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: 10524601
• 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/10524601
• 关键词: Adrenergic Agents; Award; Bilateral; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cell Line; 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; Plant Roots; 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-infiltrating immune cells; Universities; Vocational Guidance; Work; base; cancer cell; career; chromatin immunoprecipitation; clinically actionable; clinically relevant; epigenomics; experience; high risk; immune checkpoint blockade; immunogenic; improved; improved outcome; in vivo; inhibitor; mortality; mouse model; neuroblastoma cell; novel; overexpression; prevent; 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.

项目摘要和摘要 这项拟议的五年培训计划的目标是促进申请者 作为一名儿科肿瘤学家，独立研究生涯专注于利用炎症感知途径来 改进儿童实体瘤的免疫治疗。应聘者已经完成了严格的临床培训课程 并有雄厚的研究基础。短期内，他将从获得研究技能的培训中受益 研究转录调控，研究免疫活性的神经母细胞瘤小鼠模型，并分析 肿瘤免疫微环境。他的这个奖项的导师是著名的癌症生物学家迟当博士，他的 研究转录调控的专业知识，以及神经母细胞瘤的世界领先者Michael Hogarty博士 研究。为了增加广泛的科学专业知识并提供额外的职业指导，他已经组建了一个 由来自不同领域和互补领域的科学家组成的指导委员会。沃尔帕博士将从中受益 从费城儿童医院提供的丰富资源和机会中， 宾夕法尼亚州和维斯塔尔学院。 拟开展的研究重点是研究炎症感受性cGAS-STING的调控 神经母细胞瘤促进间充质状态神经母细胞瘤免疫靶向的途径。 神经母细胞瘤是由肾上腺素能(NBLADR)状态的细胞组成的，在诊断和 NBLMES状态，最初是一个较小的亚群，但却是复发的驱动因素。沃尔帕博士之前的研究表明 NBLMES细胞在体外和体内的基线水平具有更高的炎症信号水平，并且更具反应性 对一些炎性刺激，这表明这一关键人群的独特免疫脆弱性。他目前的情况 Proposal利用这些发现，将重点放在临床相关的炎症感应cGAS-STING上 路径。这一途径通过广泛激活炎症信号来响应胞浆DNA，是必需的 对于放射治疗的免疫原性反应，包括局部放射时的协同和全身效应 与免疫检查站封锁相结合。他的初步数据支持这样一种假设，即 CGAS-STING将使NBLMES细胞容易受到免疫放射治疗的影响。为了检验这一假说，Dr。 Wolpaw将追求两个特定的目标：1)阐明NBLADR/NBLMES状态对转录的影响 CGAS-STING的调控和2)确定恢复的cGAS表达对辐射反应的影响。 总之，这些目标将促进我们对像cGAS-sting这样的炎症传感器是如何 神经母细胞瘤中的调控，以及它们的操作如何促进肿瘤-免疫相互作用。这将为 为改善神经母细胞瘤的免疫疗法提供基础，并提供所需的培训和经验 将Wolpaw博士转变为一名独立的内科科学家。