Enhancing glioblastoma therapy with a recombinant Newcastle disease virus harboring the PTEN gene.

Abstract

e15185 Background: Glioblastoma (GBM), a highly aggressive brain tumor, is challenging to treat due to its resistance to conventional therapies and the restrictive nature of the blood-brain barrier (BBB). Loss or dysfunction of the tumor suppressor PTEN, prevalent in approximately 40% of GBM cases, contributes to tumor progression via activation of the PI3K/AKT/mTOR pathway. Newcastle disease virus (NDV), an intrinsic oncolytic virus, demonstrates the unique ability to penetrate the BBB and selectively target tumor cells. Methods: A recombinant NDV encoding the human PTEN gene (rNDV-PTEN) was developed to enhance therapeutic efficacy. PTEN was strategically inserted between the NP and P genes of the NDV genome for optimal expression. In vitro and in vivo studies evaluated rNDV-PTEN’s capacity to restore PTEN expression, inhibit tumor growth, and cross the BBB. Human GBM cell lines (e.g., U87-MG) and an orthotopic mouse model were used for functional analyses, including proliferation, migration, apoptosis, and tumor burden assessments. Results: rNDV-PTEN successfully delivered the PTEN gene to GBM cells, resulting in significant PTEN protein expression and restoration of its tumor suppressor function. This restoration inhibited tumor growth by suppressing the PI3K/AKT/mTOR pathway. In vitro, rNDV-PTEN treatment reduced GBM cell proliferation and migration while inducing apoptosis. In vivo, intravenous administration of rNDV-PTEN demonstrated efficient BBB penetration, leading to localized PTEN delivery, significant tumor size reduction, and improved survival in GBM-bearing mice. MRI and histopathological evaluations confirmed these effects. Notably, rNDV-PTEN exhibited specificity for tumor cells, leaving normal astrocytes unaffected. Conclusions: This study highlights the potential of rNDV as a delivery vehicle capable of crossing the BBB and selectively targeting GBM. The combination of NDV’s intrinsic oncolytic properties and PTEN’s tumor-suppressive functions offers a promising therapeutic strategy for treating PTEN-deficient GBM.