Targeting Acid Ceramidase to Improve the Efficacy of Herpes Oncolytic Virus

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Dysregulated sphingolipid metabolism is associated with neurodegenerative disorders and cancer, but the balance between ceramides and sphingosine-1 phosphate that is critical for regulating cell fate, the sphingolipid rheostat, is less well-studied in neural stem cells or brain tumors. Ceramides can be converted by ceramidases to sphingosine, which can then be converted by sphingosine kinase 1 to sphingosine-1-phosphate. Shifts toward sphingosine-1-phosphate production may allow cells to evade apoptosis, while shifts toward ceramides may favor cell death. In the deadly brain tumor glioblastoma (GBM), a shift in the sphingolipid balance towards sphingosine-1-phosphate can be mediated by acid ceramidase (ASAH1). ASAH1 is highly expressed in GBM, including in the radio- and chemoresistant neural stem cell-like brain tumor initiating cells. ASAH1 inhibitors increased pro-apoptotic ceramides and blocked the progression of some cancer types. Supporting the potential of targeting ASHA1 for anti-GBM treatments, our novel preliminary data demonstrated that the blood brain barrier penetrant ASAH1 inhibitor, carmofur, reduced BTIC cell growth as did ASAH1 knockdown. A recent report using Asah1 knockout mice also demonstrated that acid ceramidase in macrophages inhibited herpes virus propagation. Immunovirotherapy, specifically oncolytic herpes virus (oHSV), has demonstrated significant improvement in survival for pediatric high-grade glioma in clinical trials. Unfortunately, the same extent of response has not been observed in adult GBM. Together, these data suggest that targeting of ASAH1 may improve oHSV efficacy. We will, therefore, determine if genetic or pharmacologic inhibition of ASAH1 increases oHSV-mediated cell death of BTICs derived from parental and temozolomide-resistant patient-derived xenografts. We will also explore whether there are additional benefits for targeting ASAH1 in the tumor microenvironment through effects on glioma associated macrophages/microglia. We anticipate that the studies proposed here will provide key preliminary data to support a larger research program to determine whether shifting the sphingolipid rheostat is an effective therapeutic strategy to improve immunovirotherapy in GBM.