CSIG-13. TARGETING GENETIC DEPENDENCIES EXPOSES DIFFUSE MIDLINE GLIOMA CELL OF ORIGIN VULNERABILITIES

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Abstract Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), are uniformly fatal brain cancers affecting children, adolescents, and young adults. These tumors are characterized by ‘oncohistone’ mutations in histone H3 genes (H3F3A, HIST1H3B, HIST1H3C), resulting in the substitution of lysine 27 to methionine (H3K27M), resulting in dominant negative hypomethylation at lysine 27 (H3K27) and a global loss of gene silencing. CRISPR-Cas9 loss-of-function gene deletion screens identified mutation-independent dependencies on PIK3CA and MTOR genes for tumor growth and proliferation, highlighting a targetable molecular dependency across DMG patient-derived models (n=38). However, systemic PI3K/mTOR inhibition increased blood glucose and insulin levels, promoting hyperinsulinemia/hyperglycemia and reduced efficacy in vivo. To exploit genetic dependencies while maintaining compliance and therapeutic benefit, we optimized combinations of clinically relevant PI3K inhibitors (paxalisib, GCT007, everolimus) with the antiglycemic drug metformin to restore glucose homeostasis and decrease DMG insulin receptor activity in vivo, extending the survival of DIPG xenograft models. Phosphoproteomic profiling of DIPG models treated with PI3K/mTOR inhibitors promoted calcium-activated PKC signaling. The brain-penetrant PKC inhibitor enzastaurin in combination with paxalisib, synergistically extended the survival of DIPG xenograft models, including those mimicking disease progression, with further benefits potentiated using metformin in a multimodality approach. Combined PI3K-PKC inhibition in vivo promoted differentiation of OPC-like DMG to more OC-like cells, enhancing PDGFRA-JAK/STAT proinflammatory signaling, showing features of demyelination and MHC-II+ antigen expression, including PD1/PDL1. In parallel, combined PI3K/mTOR and PDGFRA inhibition using paxalisib and avapritinib synergistically extended the survival of patient-derived xenograft models, showing the preclinical relevance of simultaneously targeting these vulnerabilities. Together, we reveal that therapeutic inhibition of PI3K/mTOR and compensatory PKC signaling, while mitigating side effects with metformin, altered the chromatin architecture, leading to cellular differentiation and opening the door for clinically relevant checkpoint inhibitors. This combination strategy addresses DMG genetic dependencies, cellular and systemic responses to precision therapies, while harnessing the immune system for potential clinical translation.

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