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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要小儿癌症是儿童疾病相关死亡的主要原因，但很少有药物专门针对小儿癌症被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治疗结果，这是我们的长期目标。具体来说，弥漫性儿科高级神经胶质瘤 (pHGG) 对多模式治疗具有抵抗力，并且目前还没有 FDA 批准的新药物过去20年来，这些肿瘤患者迫切需要新颖、有效的治疗策略。异常剪接有助于新表位的形成，代表一类尚未开发的靶向遗传基因 pHGG 中很大程度上尚未探索的改变。我们这个研究计划的中心假设是异常的剪接事件可以在 pHGG 中产生肿瘤特异性新表位，并且可以快速利用这些数据并优先考虑治疗目标。拟议的工作将通过两个集成的特定目的：1) 识别 pHGG 中假定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并验证免疫治疗剪接目标临床前测试。这些研究将转录剪接事件与肿瘤组织表达整合起来（PBTA 和 Kids First X01）、正常组织表达（GTEx 和可用的儿科匹配组织正常值）、肽序列 (UniProt) 和已知的胞外域注释 (UniProt) 来识别和确定优先级 pHGG 中产生新表位。这项工作将阐明新型剪接驱动的免疫治疗靶点通过对 pHGG 肿瘤中剪接变异的严格综合计算分析，结合正交分子测定，以验证这些靶标的存在和表达。顺利完成该项目的研究将产生关于 pHGG 中异常剪接程序的重要新知识，并将确定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剪接到儿科癌症，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，并将作为其他新表位研究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推进科学知识并确定提高癌症患者总体生存率的新策略。