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首页> 美国卫生研究院文献>Neuro-Oncology >COMBINED DRUG SCREENING AND PHOSPHOPROTEOMICS IDENTIFIES CANDIDATE BRAIN TUMOR THERAPEUTICS AND NOVEL TARGETS IN PRIMARY HUMAN BRAIN TUMOR-INITIATING CELLS
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COMBINED DRUG SCREENING AND PHOSPHOPROTEOMICS IDENTIFIES CANDIDATE BRAIN TUMOR THERAPEUTICS AND NOVEL TARGETS IN PRIMARY HUMAN BRAIN TUMOR-INITIATING CELLS

机译：药物筛查和磷酸化蛋白质组学相结合可鉴定人原发性肿瘤细胞中的脑肿瘤治疗方法和新靶标

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BACKGROUND: “Therapeutic Targeting of Glioblastoma” is a new pan-Canadian research team of the Terry Fox Research Institute and the Canadian Stem Cell Network funded to discover efficacious therapeutics for GBM. The team's goals are also to discover novel signaling pathways regulating GBM cell survival and genetic alterations that mediate drug resistance. As a platform, we use our collection of over 100 primary GBM tumor-initiating lines (BTIC) that are subjected to drug screening by over 1400 compounds, and to genetic and phosphoproteomic analysis. METHODS: We performed drug screening of 21 BTIC lines that represent the molecular heterogeneity of GBM patients, with a library of 110 clinically-relevant kinase inhibitors at three concentrations. We have also completed a phosphotyrosine characterization of 14 BTIC lines using phosphoproteomics. RESULTS: Multiple compounds that exhibit nanomolar cytotoxicity towards all of the lines were prioritized based upon their potency, novelty for GBM, ability to accumulate to relevant concentrations in brain, clinical status and cytotoxicity towards normal cells. Of the several hit compounds that fulfilled all of these criteria, the CDK inhibitor dinaciclib was chosen as our lead compound. We are currently investigating its mechanism of action using phosphoproteomics and RNAi as well as testing its efficacy in vivo in an orthotopic xenograft model as a single agent and in combination with TMZ. Furthermore, we have identified several compounds that exhibit selective cytotoxicity towards only a specific set of BTIC lines, suggesting that genetic differences between the lines account for differential sensitivities. The sensitivity of BTICs to one such compound, EMD-1214063, a selective MET inhibitor, may correlate with Met amplification status. Finally, phosphoproteomics results show activation of RTKs (EGFR, FGFR, PDGFRA, Eph receptor family) and non-receptor kinases (FYN, FAK1, GSK3b, MAPK, CDKs, DYRK) in the majority of BTIC lines, and of adaptor/scaffold proteins and proteins important in adhesion and migration. We are now (1) determining whether drugs that inhibit the activity of identified phosphoproteins suppress BTIC survival in culture and in orthotopic models, (2) validating the importance of those phosphoproteins in GBM survival, and (3) asking whether the prioritized drug hits from our drug screens suppress the phosphorylation of the identified phosphoproteins. CONCLUSIONS: We anticipate that our drug screening approach will generate several clinical candidates that will enable us to proceed to the clinic in the next several years. We also believe that our phosphoproteomics results will lead to identification of novel therapeutic targets for GBM. SECONDARY CATEGORY: Preclinical Experimental Therapeutics.
机译：背景：“胶质母细胞瘤的靶向治疗”是特里福克斯研究所和加拿大干细胞网络的新的泛加拿大研究小组，该研究小组获资助发现了GBM的有效疗法。该小组的目标还在于发现调节GBM细胞存活和介导耐药性的遗传改变的新型信号通路。作为平台，我们使用了100多个原发性GBM肿瘤起始株（BTIC）的集合，这些株系已通过1400多种化合物进行了药物筛选，并进行了遗传和蛋白质组学分析。方法：我们对11种BTIC品系进行了药物筛选，这些品系代表了GBM患者的分子异质性，并具有110种临床相关激酶抑制剂（三种浓度）的库。我们还使用磷酸化蛋白质组学完成了14条BTIC品系的磷酸酪氨酸表征。结果：根据对所有系表现出纳摩尔细胞毒性的多种化合物，根据其效力，GBM的新颖性，在大脑中积累至相关浓度的能力，临床状况和对正常细胞的细胞毒性进行了优先排序。在满足所有这些标准的几种热门化合物中，CDK抑制剂dinaciclib被选为我们的主要化合物。我们目前正在研究其使用磷酸化蛋白质组学和RNAi的作用机理，以及在原位异种移植模型中作为单一药物并与TMZ结合在体内测试其功效。此外，我们已经鉴定了几种仅对一组特定的BTIC品系表现出选择性细胞毒性的化合物，这表明这些品系之间的遗传差异导致了敏感性的差异。 BTIC对一种此类化合物EMD-1214063（一种选择性MET抑制剂）的敏感性可能与Met扩增状态相关。最后，磷酸化蛋白质组学结果显示，在大多数BTIC品系以及衔接子/支架蛋白中，RTK（EGFR，FGFR，PDGFRA，Eph受体家族）和非受体激酶（FYN，FAK1，GSK3b，MAPK，CDK，DYRK）被激活以及对黏附和迁移重要的蛋白质。我们现在（1）确定抑制已鉴定的磷蛋白活性的药物是否能抑制培养物中和原位模型中的BTIC存活；（2）验证这些磷蛋白在GBM存活中的重要性；以及（3）询问优先药物是否从我们的药物筛选可抑制已鉴定的磷蛋白的磷酸化。结论：我们预计我们的药物筛选方法将产生几种临床候选药物，这将使我们能够在未来几年内进入临床。我们还相信，我们的磷酸化蛋白质组学结果将导致鉴定GBM的新型治疗靶标。次要类别：临床前实验疗法。

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