Doctors look to personalize cancer care

A group of Boston physicians and researchers has taken a crucial step toward personalized cancer treatment, identifying novel drug combinations that show promise against cancer cells that have developed a resistance to therapy.

The technology is not yet ready for the ultimate test, in which the promising drug combinations are given directly to patients. However, the researchers saw tantalizing hints of the potential of the approach when they grew a handful of the drug-resistant cancers in mice and observed that in all cases, the new drug regimens were effective at shrinking tumors.

“You could imagine in the future — maybe the not-too-distant future — we could start to do this as clinical trials where we would assign patients to treatments based on the results of what their cancer cells showed susceptibility to,” said Dr. Jeffrey Engelman, director of thoracic oncology at Massachusetts General Hospital, who co-led the work published Thursday in the journal Science. A revolution in medicine has made genetic testing of tumors almost routine when selecting treatment for many types of cancer. However, resistance to targeted therapy almost invariably develops and genetic clues, though powerful, have not always been sufficient to identify the best treatment.

That has spurred a range of efforts to personalize treatment and monitor cancer’s evolution. This summer, a Mass. General team showed that it was possible to isolate rare tumor cells circulating in the blood and analyze them to understand how a patient’s cancer was changing. Other researchers have been working on developing mouse avatars, in which a patient’s tumor is grown in a lab animal in which new therapies can be tested.

In the new study, the researchers started with 55 samples of cancer cells that had developed resistance to a targeted drug. Nearly half of the cells had been harvested directly from lung cancer patients whose cancer had returned.

The researchers then used a relatively new technique to grow those cancer cells in a dish, establishing a population of cells that could be used to screen for possible treatments.

Next, the scientists bombarded those cancer cells with an array of 76 different drugs and watched to see which ones would be effective. In 45 cases, they found that a novel drug combination worked; the cancer cells became resensitized to the initial drug that had stopped working.

Outside researchers said the study pointed to a future direction for care and was exciting because some of the drug combinations could not have been predicted by genetic testing alone. Dr. Richard Schlegel, director of the Center for Cell Reprogramming at Georgetown University School of Medicine, said the work was “a mirror into the future” of cancer care.

But significant hurdles still exist before the tool could be used to direct a drug regimen.

Researchers must show that the drug predictions that seem so promising in a dish actually work in patients. They also will need to deal with technological issues, such as the time it takes to grow patients’ tumor cells in a dish — between two and six months in the study, and not every attempt was successful.

“For decades, literally decades, people have wanted to do patient-specific chemotherapy sensitivity testing, and it’s been a very hard problem,” said Dr. James Eshleman, a professor of pathology and oncology at Johns Hopkins University School of Medicine, who was not involved in the work. “One problem which is totally counterintuitive is that cancers grow in patients just fine, but” in a dish, “it’s relatively hard to generate cell lines, and specific cancers are extraordinarily difficult, largely for reasons that we don’t understand.”

The researchers believe that with time, those technological issues can be resolved. The study used an imperfect source of cells — leftovers taken from biopsies that had been done for other purposes. If the biopsies were taken with the idea of growing cells and testing drugs, it is likely that the process could be quicker and more efficient.

A far bigger question looms: Sometimes, therapies that seem like a home run in laboratory tests or even animal models of cancer do not work in people.

“This is really setting up the criteria for what we have to look at next,” Schlegel said. “Someone has to figure out if we grow up these cells, how many times is this going to be an adequate predictor of patient response?”

Engelman said he already is beginning to work on the answer to that question.

His team will start by reexamining clinical trials in which patients received drugs and their responses were known. Researchers will then grow cells harvested from their tumors in a dish to see whether the people who had the best responses to the drug also happened to have cells that were more sensitive to the treatment, as researchers would expect.

If that work shows promise, it will help provide the evidence needed to begin using the tool to guide cancer care in patients.