Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

Despite aggressive surgery, radiotherapy and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumours stimulate the formation of new blood vessels through processes driven primarily by vascular endothelial growth factor (VEGF). However, the resulting vessels are structurally and functionally abnormal, and contribute to a hostile microenvironment (low oxygen tension and high interstitial fluid pressure) that selects for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that anti-VEGF therapies are potentially effective in glioblastoma--the most frequent primary brain tumour--and can transiently normalize tumour vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.

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