Targeting vulnerabilities of PPM1D-mutant gliomas

针对 PPM1D 突变神经胶质瘤的脆弱性

基本信息

批准号：
10570220
负责人：
Pratiti Bandopadhayay
金额：
$ 39.55万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570220
关键词：
Affect Apoptosis Attenuated Biological Assay Biological Models CHEK1 gene CHEK2 gene CRISPR/Cas technology Cell Cycle Arrest Cell Cycle Checkpoint Cells Child Childhood Brain Neoplasm Childhood Glioma Coupling DNA DNA Damage DNA Repair Gene DNA damage checkpoint Data Dependence Development Diagnosis Endometrial Carcinoma Event FRAP1 gene Genes Genetic Glioma Gliomagenesis Growth Factor Histones Human Immunoprecipitation In Vitro Induced Mutation MDM2 gene Malignant Neoplasms Mass Spectrum Analysis Mitogen-Activated Protein Kinases Modeling Mutation Oncogenes Oncogenic PIK3CA gene PPM1D gene Pathway interactions Patients Peptide Hydrolases Process Proliferating Protein phosphatase Proteins Radiation Recurrence Reporter Role Secondary to Signal Pathway Signal Transduction Stress TP53 gene Testing Therapeutic Ubiquitin Variant attenuation clinically relevant combinatorial curative treatments diffuse midline glioma driver mutation experimental study genetic regulatory protein genome-wide in vivo in vivo Model inhibitor insight leukemia mutant nerve stem cell optimism p38 Mitogen Activated Protein Kinase patient population phosphoproteomics precision medicine protein degradation replication stress response stem cell model therapeutic target tumor whole genome

项目摘要

Project Summary/Abstract Diffuse midline gliomas (DMGs) are devastating brain tumors of childhood with no curative treatments. We and others have observed up to 15% of all DMGs to harbor activating mutations in PPM1D which encodes the WIP1 protein phosphatase. Similar mutations are also observed in other cancers, including leukemias and endometrial cancers. PPM1D has been well-documented to regulate pathways important in DNA-damage responses, including TP53. We have found PPM1D mutations to be sufficient to enhance glioma formation and for PPM1D to be necessary for ongoing proliferation, nominating PPM1D as a potential therapeutic target for children with PPM1D-mutant DMGs. The experiments outlined in this proposal will dissect the mechanisms through which PPM1D mutations induce tumor formation and will identify vulnerabilities associated with these processes that can be therapeutically targeted. The results of these experiments will be relevant to children with PPM1D-mutant DMGs, in addition to a larger population of patients who harbor PPM1D-mutant cancers.

项目摘要/摘要弥漫性中线神经胶质瘤（DMG）是毁灭性的儿童脑肿瘤，没有治疗性治疗。我们和其他人则观察到所有DMG的15％以携带PPM1D中的激活突变，该突变编码WIP1 蛋白质磷酸酶。在其他癌症中也观察到类似的突变，包括白血病和子宫内膜癌症。 PPM1D已有充分记录在调节DNA破坏反应中重要的途径，包括TP53。我们发现PPM1D突变足以增强神经胶质瘤的形成和PPM1D 要持续扩散是必要的，将PPM1D提名为 PPM1D突变DMG。该提案中概述的实验将阐明 PPM1D突变会诱导肿瘤形成，并将确定与这些过程相关的漏洞可以针对治疗。这些实验的结果将与PPM1D突变的儿童有关 DMG，除了携带PPM1D突变癌的患者群体外。