Research ArticleCancer

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

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Science Translational Medicine  20 Nov 2019:
Vol. 11, Issue 519, eaaw0064
DOI: 10.1126/scitranslmed.aaw0064

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A systematic attack against brain tumors

Diffuse midline gliomas are aggressive childhood brain tumors that are difficult to access surgically and therefore universally lethal. To search for potential therapeutic options for this devastating cancer, Lin et al. performed high-throughput screening on patient-derived glioma cells, followed by validation in cell cultures and mouse models of the disease. With this approach, the authors identified some potentially useful drug combinations, with the most promising one being that of the epigenetic targeting treatment panobinostat and the proteasome inhibitor marizomib. The authors also investigated the mechanism of the proposed therapeutic combination, linking its effectiveness to the induction of metabolic catastrophe in the tumor cells.

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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