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

ABSTRACT: Diffuse midline gliomas (DMG) are a group of molecularly related malignancies occurring in midline structures of the childhood central nervous system, including thalamus, pons, and spinal cord. These cancers are characterized by high prevalence of the histone-3K27M mutation and are universally lethal, with median survival of only 9-11 months for pontine DMG (a.k.a. DIPG). In search of novel therapeutic options, we examined multiple cell models in sequential, quantitative high-throughput screens of approved and investigational drugs. This effort generated a total of 17,456 single-agent dose responses that inspired a subsequent series of HTS-enabled drug combination assessments encompassing a total of 8883 drug-drug examinations. Top combinations were validated across a panel of patient-derived cell lines representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-HDAC inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to the cellular unfolded protein response and key metabolic processes following treatment with panobinostat and marizomib. Rescue of drug induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking NAD+ production via NAMPT inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study represents the most comprehensive single-agent and combinatorial drug screen for DIPG reported to date and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores under-recognized metabolic vulnerabilities in DIPG. The combined screening outcomes represent a public resource for the DMG community.

ORGANISM(S): Homo sapiens

PROVIDER: GSE123278 | GEO | 2019/11/29

REPOSITORIES: GEO

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Project description:Diffuse midline glioma (DMG) is an aggressive pediatric tumor localized in the brainstem. The median survival after diagnosis is less than one year. Surgical resection is not possible due to the critical localization of the tumor and radiation therapy alone or in combination with chemotherapy show only minimal benefit. In 80% of cases, DIPGs are harbor genetic abnormalities such as a K27M mutation in histone H3, suggesting drugs targeting epigenetic anomalies might be efficient. Indeed, Grasso et al. (Nature Medicine, 2015) have shown that the histone deacetylase inhibitor panobinostat (PS) affects glioma cell growth in vitro and in vivo. PS is currently undergoing phase 1 clinical trials. To better understand the mechanism of action of PS on tumor cells, we performed a proteomic analysis by comparing DMG cells treated with panobinostat to control cells. We identified 2 proteins in PS-treated cells: EBP50 (or NHERF-1) and IRSp53 (or BAIAP2). EBP50 protein is implicated in invasion (Kislin et al. Neoplasia, 2009) but it can also act like a tumor suppressor on glioblastoma (Molina et al. Cancer Research, 2010). There is a dual role of the protein which depends on its localization in the cell: when localized at the cell membrane, EBP50 acts as a tumor suppressor, but has oncogenic properties when present in the cytoplasm or nucleus. Using electron microscopy combined with immunofluorescence, we could validate expression of EBP50 in all cellular compartments. IRSp53 is implicated in proliferation of tumor cells (Liu P.S. Oncogene, 2010) and may have an important role during migration and invasion (Funato et al., Cancer Research 2004). To elucidate the role of the two proteins in DIPG, we investigated effects of gene knockdown by siRNA and stable overexpression using lentiviruses. For each protein, we found a significant diminution of proliferation, migration and invasion and an increase in apoptosis cells were transfected with siRNAs. In contrast, overexpression of EBP50 did not have any effect on cells. Our results suggest that the two proteins induced by PS treatment are implicated in tumor progression and might constitute novel additional therapeutic targets, especially as adjuvant treatment together with PS.

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

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