AZD2171,normalizes tumor vasculature and alleviates edema in glioblastoma patients

The imaging studies, which used specially adapted Magnetic Resonance Imaging (MRI) scans, exposed a "window" during which the blood system feeding the tumor reverted to a more normal state, before morphing again into the leaky, dilated vessels that make drug treatment difficult.

The blood biomarker studies showed that as tumors stopped relying on vascular endothelial growth factors (VEGF) to pump up blood flow to them -and VEGF is what AZD2171 targets-they started using two other growth factors, neither of which had previously been recognized as important for human tumor blood vessel growth.

The study is unique because it is the first to test AZD2171 in glioblastoma patients, and to find that it "offered promising benefits such as tumor shrinkage and reduction of brain swelling," said Tracy Batchelor, M.D., chief of neuro-oncology at Massachusetts General Hospital.

Of 31 patients who participated, more than half experienced tumor shrinkage of 50 percent or more, and median time to tumor regrowth was 111 days. "This was not a randomized study, but compared to historical benchmarks, in which response to conventional therapies is approximately 10 percent and progression is usually 63 days, these results are encouraging," Dr. Batchelor said.

The agent, which has been tested in other tumor types but is not yet approved, also reduced edema, or swelling, in the brain, he said. Because of that, some patients were able to stop using steroids, which can cause debilitating side effects.

The clinical trial also provided insights into how AZD2171 functions and how the therapy might be improved, the researchers say. MRI scans taken before, during, and after treatment provided a timeline picture of AZD2171's effectiveness, and then loss of function as tumors began to resist the agent.

"This was beautiful," said Rakesh Jain, Ph.D., professor of tumor biology at Harvard Medical School. "We were able to see changes within 24 hours of taking a single dose."

Jain and his colleagues have spent years documenting how developing cancers promote blood growth factor signaling, which causes blood vessel architecture to go seriously awry: vessels loop back on each other, send blood in the wrong direction, and become enlarged as well as leaky due to holes that develop. They have found regions in solid tumors in which blood flows briskly, and others in which there is little or none. "If we try to deliver drugs to those latter areas, they do not arrive," Jain said.

Still, cancer cells are alive in those hypoxic regions, and, in fact, they morph into much more aggressive cells, he said. It is also in these areas where cancer stem cells might hide. "Buried deep in this hostile environment are the cells responsible for invasion and metastasis," Jain said.

The blood biomarker studies allowed them to track what was happening in the tumors. The researchers discovered that as expression of VEGF proteins decreased, levels of two other proteins increased as the tumor switched to other pathways. One of these proteins, fibroblast growth factor (FGF), was thought to be involved in angiogenesis, but the other, chemokine stroma-cell-derived factor 1 alpha (SDF1 alpha), was a new discovery, Jain said. "We threw a net up with the biomarker studies and found the involvement of FGF, which had never been documented in patients, and SDF1 alpha, which was not known to be one of several dozen pro-angiogenic molecules identified so far in such studies."

"We all recognize that what we need to do now is combine this therapy with other types of treatments, either existing or to be developed, and to deliver these drug combinations during the window we have identified," Dr. Batchelor said. "This might help us manage patients much more effectively." -American Association for Cancer Research