title: Synergistic Effects of Crizotinib and Temozolomide in Experimental FIG-ROS1 Fusion-Positive Glioblastoma.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Arabinda
authors.initials: A
authors.lastname: Das
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Ron Ron
authors.initials: RR
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Megan L T
authors.initials: ML
authors.lastname: Hilbert
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Yaenette N
authors.initials: YN
authors.lastname: Dixon-Moh
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Decandio
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: William Alex
authors.initials: WA
authors.lastname: Vandergrift
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA. ; Ralph H. Johnson VA Medical Center, Charleston, SC, USA.
authors.forename: Naren L
authors.initials: NL
authors.lastname: Banik
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lindhorst
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: David
authors.initials: D
authors.lastname: Cachia
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Abhay K
authors.initials: AK
authors.lastname: Varma
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Sunil J
authors.initials: SJ
authors.lastname: Patel
authors.affiliation: Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA. ; Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
authors.forename: Pierre
authors.initials: P
authors.lastname: Giglio
keywords: ALK; FIG; ROS1; c-Met inhibitor; crizotinib; glioblastoma; temozolomide