Tumor Treatment Reduces Swelling of Brain

When cancerous cells form a tumor and begin to grow uncontrollably, they need to induce the formation of new blood vessels to bring them oxygen and nutrients—a process known as angiogenesis.

A team of researchers at Massachusetts General Hospital has discovered that the main effects of an angiogenesis inhibitor in treating glioblastoma, a severe kind of brain tumor, stem from the reduction of brain swelling, rather than any effect on tumor growth.

In these tumors, blood vessels can be leaky, which causes swelling in the brain known as edema. This, in turn, can cause drowsiness, loss of consciousness, and brain damage.

A Phase II clinical trial with the experimental drug cediranib conducted several years ago showed that patients treated with the drug survived longer compared to historical controls. Researchers wanted to know why this occurred, said Tracy T. Batchelor, one of the authors of the study and a consultant to AstraZeneca Pharmaceuticals, which produces cediranib.

“This was a bench to bedside and back to bench journey,” added Batchelor, referring to the return to the laboratory after the drug’s clinical trial.

The researchers used rodent models with three different kinds of glioblastoma and placed a window in the animals’ cranium so they could observe the brain tumor—which they labeled with a fluorescent reporter—while the animals were still alive.

They found that the mice treated with the drug survived longer compared to controls given only saline, which mimicked what occurred in the clinical trial, said Rakesh K. Jain, director of the Steele Laboratory in the MGH Department of Radiation Oncology and a professor of oncology at Harvard Medical School.

Yet surprisingly, the drug was not affecting tumor growth—the tumors continued to grow in mice given the drug, Jain said.

“These treatments allowed animals to survive longer despite not slowing the tumor at all,” said Walid S. Kamoun, one of the lead authors and a research fellow in radiation oncology at MGH.

Several years ago, Jain had proposed that anti-angiogenic drugs might be repairing the tumor blood vessels, which he called “normalization”.

“This would reduce edema—swelling—in brain tumors,” Jain said. “Edema is a major cause of mortality and morbidity in these patients.”

The researchers showed that this was indeed the case in their rodent models—the main effect of the drug was to normalize the blood vessels and reduce swelling, allowing the animals to live longer with the tumor, said Kamoun.

“This was the first preclinical study to show that normalization of vessels alone without chemotherapy and radiation can prolong life,” Jain said.

Currently, clinical trials using cediranib to treat patients with both recurrent and newly-diagnosed glioblastoma are underway in Boston and internationally to further study the drug’s efficacy.

In the future, the researchers hope the drug can be used in combination with traditional chemotherapy and radiation—both of which are more effective when blood flow to the tumor is normal—to enhance their effects on reducing tumor growth, said Jain.

—Staff writer Alissa M. D’Gama can be reached at adgama@fas.harvard.edu.