discovery wouldn’t have been possible without the cooperation of patients with a rare form of cancer, called a gastrointestinal stromal tumor, or GIST. Fewer than 10,000 such cancers are diagnosed each year in the United States. Patients typically die within a year or two of diagnosis.

Less than five years ago, researchers in Japan identified the genetic defect responsible for more than 85 percent of cases. It produces a broken signaling protein called KIT. The drug Gleevec, originally developed for leukemia, has proved helpful in treating many patients with GIST because the KIT protein is closely related to the defective protein that causes chronic myeloid leukemia.

But the cause of 15 percent of cases was never accounted for. And nobody could explain why some patients respond to Gleevec while others do not. “The search has been on to find what may be driving those tumors,” Cherrington said.

The OHSU researchers joined with Dr. Jonathan Fletcher of Harvard Medical School to solve the problem. Fletcher’s lab had developed a powerful new method to detect proteins that are abundant and active in a tumor. The test revealed a signaling protein called PDGFR alpha. The OHSU scientists compared normal gene sequences with the PDGFR genes from their sample tumors. The comparison revealed seven mutant sequences. Further tests proved that the mutated genes caused cells to produce defective signaling proteins.

“We are the first to show that these types of mutations can activate the gene,” said Dr. Christopher Corless, an associate professor at the Portland VA and OHSU, and a co-author of the study.

Cherrington said the work could lead to new treatments for GIST — and for more common forms of cancer. Faulty signaling in the PDGFR pathway has already been implicated in a number of malignancies, from cancers of blood cells to solid tumors of the brain and other organs.

“It’s likely that PDGFR mutations are playing a role in other types of cancer,” she said.

Sugen has already developed a drug called SU11248 that targets PDGFR alpha and two closely related signaling proteins, called KIT and FLT3. In an early phase clinical trial — intended primarily to test safety and tolerability — the agent shrank tumors in a small number of patients. Cherrington said Sugen is beginning a second phase of studies in a variety of solid tumors including GIST.

Other important questions remain unanswered. Researchers still can’t account for the cause of about 5 percent of GIST cases. It’s not yet clear whether cases with PDGFR mutations will require different medical treatment than tumors with the more common KIT mutations. Heinrich said tumors with PDGFR mutations should respond to treatment with Gleevec.

“We’re trying to figure out if different types of mutations might respond differently,” for instance, requiring higher drug doses, he said.

The work highlights how cancer care is evolving rapidly toward a new model based on the genetic profile of a tumor.

“For the most part, we still classify cancer using technology and systems from the 1800s — light microscopes and where the tumor was found,” Heinrich said. In the future, he said, the choice of treatment will rely far more on the determination of what genes are active in a tumor.

From the Jan. 10 issue of The Oregonian. Reprinted with permission.