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

项目摘要 儿童癌症是儿童疾病相关死亡的主要原因，但很少有药物专门用于治疗儿童癌症。 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。尤其是弥漫性小儿高- 分级胶质瘤（pHGG）对多模式治疗具有耐药性，并且没有FDA批准的新药， 因此，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，并代表了一类未开发的靶向遗传修饰。 这些变化在pHGG中很大程度上未被探索。我们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，并且可以快速利用这些数据 并优先用于治疗靶向。拟议的工作将测试这一假设与两个集成的具体 目的：1）鉴定pHGG中假定的免疫缺陷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 临床前测试这些研究将整合转录剪接事件与肿瘤组织表达（PBTA 和Kids First X 01）、正常组织表达（GTEx和可用的儿科匹配组织正常）、肽 序列（UniProt）和已知的细胞外结构域注释（UniProt），以识别和优先化 在pHGG中产生的新表位。这项工作将阐明新的剪接驱动的免疫靶点 通过对pHGG肿瘤中剪接变异的严格综合计算分析， 正交分子测定，以验证这些靶标的存在和表达。圆满完成 该项目的研究将产生pHGG中异常剪接程序的重要新知识，并将确定 潜在的免疫靶点这项工作对于理解异常的遗传贡献是至关重要的。 剪接到儿科癌症，将使研究和临床社区合理地告知新的 pHGG的免疫策略，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， 推进科学知识和确定新的策略，以提高癌症患者的总体生存率。

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.