Targeting vulnerabilities of PPM1D-mutant gliomas

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。

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.