Das Arabinda, Cheng Ron Ron, Hilbert Megan L T, Dixon-Moh Yaenette N, Decandio Michele, Vandergrift William Alex, Banik Naren L, Lindhorst Scott M, Cachia David, Varma Abhay K, Patel Sunil J, Giglio Pierre
Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA. ; Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
Cancer Growth Metastasis. 2015 Dec 1;8:51-60. doi: 10.4137/CGM.S32801. eCollection 2015.
Glioblastoma (GB) is the most common malignant brain tumor. Drug resistance frequently develops in these tumors during chemotherapy. Therefore, predicting drug response in these patients remains a major challenge in the clinic. Thus, to improve the clinical outcome, more effective and tolerable combination treatment strategies are needed. Robust experimental evidence has shown that the main reason for failure of treatments is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK), c-Met (hepatocyte growth factor receptor), and oncogenic c-ros oncogene1 (ROS1: RTK class orphan) fusion kinase FIG (fused in GB)-ROS1. As such, these could be attractive targets for GB therapy. The study subjects consisted of 19 patients who underwent neurosurgical resection of GB tissues. Our in vitro and ex vivo models promisingly demonstrated that treatments with crizotinib (PF-02341066: dual ALK/c-Met inhibitor) and temozolomide in combination induced synergistic antitumor activity on FIG-ROS1-positive GB cells. Our results also showed that ex vivo FIG-ROS1+ slices (obtained from GB patients) when cultured were able to preserve tissue architecture, cell viability, and global gene-expression profiles for up to 14 days. Both in vitro and ex vivo studies indicated that combination blockade of FIG, p-ROS1, p-ALK, and p-Met augmented apoptosis, which mechanistically involves activation of Bim and inhibition of survivin, p-Akt, and Mcl-1 expression. However, it is important to note that we did not see any significant synergistic effect of crizotinib and temozolomide on FIG-ROS1-negative GB cells. Thus, these ex vivo culture results will have a significant impact on patient selection for clinical trials and in predicting response to crizotinib and temozolomide therapy. Further studies in different animal models of FIG-ROS1-positive GB cells are warranted to determine useful therapies for the management of human GBs.
胶质母细胞瘤（GB）是最常见的恶性脑肿瘤。在化疗期间，这些肿瘤常常会产生耐药性。因此，预测这些患者的药物反应仍然是临床上的一项重大挑战。所以，为了改善临床结果，需要更有效且耐受性良好的联合治疗策略。有力的实验证据表明，治疗失败的主要原因是由于几种功能相关的受体酪氨酸激酶（RTK）共同激活导致的信号冗余，这些激酶包括间变性淋巴瘤激酶（ALK）、c-Met（肝细胞生长因子受体）以及致癌性c-ros癌基因1（ROS1：RTK类孤儿）融合激酶FIG（在GB中融合）-ROS1。因此，这些可能是GB治疗的有吸引力的靶点。研究对象包括19例接受GB组织神经外科切除的患者。我们的体外和离体模型很有前景地证明，克唑替尼（PF-02341066：ALK/c-Met双重抑制剂）与替莫唑胺联合治疗对FIG-ROS1阳性GB细胞具有协同抗肿瘤活性。我们的结果还表明，离体培养的FIG-ROS1+切片（取自GB患者）能够在长达14天的时间内保持组织结构、细胞活力和整体基因表达谱。体外和离体研究均表明，对FIG、p-ROS1、p-ALK和p-Met的联合阻断增强了细胞凋亡，其机制涉及Bim的激活以及survivin、p-Akt和Mcl-1表达的抑制。然而，需要注意的是，我们未观察到克唑替尼和替莫唑胺对FIG-ROS1阴性GB细胞有任何显著的协同作用。因此，这些离体培养结果将对临床试验的患者选择以及预测对克唑替尼和替莫唑胺治疗的反应产生重大影响。有必要在FIG-ROS1阳性GB细胞的不同动物模型中进行进一步研究，以确定治疗人类GB的有效疗法。
