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Sci Transl Med. 2019 Nov 20;11(519). pii: eaaw0064. doi: 10.1126/scitranslmed.aaw0064.

Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening.

Author information

1
Department of Neurology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
3
Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH 43205, USA.
4
Laboratory of Cancer Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
5
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
6
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. katherinee_warren@dfci.harvard.edu craigt@mail.nih.gov mmonje@stanford.edu.
7
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA. katherinee_warren@dfci.harvard.edu craigt@mail.nih.gov mmonje@stanford.edu.
8
Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
9
Department of Neurology, Stanford University School of Medicine, Stanford, CA 94305, USA. katherinee_warren@dfci.harvard.edu craigt@mail.nih.gov mmonje@stanford.edu.
10
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
11
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
12
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
13
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
14
Stanford Institute for Stem Cell and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.

Abstract

Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.

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