NEW HOT PAPERS - 2008

 Why do you think your paper is highly cited?

This paper—by combining cutting-edge imaging with tissue and circulating biomarkers—provides the first clinical evidence for a potential mechanism of action of cediranib (AZD2171), an oral antiangiogenic agent, in patients whose brain tumors have recurred despite surgery, radiation, and chemotherapy.

 Does it describe a new discovery, methodology, or synthesis of knowledge?

This paper demonstrates that cediranib can decrease edema (swelling) associated with brain tumors. It uses advanced imaging to confirm the existence of a "window of normalization" created by an antiangiogenic vascular therapy in brain tumor patients—a finding previously discovered using transplanted tumors in mice. Finally, it identifies potential molecular pathways brain tumors might use to escape from cediranib and potential biomarkers associated with tumor response and recurrence.

 Would you summarize the significance of your paper in layman's terms?

Gregory Sorensen Rakesh Jain

Blood vessels in tumors look abnormal and function abnormally. This creates swelling in the brain—which can be debilitating. Steroids—used to treat this swelling for nearly 50 years—have their own side effects. Thus, antiangiogenic agents—such as those tested in our study—could be used for controlling edema.

The vascular abnormality also makes it difficult to deliver drugs to tumors and reduces their efficacy when they reach the tumor. Previous studies from our lab had shown that antiangiogenic agents can "normalize" tumor vessels for a period, which creates a vascular "window of opportunity" for delivering therapeutics effectively (Winkler F, et al. "Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, Angiopoietin-1, and matrix metallproteinases," Cancer Cell 6: 553-62, 2004).

We also showed that radiation therapy works best when it is given during a period of normalization. Our present clinical study identifies the window of opportunity created by the antiangiogenic agent, cediranib—when administration of chemotherapy or radiotherapy is most likely to offer increased benefit to the patient. This prediction is currently being tested in a larger (randomized) trial.

Finally, our study shows how measurement of certain imaging findings, molecules, and cells—known as biomarkers—could potentially identify what new drugs to give to patients as their tumors become resistant to cediranib—in order to keep the disease in check.

 How did you become involved in this research, and were there any problems along the way?

This multidisciplinary translational study involved close collaboration between three principal investigators and their teams—a neuro-oncologist (Batchelor), a neuro-radiologist (Sorensen) and a tumor biologist (Jain).

Jain's team had been studying the biology of tumor blood vessels for nearly three decades and dissected the causes and consequences of abnormal blood vessels in tumors. In 2001, they formally proposed that antiangiogenic therapy has the potential to "normalize" (repair) tumor vessels (Jain RK, "Normalizing Tumor Vasculature with Anti-Angiogenic Therapy: A New Paradigm for Combination Therapy," Nature Medicine 7: 987-89, 2001).

After validating this hypothesis in a number of animal models, they collaborated with Dr. Christopher Willett, a radiation oncology professor at MGH, to show that Avastin—an approved antiangiogenic drug—can normalize the blood vessels of rectal tumors by day 12 (Willett C, et al. "Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer," Nature Medicine 10: 145-47, 2004). However, this study did not demonstrate when the period of normalization began and ended.

Dr. Batchelor had been conducting clinical trials in brain tumor patients and was looking for a new agent that could benefit these patients. Soon after Jain and Batchelor met, the National Cancer Institute (NCI) issued a Request for Application (RFA) for a testing a new antiangiogenic compound—cediranib—and they decided to respond to this RFA.

To understand the effects of the compound, they needed an imaging expert to visualize and measure its effect in patients before and during treatment. For this, Dr. Greg Sorensen—a world-renowned MRI expert at MGH—joined hands with them.

They went on to assemble a team of 20 physician-scientists and in 10 months accrued 31 patients for this clinical trial.

 Where do you see your research leading in the future?

This trial has spawned a number of preclinical and clinical studies. The clinical studies include a randomized phase III trial of cediranib versus lomustine in recurrent glioblastoma; and a NCI-sponsored phase II study of cediranib, temozolomide, and radiation in newly diagnosed glioblastoma. Preclinical studies include developing strategies for extending the window of normalization and identifying imaging, molecular and cellular biomarkers for optimally combining and sequencing antiangiogenic agents with conventional and other novel therapeutics.

 Do you foresee any social or political implications for your research?

The newly approved antiangiogenic agents are very expensive and give only a modest survival benefit—on the order of months—to patients. Some patients do not benefit at all. Therefore, studies are needed to help identify which patients are likely to benefit from such medications and how to administer the medications in order for them to be of maximal benefit.

If antiangiogenic agents can improve vascular function, even if only transiently, it may increase the efficiency of delivery of various chemotherapies, and will likely allow clinical benefits to be achieved at reduced doses, and therefore, with potentially fewer side effects. We are hopeful about this knowledge improving both the rates of survival and the quality of life for cancer patients.

Tracy T. Batchelor, M.D., M.P.H.
Executive Director
Stephen E. & Catherine Pappas Center for Neuro-Oncology
Massachusetts General Hospital Cancer Center
Boston, MA, USA

A. Gregory Sorensen, M.D.
Associate Professor in Radiology at Harvard Medical School
Associate Radiologist at Massachusetts General Hospital
Co-Director, Athinoula A. Martinos Center for Biomedical Imaging
at Martinos Center
Department of Radiation Oncology
Massachusetts General Hospital
Boston, MA, USA

Rakesh K. Jain, Ph.D.
Andrew Werk Cook Professor of Tumor Biology
Harvard Medical School
Director, Edwin L. Steele Laboratory for Tumor Biology
Department of Radiation Oncology
Massachusetts General Hospital
Boston, MA, USA

Keywords: AZD2171, cediranib, oral antiangiogenic agent, pan-VEGF receptor tyrosine kinase inhibitor, glioblastoma patients, brain tumor patients, edema, antiangiogenic vascular therapy, potential biomarkers, vascular abnormality, chemotherapy, radiotherapy, tumor blood vessels, National Cancer Institute (NCI), cediranib versus lomustine, recurrent glioblastoma, temozolomide