Recurrent glioblastoma is a uniformly fatal disease. One of the hallmarks of glioblastoma is endothelial proliferation. Thus, antiangiogenic agents, which are new therapeutics that have entered clinical practice for the therapy of other solid tumors, are promising therapeutics in glioblastoma.
Using magnetic resonance imaging techniques we show that normalization of tumor vessels in 29 consecutive 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 a significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. This is the first study to identify the onset and duration of a vascular normalization window created by an antiangiogenic agent in any human tumor. This is also the first evidence that recurrent glioblastomas remain responsive to antiangiogenic therapy following progression during drug interruption. Basic FGF, SDF1α 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. Moreover, we show that viable CECs, which correlated with tumor progression through treatment, constitute different biomarkers than CPCs, which correlated with tumor relapse after drug interruption. On the other hand, plasma bFGF and SDF1α levels increase with tumor progression and vessel size, highlighting these angiogenic pathways as potential targets for therapy. Finally, this study demonstrated that AZD2171, a multitargeted tyrosine kinase inhibitor, can alleviate edema, a major cause of morbidity in glioblastoma, and is associated with a steroid-sparing effect in these patients.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA