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.

项目摘要 小儿癌是儿童与疾病相关的主要原因，但很少有药物专门 标记为儿科恶性肿瘤，强调需要鉴定出新的分子治疗靶标的 改善癌症儿童的结果，这是我们的长期目标。具体而言，弥漫性小儿高 - 级别的神经胶质瘤（PHGGS）对多模式治疗有抵抗力，并且没有新的FDA批准药物 在过去的20年中，患有这些肿瘤的患者迫切需要新型，有效的治疗策略。 异常剪接有助于新EPITOPE形成，代表一类未开发的靶向遗传 在PHGG中基本未探索的变化。我们对该研究计划的中心假设是异常 剪接事件可能导致PHGG中的肿瘤特异性新EPITOP，这些数据可以迅速利用 并优先考虑治疗靶向。拟议的工作将用两个集成的特定特定于 目的：1）确定PHGG中的假定的免疫治疗性亚型特异性剪接目标，2）表征 PHGG临床前模型中异常的剪接变化并验证免疫治疗剪接目标 临床前测试。这些研究将将转录剪接事件与肿瘤组织表达（PBTA）相结合 和孩子的第一个X01），正常组织表达（GTEX和可用的小儿匹配的组织正常），肽 序列（UNIPROT）和已知的细胞外域注释（UNIPROT），以识别和优先级 phggs产生的新ePitopes。这项工作将阐明新型剪接驱动的免疫治疗目标 通过对PHGG肿瘤中剪接变化的严格整合计算分析，并与 正交分子测定，以证明这些靶标的存在和表达。成功完成 该项目将在PHGG中产生有关异常拼接程序的重要新知识，并将确定 潜在的免疫治疗靶标。这项工作对于理解异常的遗传贡献至关重要 小儿癌的剪接将使研究和临床社区能够合理地为新颖 PHGG的免疫治疗策略，并将作为调查其他新皮标的路线图 小儿脑肿瘤。这项工作与国家癌症研究所的关键使命高度相关 提高科学知识并确定改善癌症患者整体生存的新策略。