oHSV therapy increases trametinib access to brain tumors and sensitizes them in vivo

oHSV therapy increases trametinib access to brain tumors and sensitizes them in vivo

Yoo Ji Young; Swanner Jessica; Otani Yoshihiro; Nair Mitra; Park Flora; Banasavadi-Siddegowda Yeshavanth; Liu Joseph; Jaime-Ramirez Alena Cristina; Hong Bangxing; Geng Feng; Guo Deliang; Bystry Darlene; Pelphs Mitch; Quadri Haroon; Lee Tae Jin; Kaur Balveen

Neuro-Oncology

2019

2019-05

BACKGROUND: Hyperactivation of the RAS-RAF-MEK-ERK signaling pathway is exploited by glioma cells to promote their growth and evade apoptosis. MEK activation in tumor cells can increase replication of ICP34.5-deleted HSV-1 viruses, but paradoxically its activation in tumor-associated macrophages promotes a pro-inflammatory signaling that can inhibit virus replication and propagation. Here we investigated effect of blocking MEK signaling in conjunction with oncolytic HSV-1 (oHSV) for brain tumors. METHODS: Infected glioma cells co-cultured with microglia or macrophages treated with or without trametinib were used to test trametinib effect on macrophages/microglia. ELISA, western blotting, and flow cytometry were utilized to evaluate the effect of the combination therapy. Pharmacokinetic (PK) analysis of mouse plasma and brain tissue was used to evaluate trametinib delivery to the CNS. Intracranial human and mouse glioma-bearing immune deficient and immune competent mice were used to evaluate the anti-tumor efficacy. RESULT: oHSV treatment rescued trametinib-mediated feed-back reactivation of the MAPK signaling pathway in glioma. In vivo, PK analysis revealed enhanced blood-brain barrier penentration of trametnib after oHSV treatment. Trametinib, a MEK Kinase inhibitor, treatment led to a significant reduction in microglia- and macrophage-derived TNFα secretion in response to oHSV-treatment and increased survival of glioma-bearing mice. Despite the reduced TNFα production observed in vivo, the combination treatment activated CD8+ T cell-mediated immunity, and increased survival in a glioma-bearing immune-competent mouse model. CONCLUSION: This study provides a rationale for combining oHSV with trametinib for the treatment of brain tumors.

glioblastoma (GBM); oncolytic herpes simplex virus-1 (oHSV); RAS-RAF-MEK-ERK signaling; Trametinib; Tumor necrosis factor α (TNFα)

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