PDTM-22. TARGETING A NOVEL METABOLIC DEFECT IN PPM1D-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMAS

Somatic truncating mutations within the oncogenic phosphatase PPM1D, have been identified in diffuse intrinsic pontine glioma (DIPG) and other high grade pediatric brain tumors. These stabilizing mutations result in an overabundance of the mutant protein within tumor cells, and inactivation of important DNA damage response (DDR) and cell cycle checkpoint targets. Despite our current understanding of these mutations, there exists no viable therapeutically viable strategy for the treatment of PPM1D-mutant tumors. Therefore, we sought to further explore the oncogenic potential of these truncating mutations, and to identify selective inhibitors of mutant DIPGs. Using isogenic astrocyte pairs with containing engineered-PPM1D mutations, we characterized the phenotypic effects of these genetic alterations on DDR and DNA repair processes. We identified numerous DNA repair defects that likely can be exploited for a therapeutic gain, including accelerated gH2AX dephosphorylation, which correlated with despite an intact 53BP1 DNA damage response (DDR), which correlated with intrinsic radiosensitivity. We then performed a small molecule screen with inhibitors of DDR-related proteins to identify novel synthetic lethal pathways in PPM1D-mutant DIPGs. These studies revealed an unexpected, clinically actionable target in PPM1D-mutant cells, involved in global cellular metabolism. This induced sensitivity was detected using multiple drugs targeting the same pathway, and was exquisitely selective, with a 104 –fold difference in sensitivity between mutant and wild type cells. Further, upon testing these compounds against patient-derived, PPM1D-mutant DIPG neurospheres, we again found remarkable levels of sensitivity, demonstrating their effects in relevant preclinical models. We will present the mechanistic basis for this described synthetic lethality, which implicates key epigenetic alterations and gene expression changes, ultimately resulting in the described metabolic defect. Overall, our novel discovery provides exciting new insights into the biology of PPM1D mutations and the treatment of these devastating pediatric diseases.