Abstract
Glioblastoma (GBM) remains an incurable disease with an extremely poor prognosis. Tumor resection is a first-line standard of care treatment, but most patients experience recurrence, which has been associated with glioblastoma stem cells (GSCs), a subpopulation of highly tumorigenic, invasive, self-renewing, and therapeutically resistant cells, that remain in the brain and can drive recurrence. As the Src-inhibitory peptide TAT-Cx43(266-283) inhibits GSC proliferation and invasion in patient-derived and mouse in vitro and in vivo models, we aimed to combine surgical resection with TAT-Cx43(266-283) administration to improve tumor resection outcome. We generated two immunocompetent GBM resection models by intracranially injecting murine (SB28, GL261-GSC) cells in C57BL/6 mice. After 14 or 10 days, respectively, tumors were resected or sham-operated, and either saline or 100 mM TAT-Cx43(266-283) were intracranially injected in the tumor area of sham mice or tumor cavity of resected mice. Survival studies were conducted and the histopathology of tumors was analyzed using hematoxylin-eosin staining. Tumor tissue western blots, immunohistochemistry, immunofluorescence and patient dataset analysis were also performed. We found that these GBM models were complementary and recapitulated different histological GBM features, including necrosis, invasive borders and proliferative spread foci. Importantly, the combination of tumor resection and TAT-Cx43(266-283) extended survival of GBM bearing mice, regardless of the effect of resection alone. TAT-Cx43(266-283) increased tumor cell apoptosis, decreased the invasive features promoted by tumor resection, reduced aberrant vascularization and modified Iba-1(+) immune cell response. Finally, the analysis of clinical datasets confirmed the interest of inhibiting Src in patients with GBM recurrence after the standard of care treatments. The combination of the tumor resection with the administration of TAT-Cx43(266-283) enhanced survival of GBM-bearing mice, as well as tumor cell apoptosis, and decreased important hallmarks of GBM recurrence, such as the invasive features of the tumors after resection. This study demonstrates the safety and effectiveness of TAT-Cx43(266-283) intracavitary application after resection, and therefore supports its use in a clinical setting.