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.
Recurrent, truncating driver mutations of PPM1D, the gene encoding the WIP1 protein phosphatase, occur across a range of human cancers, including Diffuse Midline Gliomas (DMG), a devastating brain tumor of childhood. We will evaluate the mechanisms through which PPM1D mutations drive tumor formation and will determine strategies to therapeutically target them. The results generated in this proposal will inform the development of precision medicine approaches for children with DMG, and will be relevant to thousands of other patients diagnosed with PPM1D-mutant tumors including leukemia and endometrial cancers.