Tracy T. Batchelor, Gregory
A. Sorensen & Rakesh K. Jain talk with
ScienceWatch.com and answer a few questions about
this month's New Hot Paper in the field of Biology &
Biochemistry.
Article Title: AZD2171, a pan-VEGF receptor
tyrosine kinase inhibitor, normalizes tumor vasculature and
alleviates edema in glioblastoma
patients Authors:
Batchelor,
TT;Sorensen, AG;di Tomaso, E;Zhang, WT;Duda,
DG;Cohen, KS;Kozak, KR;Cahill, DP;Chen, PJ;Zhu,
MW;Ancukiewicz, M;Mrugala, MM;Plotkin, S;Drappatz, J;Louis,
DN;Ivy, P;Scadden, DT;Benner, T;Loeffler, JS;Wen,
PY;Jain,
RK
Journal: CANCER CELL, Volume: 11, Issue: 1, Page:
83-95, Year: JAN 2007
* Massachusetts Gen Hosp, Dept Neurol, Boston, MA
02114 USA.
* Massachusetts Gen Hosp, Dept Neurol, Boston, MA
02114 USA.
(addresses have been truncated)
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.
"This paper
demonstrates that cediranib can
decrease edema (swelling)
associated with brain
tumors."
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