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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：
10337234
负责人：
Pratiti Bandopadhayay
金额：
$ 40.36万
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/10337234
关键词：
Address 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 Damage DNA Repair Gene DNA biosynthesis DNA damage checkpoint Data Dependence Development Diagnosis Endometrial Carcinoma Event FRAP1 gene Genetic Glioma Gliomagenesis Growth Factor Histones Human Immunoprecipitation In Vitro Induced Mutation Lead MDM2 gene Malignant Neoplasms Mass Spectrum Analysis Mitogen-Activated Protein Kinases Modeling Mutation Oncogenic PIK3CA gene PPM1D gene Pathway interactions Patients Peptide Hydrolases Process Protein phosphatase Proteins Radiation Recurrence Reporter Role Secondary to Signal Transduction 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/摘要弥漫性中线胶质瘤(DMGs)是儿童时期的破坏性脑瘤，目前尚无有效治疗方法。我们和其他人观察到，高达15%的DMG在编码Wip1的PPM1D中存在激活突变蛋白质磷酸酶。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癌症。PPM1D已经被很好地记录下来，以调节DNA损伤反应中的重要途径，包括TP53。我们发现PPM1D突变足以促进胶质瘤的形成和PPM1D 对于持续的增殖是必要的，提名PPM1D作为儿童的潜在治疗靶点 PPM1D-突变DMGs。这项提案中概述的实验将剖析通过 PPM1D突变会导致肿瘤形成，并将识别与这些过程相关的脆弱性，这些过程可以作为治疗的靶点。这些实验的结果将与患有PPM1D突变的儿童相关 DMGs，此外还有更多患有PPM1D突变癌症的患者。