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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.

项目总结