Targeting vulnerabilities of PPM1D-mutant gliomas

针对 PPM1D 突变神经胶质瘤的脆弱性

• 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
• 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

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/文摘