ABSTRACT
Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma; DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR/Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across patient derived models of DIPG, highlighting the therapeutic potential of the blood-brain barrier-penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human-equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance while maintaining compliance and therapeutic benefit, we combined paxalisib with the antihyperglycemic drug metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin, in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-Seq, identifying changes in myelination and tumor immune microenvironment crosstalk. Collectively, this study has identified what we believe to be a clinically relevant DIPG therapeutic combinational strategy.
Subject(s)
Brain Stem Neoplasms , Diffuse Intrinsic Pontine Glioma , Glioma , Metformin , Humans , Mice , Animals , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/genetics , Phosphatidylinositol 3-Kinases/genetics , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , TOR Serine-Threonine Kinases/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Glucose , Metformin/pharmacology , Tumor MicroenvironmentABSTRACT
Diffuse midline glioma (DMG) is a fatal pediatric cancer of the central nervous system (CNS). The location and infiltrative nature of DMG prevents surgical resection and the benefits of palliative radiotherapy are temporary; median overall survival (OS) is 9-11 months. The tumor immune microenvironment (TIME) is 'cold', and has a dominant immunosuppressive myeloid compartment with low levels of infiltrating lymphocytes and proinflammatory molecules. Because survival statistics have been stagnant for many decades, and therapies targeting the unique biology of DMG are urgently needed, this has prompted the clinical assessment of chimeric antigen receptor (CAR) T cell therapies in this setting. We highlight the current landscape of CAR T cell therapy for DMG, the role the TIME may play in the response, and strategies to overcome treatment obstacles.
