Getting real about cancer research
Science carries a news item:
[Cancer geneticist Bert] Vogelstein seems to enjoy pricking balloons. Recently, he has focused on a new target: exuberance over targeted cancer drugs. He says he got interested after seeing a paper last year on melanoma therapy. It included photos of the torso of a man with melanoma who had received a new drug aimed at a mutated gene called BRAF. Before treatment, the patient’s skin was riddled with metastatic tumors; soon after treatment, the tumors vanished, and the man looked perfectly healthy. Five months later, the tumors reappeared in exactly the same locations. The photos “blew my mind,” Vogelstein says. “Why do the tumors all return at roughly the same time? It’s almost as miraculous as when they disappear.”
Targeted drugs for other cancers usually stop working after about the same number of months, presumably because rare resistant cells in the tumors continue to grow and ultimately proliferate. To investigate, Luis Diaz and others in the Vogelstein-Kinzler lab drew on a sensitive technique they had developed for detecting mutations in the very small amount of tumor DNA present in a cancer patient’s blood. They collected a series of these “liquid biopsy” measurements from patients with advanced colorectal cancer whose tumors had become resistant to a targeted cancer drug. With Harvard University computational biologist Martin Nowak, they devised a model showing that even before the patient begins treatment, some tumor cells always carry genes with random mutations that can support resistance to targeted drugs. This form of resistance, they wrote last month in Nature, is therefore “a fait accompli.”
But the modeling study also suggested that this resistance can be delayed by combining two drugs that target different pathways. Indeed, Vogelstein and colleagues suggest that once a targeted drug has passed initial safety trials, it’s so clear that single-drug therapy will fail that they consider it unethical to give patients just one such drug. “Why shouldn’t you design a large, very expensive trial to incorporate more than one agent?” Vogelstein asks.
Memorial Sloan-Kettering Cancer Center cancer researcher Charles Sawyers, who helped develop Gleevec, the leukemia drug that paved way the way for other targeted therapies, says he agrees with Vogelstein’s message: “We have to move to combinations as quickly as possible.”
The Vogelstein-Kinzler lab is attacking cancer from several new angles, including an unusual clinical trial that involves destroying tumors by injecting them with bacteria. But the project closest to Vogelstein’s heart right now is an effort to develop the liquid biopsy method as a general cancer-screening test. The aim is to look for a set of mutations commonly found in tumors that can be isolated from circulating blood.
Vogelstein and Kinzler argue that DNA mutations offer “clarity” compared to other blood-sampling approaches that focus on more complex protein or gene-expression markers. At the AACR meeting, Vogelstein described his group’s latest blood test results for 304 patients with several types of cancer. Nearly all with metastatic tumors had detectable mutations in their circulation; more than 50% of those whose cancer had not yet metastasized had them; and none of 82 controls. “I think we’re getting very close with the technology,” says Vogelstein, who owns stock in a German company, Inostics, that is commercializing the test.