Glioblastoma (GBM) is the most common primary brain tumor and the most malignant form of astrocytoma (WHO grade IV). We have demonstrated that both GBM tumor cells and its vascular endothelium express the cell surface receptor tissue factor (TF), a critical initiator of thrombosis, while the vasculature of the normal brain does not. Here we explore mechanisms related to the upregulation of TF in the vasculature of GBM and hypothesize that a cytotoxic agent conjugated to a carrier directed at TF will specifically target blood vessels of GBM, but not non-neoplastic brain. Thus, the objective of this proposal is to develop a novel therapeutic approach for GBM, in which the TF-expressing vasculature is specifically targeted. The cytotoxic agent we have developed is EF24, a synthetic curcumin analog, which will be linked to enzymatically inactive coagulation factor VIIa (fVIIa), the high affinity ligand for TF that has exquisite specificity. We hypothesize that this drug conjugate (EF24-FFRck-fVIIa) will bind to TF on vascular endothelial cells (VECs) within the GBM, enter target cells by ligand-receptor mediated endocytosis, and elicit a cytotoxic response. The disruption of the blood brain barrier (BBB) due to targeting the VECs and to the tissue-destructive nature of GBM should also permit binding of the drug-conjugate directly to TF expressing neoplastic cells. Thus, this therapeutic approach has a high likelihood of having both an anti-angiogenic and direct anti-tumor effect.
Specific Aim I will determine the mechanisms by which malignant gliomas induce the expression of TF by vascular endothelial cells. We will establish whether PTEN loss and hypoxia lead to release of factors by gliomas that induce endothelial TF expression in vitro and will determine if these mechanisms have correlates in human brain tumor specimens.
Aim II will establish the distribution of the drug-conjugate and the drug in glioma xenografts, their associated vasculature and the adjacent normal brain. Near infrared optical imaging will be used to determine the distribution of the drug-conjugate in vitro and in vivo using Cy5.5-labeled EF24-FFRck- fVIIa. The distribution of the drug using biotinylated EF24 combined with streptavidin histochemistry will be used to more precisely localize the drug in glioma xenografts tissue sections.
Aim III will determine the efficacy of the drug-conjugate against malignant gliomas in a mouse xenograft model. We will examine the effects of the EF24-FFRck-fVIIa on survival in this model and examine the biologic correlates of drug-conjugate treatment, including tumor growth, angiogenesis and disruption of the BBB.
Glioblastoma (GBM) is the most common primary brain tumor, with 8700 new cases per year in the United States. These tumors are universally fatal and the average length of patient survival is only 60 weeks with current therapies. This proposal uses a highly innovative approach to specifically target the abnormal blood vessels of GBM in order to slow their growth. Although this proposal specifically addresses the abnormal vessels in GBM, the approach may find application in other diseases with abnormal blood vessel growth, such as diabetic retinopathy, macular degeneration, endometriosis, Crohn's disease, psoriasis, and other cancers.
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