Vilhelm Magnus Laboratory, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950, Nydalen, 0424, Oslo, Norway.
Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, P.O. Box 1112, Blindern, 0317, Oslo, Norway.
J Cancer Res Clin Oncol. 2019 Jun;145(6):1495-1507. doi: 10.1007/s00432-019-02920-4. Epub 2019 Apr 26.
Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported.
Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures.
We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p < 0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p < 0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity.
Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.
从理论框架构建，胶质母细胞瘤（GBM）的生存途径的协同破坏是九种批准用于非肿瘤适应症的药物的组合（CUSP9；阿瑞匹坦、金诺芬、卡托普利、塞来昔布、双硫仑、伊曲康唑、米诺环素、喹硫平、舍曲林）与替莫唑胺（TMZ）联合使用。这些药物在专门治疗中心之外的可用性导致患者在没有系统随访的情况下开始联合治疗。然而，尚未报道使用 CUSP9 策略在 GBM 中进行疗效的实验数据。
使用来自 15 名 GBM 患者的患者来源的 GBM 干细胞（GSC）培养物，我们描述了各个培养物的干细胞特性，确定了 CUSP9 中药物的剂量反应关系，并评估了 CUSP9 与 TMZ 的联合治疗在临床可达到的浓度下的疗效。在原发性和复发性 GSC 培养物中，通过细胞活力、细胞毒性和球体形成测定评估疗效。
我们发现 CUSP9 与 TMZ 联合使用与单独使用药物相比诱导了协同作用（p<0.0001）。通过细胞活力和细胞毒性评估，50%的 GSC 培养物对药物组合具有高敏感性。在临床血浆浓度下，CUSP9 与 TMZ 的联合作用优于 TMZ 单药治疗（p<0.001）。Wnt 信号通路在 GSC 中被证明很重要，CUSP9 显著降低了 Wnt 活性。
将实验数据添加到 CUSP9 的理论基础中，我们的结果表明 CUSP9 治疗策略可以在未经治疗和预处理的 GSC 培养物中诱导协同作用；然而，预测个体培养物的反应将需要进一步对 GSCs 进行分析。
