CONNEXIN HEMICHANNELS INHIBITION AS A POTENTIAL THERAPEUTIC APPROACH FOR GLIOBLASTOMA TREATMENT

High-grade gliomas and glioblastoma (GBM) are the leading cause of brain tumor death in both children and adults. Connexins (Cxs) have been widely studied in relation to cancer. By mediating the release of signaling molecules, Cx hemichannels (HCs) may contribute to glioma cell proliferation, migration and invasion by a variety of mechanisms [1, 2 ]. A body of evidence suggests that among the Cx subtypes implicated in GBM pathophysiology, Cx26 and Cx30 serve as negative prognostic indicators of survival when upregulated in human GBM biopsy samples. Meanwhile, upregulated Cx32 in activated microglia may influence microglial coordination within the tumor microenvironment [3]. Cx43 is highly expressed in glioma-associated astrocytes, particularly in peri-tumoral regions, where it promotes tumor cell dissemination and may contribute to hyperexcitability and epileptogenesis through deregulated Ca2+-dependent glutamatergic signalling. These evidences suggest that targeting Cx HCs could be a promising strategy for disrupting the molecular networks driving GBM pathogenesis. In this context, we employed a monoclonal antibody (mAb), that we characterized in previous work, which is capable of inhibiting Cx26, Cx30, and Cx32 HCs with high specificity and nanomolar sensitivity [4-6]. In this study, we tested the effect of this mAb in the GL261 orthotopic syngeneic mouse model of GBM, evaluating various routes of administration and protocols. We obtained promising results in tumor growth, that suggest the potential therapeutic application of the mAb for GBM treatment.