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1. CAR T cell therapies for diffuse midline glioma.

Author

Thomas BC, Staudt DE, Douglas AM, Monje M, Vitanza NA, and Dun MD

Subjects
Child, Humans, Central Nervous System, Tumor Microenvironment, Immunotherapy, Adoptive, Glioma genetics, Glioma therapy
Abstract

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., Competing Interests: Declaration of interests M.D.D. is a parent to a child lost to diffuse intrinsic pontine glioma (DIPG) and is the founder and a Director of the not-for-profit charity RUN DIPG Pty Ltd. The other authors declare no conflicts of interest., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Published
2023
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2. Transcriptional Dependencies in Diffuse Intrinsic Pontine Glioma.

Author

Nagaraja S, Vitanza NA, Woo PJ, Taylor KR, Liu F, Zhang L, Li M, Meng W, Ponnuswami A, Sun W, Ma J, Hulleman E, Swigut T, Wysocka J, Tang Y, and Monje M

Subjects
Animals, Brain Stem Neoplasms genetics, Brain Stem Neoplasms metabolism, Brain Stem Neoplasms pathology, Cell Cycle Proteins, Cell Proliferation drug effects, Chromatin Assembly and Disassembly drug effects, Cyclin-Dependent Kinases antagonists & inhibitors, Cyclin-Dependent Kinases genetics, Cyclin-Dependent Kinases metabolism, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Drug Synergism, Female, Glioma genetics, Glioma metabolism, Glioma pathology, Histones genetics, Histones metabolism, Humans, Male, Mice, Inbred NOD, Mice, SCID, Mutation, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins genetics, Nuclear Proteins metabolism, Panobinostat, Primary Cell Culture, RNA Interference, Receptors, Eph Family genetics, Receptors, Eph Family metabolism, Signal Transduction drug effects, Time Factors, Transcription Factors antagonists & inhibitors, Transcription Factors genetics, Transcription Factors metabolism, Transfection, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinase-Activating Kinase, Antineoplastic Combined Chemotherapy Protocols pharmacology, Azepines pharmacology, Brain Stem Neoplasms drug therapy, Gene Expression Regulation, Neoplastic drug effects, Glioma drug therapy, Histone Deacetylase Inhibitors pharmacology, Hydroxamic Acids pharmacology, Indoles pharmacology, Phenylenediamines pharmacology, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Transcription, Genetic drug effects, Triazoles pharmacology
Abstract

Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric cancer with limited therapeutic options. The majority of cases of DIPG exhibit a mutation in histone-3 (H3K27M) that results in oncogenic transcriptional aberrancies. We show here that DIPG is vulnerable to transcriptional disruption using bromodomain inhibition or CDK7 blockade. Targeting oncogenic transcription through either of these methods synergizes with HDAC inhibition, and DIPG cells resistant to HDAC inhibitor therapy retain sensitivity to CDK7 blockade. Identification of super-enhancers in DIPG provides insights toward the cell of origin, highlighting oligodendroglial lineage genes, and reveals unexpected mechanisms mediating tumor viability and invasion, including potassium channel function and EPH receptor signaling. The findings presented demonstrate transcriptional vulnerabilities and elucidate previously unknown mechanisms of DIPG pathobiology., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Published
2017
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