Targeting Acid Ceramidase to Improve the Efficacy of Herpes Oncolytic Virus

靶向酸性神经酰胺酶提高疱疹溶瘤病毒的功效

基本信息

批准号：
10509476
负责人：
Anita Borton Hjelmeland
金额：
$ 14.11万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509476
关键词：
Active Sites Adult Glioblastoma Apoptosis Apoptotic Award Binding Blood - brain barrier anatomy Brain Brain Neoplasms Cell Death Cells Ceramidase Ceramides Chemoresistance Childhood Glioma Clinical Clinical Trials Combined Modality Therapy Cross Presentation Data Development Disease Engineering Enzymes Equilibrium Excision Future G207 Gene Deletion Genetic Glioblastoma Glioma Goals Growth Herpesviridae Herpesvirus 1 Hydrolysis Immune Immunocompetent Immunosuppression Immunotherapy In Vitro Infection Infection prevention Infiltration Journals Knockout Mice Knowledge Laboratories Malignant Neoplasms Malignant neoplasm of brain Mediating Medicine Metabolism Microglia Modeling Multivesicular Body Mus Neurodegenerative Disorders New England Normal Cell Oncolytic Oncolytic viruses Operative Surgical Procedures Patients Pharmacology Phase Play Production Publishing Radiation therapy Radio Recurrence Reporting Research Resistance Role SPHK1 enzyme Signal Pathway Signal Transduction Sphingolipids Sphingosine Testing The Cancer Genome Atlas Therapeutic Toxic effect Tumor Antigens Viral Virus Work base cancer type cell growth cell type chemokine experimental study galactosylgalactosylglucosylceramidase immunogenic immunotherapeutic virotherapy improved inhibitor knock-down macrophage neoplastic cell nerve stem cell neurovirulence novel patient derived xenograft model phase II trial prevent programs protein kinase R radiation resistance radioresistant recruit response sphingosine 1-phosphate standard of care stem-like cell temozolomide therapeutically effective translational research program treatment strategy tumor tumor metabolism tumor microenvironment tumorigenic

项目摘要

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.

项目概要/摘要鞘脂代谢失调与神经退行性疾病和癌症有关，但神经酰胺和 1 磷酸鞘氨醇之间的平衡，对于调节细胞命运（鞘脂）至关重要变阻器在神经干细胞或脑肿瘤方面的研究较少。神经酰胺可以被神经酰胺酶转化为鞘氨醇，然后可被鞘氨醇激酶 1 转化为 1-磷酸鞘氨醇。转向 1-磷酸鞘氨醇的产生可能使细胞逃避细胞凋亡，而转向神经酰胺可能会导致细胞死亡。有利于细胞死亡。在致命的脑肿瘤胶质母细胞瘤 (GBM) 中，鞘脂平衡向 1-磷酸鞘氨醇可由酸性神经酰胺酶 (ASAH1) 介导。 ASAH1 在 GBM 中高表达，包括放射和化学抗性神经干细胞样脑肿瘤起始细胞。 ASAH1 抑制剂增加促凋亡神经酰胺并阻止某些癌症类型的进展。支持潜力在针对 ASHA1 进行抗 GBM 治疗时，我们新的初步数据表明，血脑屏障渗透性 ASAH1 抑制剂卡莫氟 (carmofur) 与 ASAH1 敲除一样，可减少 BTIC 细胞生长。最近的一份报告使用Asah1基因敲除小鼠也证明巨噬细胞中的酸性神经酰胺酶可以抑制疱疹病毒传播。免疫病毒疗法，特别是溶瘤疱疹病毒（oHSV），已被证明具有显着的疗效临床试验中儿童高级别胶质瘤的生存率得到改善。不幸的是，同样的程度在成人 GBM 中尚未观察到反应。总之，这些数据表明 ASAH1 的靶向可能提高 oHSV 疗效。因此，我们将确定 ASAH1 的遗传或药物抑制是否会增加 oHSV 介导的源自亲本和替莫唑胺耐药患者的 BTIC 细胞死亡异种移植物。我们还将探讨针对肿瘤中的 ASAH1 是否有额外的好处微环境通过对神经胶质瘤相关巨噬细胞/小胶质细胞的影响。我们预计这些研究这里提出的建议将提供关键的初步数据来支持更大的研究计划，以确定是否改变鞘脂变阻器是改善 GBM 免疫病毒治疗的有效治疗策略。