Brain Cancer Study Explores Multi-Targeted Therapies
Targeted drugs such as imatinib (Gleevec) and erlotinib (Tarceva) have been tested against brain cancer, but few patients have benefited. A new study offers a possible explanation for the disappointing results and suggests that using the drugs in combination may be a more effective strategy against the deadly disease.
The researchers found that brain cancer cells may simultaneously activate a number of proteins on the cell surface called receptor tyrosine kinases, or RTKs. These proteins relay growth-promoting signals into cells, sustaining their survival. RTKs have become popular drug targets because they are frequently overactive or mutated.
By simultaneously turning on a number of RTKs, cancer cells may reduce their dependence on any one, and thereby improve their chances of survival, the researchers reported online in Science on September 13. They first observed the phenomenon in cells from patients with glioblastoma and then in other major cancers.
"We have found that a number of RTKs are simultaneously activated in virtually all the cancer cells we've examined," says Dr. Ronald DePinho of the Dana-Farber Cancer Institute, who led the study. "When one is blocked another can step in and sustain the survival signal."
What may matter most in treating the disease is to reduce the overall level of these abnormal signals in cells, he adds.
The findings support the growing view that some RTKs are more or less interchangeable, and they may help explain the feeble clinical responses when RTK inhibitors are used against solid tumors, the researchers say. Even when the drugs elicit an initial response, most cancers eventually progress and patients need additional therapies.
Glioblastoma is usually fatal within a year of diagnosis. More than 100 clinical trials over the last decade have not improved survival, with brain cancer, with the notable exception of temozolomide (Temodar) for a subset of glioblastoma patients. The lack of progress stems from not knowing which genes are involved in the disease.
Dr. DePinho and his colleague Dr. Jayne Stommel were searching for RTKs that drive glioblastoma when they uncovered the multiple coactivated RTKs. Some of the kinases, such as EGFR and Met, were known to play a role in the disease, but others were not.
Researchers may need to look more globally at RTKs that work in conjunction with known factors such as EGFR, says Dr. John Laterra, a brain cancer researcher at Johns Hopkins Medical School.
This study is timely because many scientists are looking at the networks of RTKs and the pathways they control," Dr. Laterra continues, "and they are finding evidence of close crosstalk and interplay among the pathways."
In the study, three or more targeted drugs were typically needed to control abnormal cell growth. The researchers used an experimental Met inhibitor in combination with imatinib and erlotinib to block the flow of growth signals into cells and cause them to die. They confirmed the results using RNA interference to inhibit the RTKs.
Like many in the field, the researchers envision an individualized approach to cancer therapy. Patients would have their tumors profiled to see which RTKs are active, and a regimen would be designed based on the results.
A number of RTK inhibitors have been approved for cancer and others are in development. But the first Met inhibitors, for instance, are still in early-stage clinical testing. The costs and toxicities associated with using multiple targeted drugs would need to be addressed before clinical trials could be launched.
Nonetheless, if the basic hypothesis is confirmed by other studies, researchers will have to rethink how trials for glioblastoma and other solid tumors are designed, says Dr. Antonio Omuro of the Hôpital Pitié-Salpêtrière in Paris, who coauthored a recent commentary on targeted therapy for brain cancer.
"We will need to reinforce the policy of molecularly profiling every single patient enrolled in clinical trials," he says. "We have not always done this, but everyone knows that it is essential to move the field forward."
—Edward R. Winstead