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More advanced imaging allows researchers to see not only if a drug is working but also how it is working. Here, a brain tumor distorts white matter fibers (left). After a month of treatment (right), swelling around the tumor has receded and the fibers are normalized. Reduction in swelling was an unexpected benefit that may hold the key to understanding how cediranib extends survival.

Promising Results

Cediranib led to dramatic improvements within 24 hours of the first daily oral dose. “I didn’t believe it when I first saw it,” Sorensen recalls, “but the results were very consistent and clear.” One MRI test monitored the decreasing vessel leakage. Another showed the overall mass of tumor and edema shrinking. A third revealed that the brain pathways disconnected by the tumor reconnected, presumably restoring brain function.

These results translated into clinical benefits, according to the preliminary results reported in the January 2007 issue of the scientific journal Cancer Cell. “In this study, patients live longer and their tumors shrink,” summarizes Batchelor. At the three-month point, half the patients noted a 50-percent shrinkage, and many, like Andrea, benefited even more.

While new drugs frequently pose new complications, and Andrea experienced her share, her feelings remain positive. “I’ve beaten the odds with this drug,” she acknowledges, “thanks to the support of Cancer Center staff, and my husband, friends and family, and all the hugs and kisses from my son Dylan.”

Her husband, David, adds, “We feel blessed to have had over twelve extra months so far, and that something wonderful has come out of this tragedy.” In addition, Andrea quickly weaned herself off the steroids that control swelling, thus escaping the side effects. Most patients in the trial could also reduce or stop using steroids entirely.

As the team anticipated, the tumors eventually became resistant to the drug, but they had identified a “normalization window” of reduced swelling and healthier blood flow. According to Batchelor, “this was the first trial to identify the onset and duration of a normalization window,” which typically ranged from one month to several months.

Closing the Bench-to-Bedside Loop

Next, the researchers want to test the theory that the normalization window provides an opportunity for chemotherapy drugs to penetrate the tumor more effectively and kill the cancer cells. To that end, they are recruiting glioblastoma patients for two spin-off trials of cediranib. The first, which is a large international study opening at nearly 70 sites in the United States, Europe, Canada and Australia under Batchelor’s leadership, will study patients with recurring glioblastoma. The second trial, which will investigate the efficacy of the drug in newly diagnosed glioblastoma patients, recently received a substantial grant from the National Cancer Institute. This study will combine cediranib, chemotherapy and radiation, and may allow doctors to take advantage of the normalization window created by cediranib. The doctors hope that this normalization will improve the delivery of the oral anti-cancer drug temozolomide and create other biological changes that allow chemotherapy and radiation to work better.

For those trials, the Cancer Center collaborators need to know when the normalization period is coming to an end, which will signal that chemotherapy will become less effective. Thanks to the generosity of an anonymous donor with personal ties to a glioblastoma patient, they purchased specialized machines that enable them to find blood molecules, or biomarkers, that indicate when the tumor begins to become resistant to cediranib. “This is a tremendously useful finding,” says Jain. “Markers are important because most hospitals don’t have specialized neuroimaging machines, but anyone can run a blood test.” Back in the lab, Jain is investigating these markers. He’s also researching other questions raised by the study, including methods to extend the normalization period. “This work did what trials are supposed to do,” concludes Jain. “It spawned new trials and new bench work that will lead to new treatments.” And the effort could benefit many cancer patients, not just those with glioblastoma. - Cathryrn Delude