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.

Meningiomas are by far the most common tumors arising from the meninges. A myriad of aberrant signaling pathways involved with meningioma tumorigenesis, have been discovered. Understanding these disrupted pathways will aid in deciphering the relationship between various genetic changes and their downstream effects on meningioma pathogenesis. An understanding of the genetic and molecular profile of meningioma would provide a valuable first step towards developing more effective treatments for this intracranial tumor. Chromosomes 1, 10, 14, 22, their associated genes, and other potential targets have been linked to meningioma proliferation and progression. It is presumed that through an understanding of these genetic factors, more educated meningioma treatment techniques can be implemented. Future therapies will include combinations of targeted molecular agents including gene therapy, si-RNA mediation, proton therapy, and other approaches as a result of continued progress in the understanding of genetic and biological changes associated with meningiomas. This review provides an overview of the current knowledge of the genetic, signaling and molecular profile of meningioma and possible treatments strategies associated with such profiles.

Glioblastoma is the most common and highly aggressive human brain cancer. Most of the glioblastoma patients do not survive more than a few months after the diagnosis. The prognosis for glioblastoma patients remains very poor even after aggressive treatments. Traditional therapeutic strategies are not yet satisfactory for controlling the growth of this deadly malignancy in humans. Heterogeneity of cells in glioblastoma is one of biggest hurdles in its management. Novel and innovative therapeutic agents need to be explored for targeting the key cell signaling pathways that promote proliferation and survival of different human glioblastoma cells. Receptor tyrosine kinases have been implicated in the progression of this malignancy. Anaplastic lymphoma kinase (ALK) and c-Met are two such proteins. ALK/c-Met are associated with the development and progression of many human cancers, including glioblastoma. Also, overexpression or mutation of c-ros proto-oncogene encodes a receptor tyrosine kinase, which also leads to oncogenic development of glioblastoma. In the present study, we examined the activity of the Pfizer drug crizotinib (PF-02341066, a dual ALK/c-Met inhibitor) for suppression of both ALK/c-Met pathways and induction of apoptotic death in different human glioblastoma cell lines (U87MG, T98G, U118MG, and U138MG) and fresh tumor biopsies surgically extracted from 6 glioblastoma patients. Our dose-response studies indicated that treatment with PF-02341066 for 24 h could induce morphological features (as detected by Wright staining) and also biochemical features (as detected by DNA fragmentation assay and Western blotting) of apoptosis. We used Western blotting for investigation into the molecular mechanisms of apoptotic death and found that induction of apoptosis was associated with decreases in expression of ALK, c-Met, c-Ros, Survivin, and Bcl-2 proteins after the treatment. Western blotting also demonstrated that treatment with PF-02341066 caused apoptosis due to an increase in Bax:Bcl-2 ratio and activation of caspase-3 in glionlastoma cells and tissues. Increase in activity of caspase-3 was confirmed by colorimetric assay. Most importantly, PF-02341066 significantly enhanced the anti-cancer effect of temozolomide (TMZ), a widely used anti-glioblastoma drug, in human glioblastoma cell lines (U87MG, T98G, U118MG, and U138MG) as well as in fresh tumor biopsies from 6 glioblastoma patients. Our studies also suggested that induction of apoptosis by PF-02341066 does not depend on the functional status of p53, PTEN, ALK, c-Met, or c-Ros in the glioblastoma cell lines or in the glioblastoma tissues. Further studies in different animal models of glioblastoma are warranted in the future to determine whether PF-02341066 may be useful as an anti-cancer agent alone or in combination with TMZ for the management of human glioblastomas in vivo. This investigation was supported in by Pfizer Oncology. Citation Format: Arabinda Das, Gerald C. Wallace, Catherine Haar, Michele L. DeCandio, W Alex Vandergrift, Sunil J. Patel, Swapan K. Ray, Naren L. Banik, Pierre Giglio. PF-02341066 (crizotinib), a dual ALK/c-Met inhibitor, for inhibiting growth of glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2183. doi:10.1158/1538-7445.AM2013-2183

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