Targeting vulnerabilities of PPM1D-mutant gliomas

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。

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.