Glioblastomas (GBMs) are malignant, invasive, incurable brain tumors that are poorly responsive to chemotherapy. The abnormal tumor vasculature that is a pathological hallmark of GBM is a potential mechanism of tumor resistance to cytotoxic therapies and may represent an important therapeutic target. Biologic agents such as bevacizumab, which target vascular endothelial growth factor (VEGF) are being studied in GBM and have resulted in improved progression-free survival in patients. Bevacizumab was approved by the Food and Drug Administration in 2009 as monotherapy for recurrent GBM and is now widely used in the United States in this patient population. It is unclear why patients respond to anti-VEGF treatment and what is the optimal way to incorporate these drugs into treatment regimens. The strong anti-permeability effect of anti-VEGF agents decreases the mass effect of tumors within the fixed cranial vault but may also decrease the penetration of cytotoxic chemotherapies into the tumor. However, this decrease in permeability may be offset by improvement in tumor blood flow. Improved blood flow to the tumor may actually improved delivery of cytotoxic chemotherapies to areas of the tumor that previously had not been well perfused and, thus, exposed to cytotoxic drugs. The goal of this proposal is to understand how anti-VEGF agents modulate the delivery of temozolomide, a standard chemotherapy agent used to treat GBM. We will use simultaneously acquired MRI and PET to measure vascular physiology and delivery of temozolomide in patients with recurrent GBM treated with bevacizumab. Fifteen patients will undergo MRI and FMISO PET to measure vascular changes and change in tumor oxygenation status in response to bevacizumab. An additional 15 patients will undergo MRI and PET with radiolabeled temozolomide to measure delivery and penetration of temozolomide into the tumor before and during treatment with bevacizumab.

Public Health Relevance

of this project is that it will improve our understanding of how anti-vascular endothelial growth factor (VEGF) agents modulate the delivery of cytotoxic chemotherapies to tumors. Anti-VEGF treatments are commonly used to treat several cancers but are expensive and potentially toxic. Therefore, we need a better understanding of how to optimize the use of these drugs.

National Institute of Health (NIH)
Mentored Patient-Oriented Research Career Development Award (K23)
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Subcommittee B - Comprehensiveness (NCI)
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Lim, Susan E
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Massachusetts General Hospital
United States
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