Toward Personalized Medicine

As researchers elucidate how fusions form, Chinnaiyan and others are pushing to use what’s already known to help cancer patients. By 2010, Chinnaiyan had found 23 different types of recurring gene fusions in patients with prostate tumors, and he’s seeking new prognostics that use the presence of a specific fusion gene as a genetic fingerprint. By correlating patients’ genetic fingerprints with their clinical outcome, he hopes to develop a knowledge base to help doctors distinguish fast-growing and invasive prostate tumors that require aggressive treatment from slow-growing tumors that do not.

Knowing that a patient has a cancer-driving fusion gene is not enough, however; scientists must find a way to block it. In July 2010, Chinnaiyan reported in Nature Medicine that 2 percent of prostate cancer patients—and a similar fraction of patients with gastric cancer and melanoma—have a gene fusion that encodes a tyrosine kinase. Chinnaiyan suspects that patients will be treatable with a kinase inhibitor. Although they’re a small fraction of all prostate cancer patients, they still represent several thousand cases a year in the United States alone.

Other gene fusions will be tougher to target. Most of the gene fusions found so far in prostate cancer encode gene-activating proteins, called transcription factors, rather than kinases. Drug companies have struggled for years to produce compounds that block specific transcription factors. Chinnaiyan, however, has recently identified a workaround. By blocking an enzyme required by the transcription factors, his team was able to block their activity, he reported in September 2010 at the annual scientific retreat of the Prostate Cancer Foundation. Even better, drug companies have already developed compounds that block that enzyme, he says.

Down the road, Chinnaiyan and others envision personalized cancer treatment. With such treatment, physicians would classify every cancer by its driving mutation or mutations; characterize it by its aggressiveness; and treat it with one of an armamentarium of Gleevec-like drugs that target each tumor’s Achilles heel.

In the meantime, doctors are helping whomever they can. In June 2010, Shaw and her colleagues returned to the annual ASCO conference to report the results of their expanded phase I trial on crizotinib. The drug stopped cancer from advancing in 87 percent of the 82 EML4-ALK-positive, late-stage lung cancer patients treated and shrank tumors in 57 percent of them. Results were so encouraging that investigators launched an international randomized phase III trial of EML4-ALK-positive non-small-cell lung cancer patients whose cancer withstood one earlier chemotherapy regimen. “It’s a great story,” says Sawyers.

One of the patients in the phase I trial is Schuette. From the first day he was treated, his pain disappeared and his energy returned, he says. A CT scan two months later showed that most of his tumors were gone. Since then Schuette and his wife have visited their far-flung children and grandchildren in Virginia, New York, and California. He’s back to swimming—up to a mile at a time. “I cherish the opportunity to be able to get back into the pool and do that,” he says.

Bill Schuette knows that his tumors, like leukemias treated with Gleevec, will eventually develop resistance to crizotinib. He may benefit from one of the backup therapies that Shaw says are under development. But for now, Schuette says, “I’ll take every day.”

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