Antiangiogenic Therapy for Glioblastoma

Abstract

Glioblastomas are among the most vascular tumors due to the expression of a variety of pro-angiogenic factors. New drug regimens are being developed to target angiogenesis in an attempt to arrest tumor growth. In particular, the vascular endothelial growth factor (VEGF) pathway has been a prime drug target. Preliminary results with anti-VEGF agents have been promising with prolonged progression-free survival reported. In addition, the anti-permeability effects of anti-VEGF agents have important consequences for tumor imaging and for patient quality of life by decreasing corticosteroid dependence. Unfortunately, the response to anti-VEGF therapy is transient and the majority of patients eventually relapse so more work is needed to understand mechanisms of tumor escape.

Assessment of tumor oxygenation and its impact on treatment response in bevacizumab-treated recurrent glioblastoma

“…This interpretation is supported by our previous findings in the same patient group focused on examination of perfusion (CBV and CBF) 4 where we found that a larger %PRM(À) for CBV and CBF increased the hazards for progression and death in patients treated for rGB, with the magnitude of %PRM(À) being dependent on pretreatment parameters. Combining the prior hemodynamic results with metabolic assessment from this study, blood and oxygen supply to the examined tumors appear not overall improved but specifically tumors associated with worse outcome had larger decreases in CBF and TMRO 2 and we find that CTH, and hence the OEF combines with the CBF in such a way that the overall tumor oxygenation appears to be worsened despite vascular normalization. The findings in this study provide additional insight into the underlying pathophysiology by demonstrating that changes in TMRO 2 under BEV therapy are primarily determined by changes in CBF while OEF remains relatively unchanged.…”

“…Glioblastoma (GB) secures oxygen and nutrient supply by stimulating neoangiogenesis 1,2 ; and the extent of vessel formation is an indirect marker of aggressiveness, high malignancy, and proliferative potential. Accordingly, we have previously used non-invasive dynamic susceptibilityweighted contrast-enhanced MRI (DSC-MRI) to demonstrate that (a) high pretreatment cerebral blood flow (CBF) and cerebral blood volume (CBV) predict poor BEV efficacy, 3 and that (b) patients with a higher degree of angiogenesis prior to BEV-treatment show a greater antiangiogenic effect in response to BEV, which also negatively impacts treatment outcome.…”

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

“…Recent clinical data suggest that improved tumor perfusion and oxygenation in both newly diagnosed and rGBM patients during anti-VEGF therapy correlates with significantly longer survival than seen in patients whose tumor blood perfusion does not increase or decreases (47)(48)(49)(50). In both U87 and Gl261 tumors dual therapy resulted in a vasculature that more closely resembled that of the surrounding brain.…”

“…Previously we have shown that the inhibition of VEGF during tumor growth leads to vascular normalization, the extent of which was associated with survival in preclinical models (10,11,27) and GBM patients (47)(48)(49)(50). Recent clinical data suggest that improved tumor perfusion and oxygenation in both newly diagnosed and rGBM patients during anti-VEGF therapy correlates with significantly longer survival than seen in patients whose tumor blood perfusion does not increase or decreases (47)(48)(49)(50).…”

New Applications of Nanotechnology for Neuroimaging

“…12,13 Angiogenesis imaging is important to identify patients who would benefit from antiangiogenic therapies and to monitor treatment response. To date, there have been no well-validated radiologic markers to serve these purposes.…”