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Targeted Therapies: Aiming With Precision

Cancer treatment that zeroes in on specific genetic mutations is replacing the one-size-fits-all approach.

By Cathryn Delude // The MGH Research Issue 2011
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Targeted Therapies

Dan Saelinger for Proto

Cancer chemotherapy still usually follows a cookbook formula, but a more personalized recipe is emerging. Not so long ago, patients typically received the same regimen of drugs for the same stage of lung cancer, for example. Some people responded well, while others didn’t, but no one knew why. That conundrum was in the back of Daniel Haber’s mind in 2003 when he read in the Boston Globe about a woman’s experience with a new drug, Iressa (gefitinib), then in clinical trials at Massachusetts General Hospital for late-stage non-small-cell lung cancer (NSCLC), which kills more people in the United States than any other cancer. In the trial, Iressa was ineffective in nine out of 10 people. But this woman’s tumors, which had resisted the strongest chemotherapy, somehow instantly succumbed to the small pill with none of the side effects common in standard chemotherapy.

“It reminded me of Gleevec, a targeted therapy for chronic myelogenous leukemia,” says Haber, director of the MGH Cancer Center. “Patients have a dramatic response to Gleevec, and that’s because Gleevec targets a specific genetic mutation that the leukemia cells can’t live without.”

A targeted therapy zeroes in on cancer cells that are distinguished by a particular mutation, while leaving healthy tissue mostly unscathed. But this kind of drug is powerless against cancers that don’t have the mutation. Iressa was developed to inhibit a receptor in cancer cells called EGFR, a sort of switch that tells the cell to keep growing. Maybe, Haber thought, Iressa works only on some lung cancer patients because it targets an EGFR mutation present in only some of the tumors.

At that time, most researchers thought that such targeted therapies would work only on cancers of the blood, such as CML, which has a well-defined single-genetic abnormality. Most common cancers are much more complex, with dozens or even hundreds of mutations acquired as their cells become malignant and ever more invasive. Some mutations are incidental or irrelevant to the cancer’s growth, while others are crucial. How could a targeted therapy know which to attack?

In a groundbreaking paper published a few months later, Haber and Thomas Lynch, then an MGH lung cancer specialist involved in the Iressa study, provided some of the earliest evidence that targeted therapies might also be effective against solid tumors. By genetically testing, or genotyping, patients who responded extremely well to Iressa, they found a mutation that freezes the EGFR switch in the “on” position, spurring unrestrained cancer-cell growth. The patients most likely to respond to Iressa had the mutation; all of the others, lacking the mutation, weren’t helped by the drug.

“We led the way in proving there are different subtypes of lung cancer, and that you can distinguish one group of patients from another—and determine which therapy they should receive—by genotyping their tumors,” says Lecia Sequist, one of the MGH researchers who worked on the studies. Subsequent work across the United States and abroad has confirmed those findings.

It’s now clear that other cancers also have subtypes that depend on mutations affecting protein switches in growth pathways. “There are already inhibitors that block tumor growth for many of these cancers, and more drugs are on the way,” says José Baselga, director of MGH’s newly established Henri and Belinda Termeer Center for Targeted Therapies.

To accelerate research, the center genotypes tumors when patients are diagnosed, looking for rare mutations that might make a tumor sensitive to an existing drug. That approach, a first in cancer treatment, is being emulated at institutions throughout the United States and in the United Kingdom. “We will add screens as new mutations are discovered and new drugs are developed,” says MGH pathologist John Iafrate, who runs the screening program.

Because of this approach, MGH can seize on a laboratory finding and bring it almost immediately into the clinic. For example, in 2007, researchers in Japan identified a rare mutation in the ALK gene in some lung cancers. At the time, MGH clinician Eunice Kwak was leading a trial of a new drug for gastric cancer, crizotinib, designed to inhibit a gene called MET. But the therapy was also effective against the ALK gene. MGH began testing lung cancer patients for the ALK mutation and offered crizotinib therapy to those who had it. Most had remarkable responses, proving the drug’s effectiveness in those genetically preselected cases—and providing therapy to patients with an otherwise untreatable form of lung cancer. On the basis of the MGH work, crizotinib sped through subsequent trials and received FDA approval (as Xalkori) in August 2011.

Yet even cancers that are very sensitive to targeted therapies sooner or later “learn” to circumvent the drugs by relying on alternate pathways. But even then, there may be other ways to arrest tumor growth. “Because individual cancers change so dramatically over time, if we do repeat biopsies we can find out why a drug is no longer working and what new type of treatment is needed,” says Jeffrey Engelman, director of the MGH Cancer Center’s thoracic oncology program.

In lung cancers, for example, many of the 10 or so mutations that may arise after treatment with a targeted therapy can now be targeted with second-generation drugs. In other cases, a cancer mayevade a therapy by becoming a different kind of tumor that is itself susceptible to treatment. A non-small-cell lung cancer, say, may morph into small-cell lung cancer, a very different disease that can be more vulnerable than NSCLC is to chemotherapy drugs.

This idea—that if the effect of one targeted therapy wanes, another may be able to take over—was the direct result of MGH’s pioneering study on repeat biopsies at the time of drug resistance, a novel approach. And now the hospital is developing less invasive techniques than surgical biopsy, making it possible to detect cancer cells in the bloodstream and permitting more frequent testing. “We want to be able to monitor a cancer in ‘real time,’ using circulating tumor cells in the blood, which will allow us to tailor treatments quickly for each individual receiving therapy,” says Haber, who, with Mehmet Toner, director of the Center for BioMicroElectroMechanical Systems, is creating a device that uses a silicon chip to capture CTCs from blood samples for quick and easy genotyping (see page 35).

While there’s still far to go to conquer cancer, targeted therapy has forever changed the mode of attack, and a once revolutionary idea has become mainstream. Researchers now know that seemingly similar cancers may be radically different in what drives them to grow and that only by understanding the genetic mutations in each tumor can a physician select the right drug for a particular patient. “There’s still so much we don’t know,” Haber says. “But now we can glimpse what the future will look like.”

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