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Uncovering Therapeutic Targets in Pediatric High Grade Gliomas with the H3K27M Mutation

发现具有 H3K27M 突变的儿童高级别胶质瘤的治疗靶点

基本信息

批准号：
10238927
负责人：
David Daniels
金额：
$ 17.78万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10238927
关键词：
Affect Amino Acids Apoptosis Award Basic Science Brain Brain Neoplasms Cell Cycle Cell Death Cell Line Cells Cessation of life Child Childhood Brain Neoplasm Childhood Glioma Clinical Clinical Trials Development Development Plans Diagnosis Diffuse intrinsic pontine glioma Disease Doctor of Philosophy Drug Targeting Epigenetic Process FDA approved Foundations Gene Expression Genes Genetic Engineering Glioma Goals H3 K27M mutation Health Histone H3 Histones Human In Vitro Institution Lead Life Lysine Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Mentors Methionine Mission Molecular Mutation Neurosurgeon Pathologic Pathway interactions Patients Pattern Phenotype Physicians Primary Brain Neoplasms Principal Investigator Prognosis Proteins Public Health Radiosensitization Regimen Research Research Support STAT3 gene Scientist Signal Pathway Signal Transduction Somatic Mutation Techniques Testing Therapeutic Training Translating Translational Research Tumor Cell Line United States National Institutes of Health Xenograft Model Xenograft procedure cancer cell career career development clinically relevant efficacy evaluation genome-wide histone methylation improved in vivo inhibitor/antagonist methylation pattern molecular targeted therapies mouse model neoplastic cell nerve stem cell neuro-oncology neurosurgery novel therapeutics pediatric patients research and development research clinical testing small hairpin RNA stem-like cell success therapeutic target treatment strategy tumor tumorigenesis

项目摘要

Project Summary In children, tumors affecting the brain result in more cancer-related deaths than any other type of tumor. It is thus critical to identify new therapies. Among pediatric patients, one of the most devastating brain tumor types is Diffuse Intrinsic Pontine Gliomas (DIPG). Our understanding of this deadly disease has recently been advanced by important discoveries, including the finding that the majority of DIPG tumors harbor the histone H3K27M mutation. This mutation results in global hypomethylation of H3K27 residues and is the pathological hallmark for this disease. The applicant has discovered that Wnt5a and STAT3 signaling are critically important for proliferation and survival of H3K27M tumors and inhibiting these pathways restores the reduced H3K27 methylation patterns and leads to tumor cell death. This project aims to further understand how STAT3 is critical for H3K27M tumors and validate STAT3 as a drug target in DIPG tumors. A further goal is to develop additional pediatric patient derived high grade glioma xenografts and cell lines. These techniques will be generalizable to other molecular drivers of tumorigenesis in malignant brain tumors. The proposed research is significant because it is expected to vertically advance therapeutic options for treating DIPG tumors. The candidate is an MD/PhD trained neurosurgeon-scientist with advanced clinical training in pediatric brain tumors whose career goal is to advance treatment strategies for malignant brain tumors through basic and translational research. The career development plan and research will be mentored by Dr. Jann Sarkaria, a physician-scientist whose research goals are in alignment with the candidate. This proposal combines the strengths of the candidate, the mentors, and the research institution in order to provide an opportunity for the candidate to become a successful independent neurosurgeon-scientist.

项目总结