Discovery of neoepitope immunotherapeutic targets in diffuse pediatric high-grade gliomas

弥漫性儿童高级别胶质瘤中新表位免疫治疗靶点的发现

• 批准号: 10774404
• 负责人: Jo Lynne Rokita
• 金额: $ 35.6万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2024-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10774404
• 关键词: Acceleration; Biological; Biological Assay; Brain Neoplasms; Cancer Patient; Cause of Death; Cell Line; Cell Surface Proteins; Central Nervous System Neoplasms; Cessation of life; Child; Childhood; Childhood Brain Neoplasm; Childhood Glioma; Clinical; Combined Modality Therapy; Communities; Computer Analysis; Coupled; Data; Diagnosis; Diffuse; Disease; Epitopes; Event; Extracellular Domain; FDA approved; Genetic; Genetic Transcription; Genomics; Genotype-Tissue Expression Project; Glioma; Goals; Health; Histology; Immunotherapeutic agent; Immunotherapy; Investigation; Knowledge; Label; Malignant Childhood Neoplasm; Malignant Neoplasms; Mission; Modeling; Molecular; Mutation; National Cancer Institute; Normal tissue morphology; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Preclinical Testing; Proteins; Public Health; RNA Splicing; Research; Research Project Grants; Resistance; Role; Scientific Advances and Accomplishments; Testing; Time; Transcript; Tumor Tissue; United States National Institutes of Health; Validation; Variant; Work; cancer survival; data visualization; diffuse midline glioma; effective therapy; empowerment; evidence base; extracellular; glioma cell line; improved; improved outcome; in vitro testing; molecular subtypes; molecular targeted therapies; neoantigens; new therapeutic target; novel; novel strategies; novel therapeutic intervention; novel therapeutics; patient retention; precision medicine; programs; protein aminoacid sequence; therapeutic target; therapeutically effective; transcriptome; tumor; user-friendly; web app

PROJECT SUMMARY Pediatric cancer is the leading cause of disease-related death in children, yet very few drugs are specifically labeled for pediatric malignancies, underscoring a need to identify novel molecular therapeutic targets to improve outcomes for children with cancer, which is our long-term goal. Specifically, diffuse pediatric high- grade gliomas (pHGGs) are resistant to multi-modal treatment and have had no new FDA-approved drugs in the past 20 years, thus patients with these tumors are in urgent need of novel, effective therapeutic strategies. Aberrant splicing contributes to neoepitope formation and represents a class of untapped targetable genetic alterations that are largely unexplored in pHGG. Our central hypothesis of this research plan is that aberrant splicing events can result in tumor-specific neoepitopes in pHGGs and these data can be rapidly harnessed and prioritized for therapeutic targeting. The proposed work will test this hypothesis with two integrated specific aims: 1) identify putative immunotherapeutic subtype-specific splice targets in pHGGs and 2) characterize aberrant splice variation in pHGG preclinical models and validate immunotherapeutic splice targets for preclinical testing. These studies will integrate transcriptional splice events with tumor tissue expression (PBTA and Kids First X01), normal tissue expression (GTEx and available pediatric matched tissue normals), peptide sequences (UniProt), and known extracellular domain annotations (UniProt) to identify and prioritize neoepitopes generated in pHGGs. This work will elucidate novel splice-driven immunotherapeutic targets through rigorous integrative computational analysis of splice variation in pHGG tumors, coupled with orthogonal molecular assays, to validate presence and expression of these targets. The successful completion of this project will generate significant new knowledge of aberrant splicing programs in pHGG and will identify potential immunotherapeutic targets. This work is critical to understanding the genetic contributions of aberrant splicing to pediatric cancer, will enable the research and clinical communities to rationally inform novel immunotherapeutic strategies for pHGG, and will serve as a roadmap for investigation of neoepitopes in other pediatric brain tumors. This work is highly relevant to the critical mission of the National Cancer Institute to advance scientific knowledge and identify novel strategies to improve overall survival of cancer patients.

项目总结 儿童癌症是儿童疾病相关死亡的主要原因，但很少有药物是特效的。 标记为儿科恶性肿瘤，强调需要确定新的分子治疗靶点 改善癌症儿童的预后，这是我们的长期目标。具体地说，弥漫性儿科高- 级别胶质瘤(PHGGs)对多种模式的治疗具有抵抗力，并且在 在过去的20年里，这些肿瘤患者迫切需要新的、有效的治疗策略。 异常剪接有助于新表位的形成，代表了一类未开发的靶向基因 在PHGG中大部分未被勘探的蚀变。我们对这项研究计划的中心假设是 剪接事件可以在PHGG中产生肿瘤特异性新表位，这些数据可以快速利用 并优先用于治疗靶向。拟议的工作将用两个集成的具体实例来验证这一假设 目的：1)确定PHGGs中可能的免疫治疗亚型特异性剪接靶点；2)表征 PHGG临床前模型中的异常剪接变异和验证免疫治疗剪接靶点 临床前测试。这些研究将整合转录剪接事件和肿瘤组织表达(PBTA 和儿童第一个X01)，正常组织表达(GTEx和可用的儿童匹配组织正常)，肽 序列(UniProt)和已知的细胞外域注释(UniProt)，以识别和区分优先顺序 在PHGGS中产生的新表位。这项工作将阐明新的剪接驱动的免疫治疗靶点 通过对PHGG肿瘤剪接变异的严格综合计算分析， 正交分子分析，以验证这些靶点的存在和表达。圆满完成 将在PHGG中产生关于异常剪接程序的重要新知识，并将识别 潜在的免疫治疗靶点。这项工作对于理解异常基因的遗传贡献至关重要。 拼接到儿科癌症，将使研究和临床界能够合理地告知新的 PHGG的免疫治疗策略，并将作为研究新表位的路线图 儿童脑瘤。这项工作与国家癌症研究所的关键使命高度相关 发展科学知识和确定新的战略，以提高癌症患者的总体存活率。