cGAS-STING and therapeutic immune responses in neuroblastoma

cGAS-STING 和神经母细胞瘤的治疗性免疫反应

• 批准号: 10685532
• 负责人: Adam J Wolpaw
• 金额: $ 21.13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10685532
• 关键词: Adrenergic Agents; Award; Bilateral; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cell Line; Cell Survival; Cells; Chemoresistance; Childhood Solid Neoplasm; Chromatin; Clinical; Complex; Contralateral; DNA; DNA Methylation; DNA Methylation Inhibition; Data; Development; Diagnosis; Drug Targeting; EZH2 gene; Epigenetic Process; Fostering; Foundations; Future; Genes; Goals; Growth; Human; Immune; Immune Targeting; Immune response; Immunity; Immunocompetent; Immunodeficient Mouse; Immunotherapeutic agent; Immunotherapy; Implant; In Vitro; Inflammatory; Inflammatory Response; Knock-out; Learning; Malignant Neoplasms; Measures; Mediating; Mentors; Mesenchymal; Methylation; Minor; Modeling; Mus; Neuroblastoma; Outcome; Pathway interactions; Patients; Pediatric Hospitals; Pediatric Oncologist; Pennsylvania; Philadelphia; Physicians; Population; Positioning Attribute; Predisposition; Radiation; Radiation Induced DNA Damage; Radiation therapy; Regulation; Relapse; Reporting; Repression; Research; Resources; Scientist; Signal Transduction; Stimulator of Interferon Genes; Stimulus; Target Populations; Testing; The Wistar Institute; Training; Training Programs; Transcriptional Regulation; Treatment Efficacy; Treatment Failure; Tumor Promotion; Universities; Vocational Guidance; Work; cancer cell; career; chromatin immunoprecipitation; clinical training; clinically actionable; clinically relevant; education planning; epigenomic profiling; epigenomics; experience; high risk; immune cell infiltrate; immune checkpoint blockade; immunogenic; improved; improved outcome; in vivo; inhibitor; mortality; mouse model; neuroblastoma cell; novel; overexpression; prevent; promoter; radiation response; refractory cancer; response; restoration; sensor; skills; subcutaneous; synergism; therapeutic target; transcription factor; translational study; tumor; tumor-immune system interactions

PROJECT SUMMARY AND ABSTRACT The goal of this proposed five-year training program is to foster the development of the applicant's independent research career as a pediatric oncologist focused on exploiting inflammatory sensing pathways to improve immunotherapy in pediatric solid tumors. The candidate has completed a rigorous clinical training course and has a strong research foundation. In the short term, he will benefit from training to obtain research skills to study transcriptional regulation, work with immunocompetent mouse models of neuroblastoma, and analyze the tumor immune microenvironment. His mentors for this award are Dr. Chi Dang, an eminent cancer biologist with expertise in studying transcriptional regulation, and Dr. Michael Hogarty, a world-wide leader in neuroblastoma research. To add broad scientific expertise and provide additional career guidance, he has assembled a Mentoring Committee composed of scientists from diverse and complementary fields. Dr. Wolpaw will benefit from the rich resources and opportunities available at The Children's Hospital of Philadelphia, the University of Pennsylvania, and the Wistar Institute. The proposed research focuses on investigating the regulation of the inflammatory sensing cGAS-STING pathway in neuroblastoma to promote immune-targeting of mesenchymal state neuroblastoma (NBLMES). Neuroblastomas are composed of cells in an adrenergic (NBLADR) state that predominate at diagnosis and a NBLMES state that is initially a minor subpopulation but is a driver of relapse. Dr. Wolpaw's prior work shows that NBLMES cells have higher levels of inflammatory signaling at baseline in vitro and in vivo and are more responsive to some inflammatory stimuli, suggesting a unique immune vulnerability of this critical population. His current proposal capitalizes on these findings by focusing on the clinically relevant inflammatory sensing cGAS-STING pathway. This pathway responds to cytosolic DNA by broadly activating inflammatory signaling and is required for an immunogenic response to radiation therapy, including synergistic and systemic effects when local radiation is combined with immune checkpoint blockade. His preliminary data support the hypothesis that restoration of cGAS-STING will render NBLMES cells vulnerable to immuno-radiation therapy. To test this hypothesis, Dr. Wolpaw will purse two specific aims: 1) Elucidate the impact of NBLADR/NBLMES state on the transcriptional regulation of cGAS-STING and 2) Define the effect of restored cGAS expression on the response to radiation. Together, these aims will advance our understanding of how inflammatory sensors like cGAS-STING are regulated in neuroblastoma and how their manipulation can promote tumor-immune interactions. This will lay the foundation for improved immunotherapies in neuroblastoma and provide the training and experience needed to transition Dr. Wolpaw into an independent physician scientist.

项目总结和摘要 这项拟议的五年培训计划的目标是促进申请人的发展， 作为儿科肿瘤学家的独立研究生涯，专注于利用炎症传感途径， 改善儿科实体瘤免疫治疗。候选人已完成严格的临床培训课程 有很强的研究基础。在短期内，他将受益于培训，以获得研究技能， 研究转录调控，与神经母细胞瘤的免疫活性小鼠模型合作，并分析 肿瘤免疫微环境他的导师是著名的癌症生物学家， 在研究转录调控的专业知识，和博士迈克尔Hogarty，在神经母细胞瘤的世界范围内的领导者， research.为了增加广泛的科学专业知识，并提供额外的职业指导，他组建了一个 指导委员会由来自不同和互补领域的科学家组成。沃泊博士将受益于 从费城儿童医院丰富的资源和机会， 宾夕法尼亚州和Wistar研究所。 拟议的研究重点是调查炎症传感cGAS-STING的调节 神经母细胞瘤中的免疫通路，以促进间充质状态神经母细胞瘤（NBLMES）的免疫靶向。 神经母细胞瘤由肾上腺素能（NBLADR）状态的细胞组成，在诊断时占主导地位， NBLMES指出，最初是一个较小的亚群，但却是复发的驱动因素。沃泊博士之前的工作表明， NBLMES细胞在体外和体内基线时具有更高水平的炎症信号传导， 一些炎症刺激，这表明一个独特的免疫脆弱性，这一关键群体。他现在的 该提案通过关注临床相关的炎症传感cGAS-STING来利用这些发现 通路该途径通过广泛激活炎症信号传导对胞质DNA作出反应， 对于放射治疗的免疫原性反应，包括局部放射治疗时的协同和全身效应， 与免疫检查点封锁相结合。他的初步数据支持这一假设， cGAS-STING将使NBLMES细胞易受免疫放射治疗的影响。为了验证这个假设，博士。 Wolpaw的目标有两个：1）阐明NBLADR/NBLMES状态对转录水平的影响， cGAS-STING的调节和2）定义恢复的cGAS表达对辐射响应的影响。 总之，这些目标将促进我们对cGAS-STING等炎症传感器如何影响炎症的理解。 在神经母细胞瘤中的调节以及它们的操纵如何促进肿瘤免疫相互作用。这将奠定 改善神经母细胞瘤免疫疗法的基础，并提供所需的培训和经验， 将沃泊博士转变为独立的内科科学家