Characterization Of Blood Vessels In Brain Autopsies Of Gbm Patients Who Received Antiangiogenic Treatment

2009 Background: GBs have two types of vessels: co-opted and angiogenic. We hypothesize that antiangiogenic therapy normalizes angiogenic blood vessels and increases co-option of host vessels. However, to date the morphological changes in blood vessels of human tumors treated with antiangiogenic agents have not been studied. Methods: Interim results of a phase II clinical trial with a potent oral, pan-VEGF receptor tyrosine kinase inhibitor with activity against VEGF and PDGF receptors (Cediranib; AZD2171) showed a decrease in tumor contrast enhancement of more than 50% in 16/30 patients, decreased vessel permeability and vessel diameter - all hallmarks of vascular normalization. Autopsy specimens were obtained from 3 patients who were enrolled in this trial and received AZD2171 for 56, 120, and 140 days. All these patients had stable disease and none of these patients had radiographic progression at the time of AZD2171 termination. The interval between the last dose of AZD2171 and time of death ranged from 16 days to 3 months. Sections were stained for a series of markers relevant to microvessel integrity [CD31, CD71, MDR-1, nestin, CXCR4, SDF1a, PDGFRα,β] and analyses performed on two tumor areas and two corresponding contralateral areas free of bulk tumor for each patient. Results: Morphologically, the treated tumor vessels appeared more normal: endothelial hyperproliferation and glomeruloid-like vessels dramatically decreased and vessel density was restored close to that in the contralateral brain. PDGFRβ, which was expressed on all tumor vessels prior to treatment was nearly undetectable, and CD71 (a marker of the blood-brain-barrier) expression was partially restored. These changes were not seen in patients treated with temozolomide and radiation. Conclusions: Inhibition of VEGF and PDGF receptors led to significant changes in the tumor blood vessels. The vessel density increased while the endothelium morphology reverted to a more normal phenotype (monolayer), supporting the hypothesis that anti-VEGF therapy leads to vascular normalization and to vessel co-option. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca, Dyax, Pfizer Pharmaceutical, Takeda Pharmaceutical AstraZeneca