Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening
Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening
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DOI：
10.1126/scitranslmed.aaw0064
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发表时间：
2019-11-20
影响因子：
17.1
通讯作者：
Monje, Michelle
中科院分区：
文献类型：
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作者：
Lin, Grant L.;Wilson, Kelli M.;Monje, Michelle
弥漫性中线神经胶质瘤（DMG）是一种常见的致死性恶性肿瘤，主要发生在儿童时期，累及中枢神经系统的中线结构，包括丘脑、脑桥和脊髓。这些分子相关的癌症的特征在于组蛋白H3 K27 M突变的高患病率。为了寻找有效的治疗方案，我们在2706种批准和研究药物的连续定量高通量筛选（HTS）中检查了多种DMG培养物。这项工作产生了19，936个单药剂量反应，激发了一系列HTS启用的药物组合评估，包括9195个药物-药物检查。在代表主要DMG基因型的患者来源的细胞培养物中验证了最佳组合。在患者来源的异种移植物模型中的体内测试验证了多组蛋白脱乙酰酶（HDAC）抑制剂帕比司他和蛋白酶体抑制剂marizlavin的组合作为有前景的治疗方法。转录和代谢组学研究显示，在帕比司他和marizlavin治疗后，关键代谢过程和细胞未折叠蛋白反应发生了实质性变化。外源性应用烟酰胺单核苷酸（NMN）可减轻药物诱导的细胞毒性和基础线粒体呼吸，或通过抑制烟酰胺磷酸核糖转移酶（NAMPT）阻断烟酰胺腺嘌呤二核苷酸（NAD（+））产生时可加重这些表型，这表明代谢灾难驱动了联合诱导的细胞毒性。这项研究为DMG提供了一个全面的单药和组合药物筛选，并将伴随的HDAC和蛋白酶体抑制确定为一种有前途的治疗策略，强调了DMG中未被认识到的代谢脆弱性。
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.