Abstract
High grade gliomas, including glioblastoma (GBM), are the most common and deadly brain cancers in adults. Here, we performed a quantitative and unbiased screening of 70 cancer-related antigens using comparative flow cytometry and, for the first time, identified integrin alpha-2 (ITGA2) as a novel molecular target for GBM. In comparison to epidermal growth factor receptor (EGFR), a well-established GBM target, ITGA2 is significantly more expressed on human GBM cells and significantly less expressed on normal human glial cells. We also found that ITGA2 antibody blockade significantly impedes GBM cell migration but not GBM cell proliferation. To investigate the utility of ITGA2 as a therapeutic target in GBM, we designed and engineered an ITGA2 antibody-directed liposome that can selectively deliver doxorubicin, a standard-of-care chemotherapeutic agent, to GBM cells. This novel approach significantly improved antitumor efficacy. We also demonstrated that these ITGA2 antibody-directed liposomes can effectively breach the blood-brain tumor barrier (BBTB) in vitro via GBM-induced angiogenesis effects. These findings support further research into the use of ITGA2 as a novel nanotherapeutic target for GBM.
Highlights
High grade gliomas, including glioblastoma (GBM), are the most common brain cancers in adults, representing between 15 and 20% of all brain tumors diagnosed, including a significant fraction of pediatric cases[1,2,3,4]
Of the 70 screened targets, integrin alpha-2 (ITGA2) was identified as the only target that commonly overexpressed in all three GBM cell lines (Fig. 1b) and was selected for further investigation
We have identified and characterized ITGA2 as a novel molecular target for GBM that is robustly expressed in multiple representative GBM cell lines while being absent in normal glial cells
Summary
High grade gliomas, including glioblastoma (GBM), are the most common brain cancers in adults, representing between 15 and 20% of all brain tumors diagnosed, including a significant fraction of pediatric cases[1,2,3,4] It is among the deadliest tumor types, with only approximately 5% of diagnosed GBM patients surviving 5 years post-diagnosis[3,4]. Similar results were observed for a non-targeting liposomal temozolomide in a recent pre-clinical GBM study[12] We reasoned that these unsuccessful results might be due to the fact that these nanomedicines deliver their payloads in a non-specific, non-targeted manner and that drug availability to the GBM may be severely hindered by blood-brain tumor barrier (BBTB) and tumor heterogeneity. We reported our experience in combining ITGA2-specific targeting with an engineered liposomal nanomedicine capable of crossing the BBTB in vitro and effectively target GBM cells
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