Combinatorial Effects of VEGFR Kinase Inhibitor Axitinib and Oncolytic Virotherapy in Mouse and Human Glioblastoma Stem-Like Cell Models

• Published in: Clinical cancer research Vol. 24; no. 14; pp. 3409 - 3422
• Main Authors: Saha, Dipongkor, Wakimoto, Hiroaki, Peters, Cole W, Antoszczyk, Slawomir J, Rabkin, Samuel D, Martuza, Robert L
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 15.07.2018
• Subjects: Angiogenesis; Animal models; Animals; Antiangiogenics; Anticancer properties; Antineoplastic Agents, Immunological - pharmacology; Antitumor activity; Axitinib - pharmacology; Brain; Brain tumors; Cancer; Cell culture; Cell Line, Tumor; Combinatorial analysis; Combined Modality Therapy; Cytotoxicity; Cytotoxicity, Immunologic; Disease Models, Animal; Effectiveness; Enzyme inhibitors; Experimental design; Extracellular signal-regulated kinase; Forming; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - mortality; Glioblastoma - pathology; Glioblastoma - therapy; Herpes simplex; Humans; Immune checkpoint inhibitors; Immunodeficiency; Immunohistochemistry; Infiltration; Inhibition; Inhibitors; Interleukin 1; Interleukin 12; Interleukin-12 - genetics; Interleukin-12 - metabolism; Lymphocytes T; Macrophages; Metabolic pathways; Metastases; Mice; Necrosis; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - therapy; Oncolysis; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Signal Transduction; Survival; Therapy; Tubes; Tumor Microenvironment; Tumors; Tyrosine; Vascular endothelial growth factor receptors; Viruses; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-17-1717

Glioblastoma (GBM), a fatal brain cancer, contains a subpopulation of GBM stem-like cells (GSCs) that contribute to resistance to current therapy. Angiogenesis also plays a key role in GBM progression. Therefore, we developed a strategy to target the complex GBM microenvironment, including GSCs and tumor vasculature. We evaluated the cytotoxic effects of VEFGR tyrosine kinase inhibitor (TKI) axitinib and then tested antitumor efficacy of axitinib in combination with oncolytic herpes simplex virus (oHSV) expressing antiangiogenic cytokine murine IL12 (G47Δ-mIL12) in two orthotopic GSC-derived GBM models: patient-derived recurrent MGG123 GSCs, forming vascular xenografts in immunodeficient mice; and mouse 005 GSCs, forming syngeneic tumors in immunocompetent mice. GSCs form endothelial-like tubes and were sensitive to axitinib. G47Δ-mIL12 significantly improved survival, as did axitinib, while dual combinations further extended survival significantly compared with single therapies alone in both models. In MGG123 tumors, axitinib was effective only at high doses (50 mg/kg), alone and in combination with G47Δ-mIL12, and this was associated with greatly decreased vascularity, increased macrophage infiltration, extensive tumor necrosis, and PDGFR/ERK pathway inhibition. In the mouse 005 model, antiglioma activity, after single and combination therapy, was only observed in immunocompetent mice and not the T-cell-deficient athymic mice. Interestingly, immune checkpoint inhibition did not improve efficacy. Systemic TKI (axitinib) beneficially combines with G47Δ-mIL12 to enhance antitumor efficacy in both immunodeficient and immunocompetent orthotopic GBM models. Our results support further investigation of TKIs in combination with oHSV for GBM treatment. .