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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：
10097457
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/10097457
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 Diffuse 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 Structure TP53 gene Testing Therapeutic Ubiquitin Variant attenuation clinically relevant combinatorial curative treatments driver mutation experimental study genetic regulatory protein genome-wide in vivo in vivo Model inhibitor/antagonist 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.

项目总结/摘要弥漫性中线胶质瘤（DMG）是一种儿童期的破坏性脑肿瘤，目前尚无治愈性治疗。我们和其他人已经观察到高达15%的DMG在编码WIP 1的PPM 1D中具有激活突变蛋白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。癌的PPM 1D已被充分证明可调节DNA损伤反应中重要的途径，包括TP 53。我们已经发现PPM 1D突变足以增强胶质瘤的形成，对于持续的增殖是必要的，提名PPM 1D作为儿童的潜在治疗靶点， PPM 1D突变体DMG。本提案中概述的实验将剖析 PPM 1D突变诱导肿瘤形成，并将识别与这些过程相关的漏洞，可以作为治疗靶点。这些实验的结果将与PPM 1D突变的儿童相关 DMG，除了更大的携带PPM 1D突变型癌症的患者人群之外。