治疗初发胶质母细胞瘤患者特异性药物敏感性的肿瘤间异质性。

Intertumoral heterogeneity in patient-specific drug sensitivities in treatment-naïve glioblastoma.

机构信息

Vilhelm Magnus Laboratory for Neurosurgical Research, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424, Oslo, Norway.

Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, P.O. Box 1112 Blindern, 0317, Oslo, Norway.

出版信息

BMC Cancer. 2019 Jun 25;19(1):628. doi: 10.1186/s12885-019-5861-4.

DOI:10.1186/s12885-019-5861-4

PMID:31238897

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6593575/

Abstract

BACKGROUND

A major barrier to effective treatment of glioblastoma (GBM) is the large intertumoral heterogeneity at the genetic and cellular level. In early phase clinical trials, patient heterogeneity in response to therapy is commonly observed; however, how tumor heterogeneity is reflected in individual drug sensitivities in the treatment-naïve glioblastoma stem cells (GSC) is unclear.

METHODS

We cultured 12 patient-derived primary GBMs as tumorspheres and validated tumor stem cell properties by functional assays. Using automated high-throughput screening (HTS), we evaluated sensitivity to 461 anticancer drugs in a collection covering most FDA-approved anticancer drugs and investigational compounds with a broad range of molecular targets. Statistical analyses were performed using one-way ANOVA and Spearman correlation.

RESULTS

Although tumor stem cell properties were confirmed in GSC cultures, their in vitro and in vivo morphology and behavior displayed considerable tumor-to-tumor variability. Drug screening revealed significant differences in the sensitivity to anticancer drugs (p < 0.0001). The patient-specific vulnerabilities to anticancer drugs displayed a heterogeneous pattern. They represented a variety of mechanistic drug classes, including apoptotic modulators, conventional chemotherapies, and inhibitors of histone deacetylases, heat shock proteins, proteasomes and different kinases. However, the individual GSC cultures displayed high biological consistency in drug sensitivity patterns within a class of drugs. An independent laboratory confirmed individual drug responses.

CONCLUSIONS

This study demonstrates that patient-derived and treatment-naïve GSC cultures maintain patient-specific traits and display intertumoral heterogeneity in drug sensitivity to anticancer drugs. The heterogeneity in patient-specific drug responses highlights the difficulty in applying targeted treatment strategies at the population level to GBM patients. However, HTS can be applied to uncover patient-specific drug sensitivities for functional precision medicine.

摘要

背景

胶质母细胞瘤（GBM）有效治疗的一个主要障碍是遗传和细胞水平上的巨大肿瘤间异质性。在早期临床试验中，经常观察到患者对治疗的反应存在异质性；然而，肿瘤异质性如何反映在治疗前的胶质母细胞瘤干细胞（GSC）的个体药物敏感性中尚不清楚。

方法

我们培养了 12 例患者来源的原发性 GBM 作为肿瘤球体，并通过功能测定验证了肿瘤干细胞特性。我们使用自动化高通量筛选（HTS），在涵盖大多数 FDA 批准的抗癌药物和具有广泛分子靶点的研究化合物的药物库中评估了对 461 种抗癌药物的敏感性。使用单向方差分析和斯皮尔曼相关性进行统计分析。

结果

尽管在 GSC 培养物中证实了肿瘤干细胞特性，但它们的体外和体内形态和行为表现出相当大的肿瘤间变异性。药物筛选显示抗癌药物的敏感性存在显著差异（p<0.0001）。抗癌药物的患者特异性脆弱性表现出异质性模式。它们代表了多种机制药物类别，包括凋亡调节剂、传统化疗药物、组蛋白去乙酰化酶、热休克蛋白、蛋白酶体和不同激酶抑制剂。然而，在一类药物中，个体 GSC 培养物在药物敏感性模式上表现出高度的生物学一致性。一个独立的实验室证实了个体药物反应。