No abstract

Glioblastoma, the most malignant and lethal of brain tumors, remains incurable despite aggressive chemotherapy and surgical interventions. Few new chemotherapeutics for glioblastoma therapy have been explored in preclinical models, and some agents approved for have reached the clinical setting. However success rates are not significant. Previous investigations involving diallyl trisulfide (DATS), a garlic constituent, have indicated significant anti-cancer effects in vitro, including: glioblastoma growth inhibition, extrinsic and intrinsic apoptotic pathway activation, and cell death. DATS has also been shown to inhibit histone deacetylase activity and impede glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG induced tumors by inhibiting multiple pro-apoptotic pathways via HDAC. To this end, ectopic tumors were developed in SCID mice and subsequently treated with daily intraperitoneal injections of DATS. Results indicate that a range of DATS doses (10μg/kg-10mg/kg) dose-dependently reduced tumor volume and number of mitotic cells within tumors after seven days. Our histological and biochemical assays demonstrate that DATS reduces mitosis in tumors, decreases HDAC activity, increases in acetylation of H3 and H4, inhibits cell cycle progression, promotes apoptotic cascade activation (m-calpian, Bax, caspase-3) and decreases pro-survival markers (Survivin, Bcl-2, p-Akt, c-Myc, mTOR, EGFR, VEGF). Our data also demonstrates an increase in p21/WAF1 expression, which correlates with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and enzyme assays suggest that even the highest dose of DATS administered in this study did not negatively impact hepatic function. These in vivo findings strongly support orthotopic investigation into the therapeutic potential of DATS and further review of the epigenetic mechanisms behind its anti-cancer activities.

The pedicled nasoseptal flap is an effective means of reconstruction after endoscopic skull base surgery. Avoidance of extensive stripping of the surrounding mucosa does not result in a significant rate of postoperative mucocele formation in the short term. Long-term follow-up is still indicated.

Glioblastoma is the most common aggressive, highly glycolytic, and lethal brain tumor. In fact, it is among the most commonly diagnosed lethal malignancies, with thousands of new cases reported in the United States each year. Glioblastoma's lethality is derived from a number of factors including highly active pro-mitotic and pro-metastatic pathways. Two factors increasingly associated with the intracellular signaling and transcriptional machinery required for such changes are anaplastic lymphoma kinase (ALK) and the hepatocyte growth factor receptor (HGFR or, more commonly MET). Both receptors are members of the receptor tyrosine kinase (RTK) family, which has itself gained much attention for its role in modulating mitosis, migration, and survival in cancer cells. ALK was first described as a vital oncogene in lymphoma studies, but it has since been connected to many carcinomas, including non-small cell lung cancer and glioblastoma. As the receptor for HGF, MET has also been highly characterized and regulates numerous developmental and wound healing events which, when upregulated in cancer, can promote tumor progression. The wealth of information gathered over the last 30 years regarding these RTKs suggests three downstream cascades that depend upon activation of STAT3, Ras, and AKT. This review outlines the significance of ALK and MET as they relate to glioblastoma, explores the significance of STAT3, Ras, and AKT downstream of ALK/MET, and touches on the potential for new chemotherapeutics targeting ALK and MET to improve glioblastoma patient prognosis.

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.