miR-3174 Is a New Tumor Suppressor MicroRNA That Inhibits Several Tumor-Promoting Genes in Glioblastoma.

microRNAs (miRNAs) play an important role in the pathology of glioblastoma (GBM), which is the most malignant and most common primary malignant brain tumor. miRNAs can target multiple genes simultaneously and are considered as potential therapeutic agents or targets. This study aimed to determine the role of miR-3174 in the pathobiology of GBM using both in vitro and in vivo approaches. This is the first study deciphering the role of miR-3174 in GBM. We studied the expression of miR-3174 and found it to be downregulated in a panel of GBM cell lines, GSCs and tissues relative to astrocytes and normal brain tissue. This finding led us to hypothesize that miR-3174 has a tumor-suppressive role in GBM. Exogenous expression of miR-3174 inhibited GBM cell growth and invasion, and hampered the neurosphere formation ability of GSCs. miR-3174 downregulated the expression of multiple tumor-promoting genes including CD44, MDM2, RHOA, PLAU and CDK6. Further, overexpression of miR-3174 reduced tumor volume in nude mice with intracranial xenografts. Immuno-histochemical study of brain sections with intracranial tumor xenografts revealed the pro-apoptotic and anti-proliferative activity of miR-3174. In conclusion, we demonstrated that miR-3174 has a tumor-suppressive role in GBM and could be exploited for therapeutic purposes.

Diagnostic Value of Potential MicroRNAs in CRC: A Meta-Analysis.

BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNA molecules involved in the post-transcriptional regulation of genes. Deregulated expression of miRNAs is involved in different pathogenic mechanisms, particularly colorectal cancer (CRC) carcinogenesis. Due to their stability and accessibility, circulating miRNAs represent a new family of biomarkers with great potential. Therefore, certain miRNAs can be used as diagnostic biomarkers in CRC. OBJECTIVE: This systematic analysis aimed to explore the individual efficacy of the most investigated blood-based miRNAs for CRC diagnosis, namely miR-21, miR-29a and miR-92a. METHODS: Articles were retrieved from databases such as PubMed and Google Scholar, and studies designed to evaluate the diagnostic value of microRNAs in CRC were then selected. We subsequently explored the diagnostic accuracy of each miRNA using parameters such as (SE, SPE, PLR, NLR). The meta-analysis was performed using the Review Manager (Revman) 5.4 software and the Meta Disc software. RESULTS: Our results suggested that serum miR-21 levels showed great potential as a diagnostic molecular marker. The overall pooled results for sensitivity, specificity, area under the curve (AUC), PLR, and NLR were 78%, 91%, 0.9519, 8.12 and 0.17, respectively. CONCLUSION: miRNAs have become increasingly important in the diagnosis of CRC. Based on these findings, circulating miR-21 levels may have a potential value for early detection and might be used as a novel diagnostic biomarker for CRC.

Targeting IL-1ß in patients with advanced Helicobacter pylori infection: a potential therapy for gastric cancer.

Helicobacter pylori (H. pylori) infection is a causal factor of gastric cancer. Among the cytokines secreted during this infection, IL-1ß is highly associated with promotion and progression of gastric cancer. On the therapeutic front, eradication of H. pylori was thought to be efficient to restore gastric homeostasis. However, successful H. pylori eradication in patients with advanced stages (intestinal metaplasia) failed to diminish inflammation that is due to heightened Th17 response and elevated IL-1ß levels. In fact, association between these two components was established, suggesting that IL-1ß is a critical target in these cases. In this review, we will discuss the functional relevance of IL-1ß in advanced H. pylori infection and how its targeting may bring clinical benefit.

Helicobacter pylori (H. pylori) infection is a causal factor of gastric cancer. This disease is strongly associated to an inflammatory factor (interleukin 1ß). On the therapeutic front, eradication of H. pylori was thought to be efficient to restore gastric comfort. However, successful H. pylori eradication in patients with advanced stages of this infection failed to diminish inflammation, due to the inflammatory factor cited preciously, thereby exacerbating gastric tissue damage. In this review, we will discuss the functional relevance of IL-1ß in advanced H. pylori infection and how its targeting may bring clinical benefit.

MicroRNAs: Key Regulators in Lung Cancer.

Noncoding RNAs have emerged as key regulators of the genome upon gene expression profiling and genome-wide sequencing. Among these noncoding RNAs, microRNAs are short noncoding RNAs that regulate a plethora of functions, biological processes and human diseases by targeting the messenger RNA stability through 3'UTR binding, leading to either mRNA cleavage or translation repression, depending on microRNA-mRNA complementarity degree. Additionally, strong evidence has suggested that dysregulation of miRNAs contributes to the etiology and progression of human cancers, such as lung cancer, the most common and deadliest cancer worldwide. Indeed, by acting as oncogenes or tumor suppressors, microRNAs control all aspects of lung cancer malignancy, including cell proliferation, survival, migration, invasion, angiogenesis, cancer stem cells, immune-surveillance escape, and therapy resistance; and their expressions are often associated with clinical parameters. Moreover, several deregulated microRNAs in lung cancer are carried by exosomes and microvesicles and secreted in body fluids, mainly the circulation, where they conserve their stable forms. Subsequently, seminal efforts have been focused on extracellular microRNAs levels as noninvasive diagnostic and prognostic biomarkers in lung cancer. In this review, focusing on recent literature, we summarize the deregulation, mechanisms of action, functions and highlight clinical applications of miRNAs for better management and design of future lung cancer targeted therapies.

Encephalomyeloradiculoneuropathy Revealing a Rare Case of Intravascular Large B-Cell Lymphoma.

Intravascular large B cell lymphoma (IVLBCL) is a rare form of extranodal non-Hodgkin's lymphoma, usually of B-cell lineage. Several organs are affected, most commonly the skin and the nervous system. We report a case of a 52-year-old man, with no medical history admitted with a five-month history of back pain with lower extremity numbness and tingling evolved to weakness associated with urinary retention, constipation and abdominal pain. Spinal magnetic resonance imaging (MRI) showed a gadolinium-enhancing lesion in the conus medullaris (CM). Electromyography (EMG) and nerve conduction velocity (NCV) test was consistent with demyelinating polyradiculoneuropathy in lower limbs. Slight clinical improvement with corticosteroids was observed. Three months after discharge, he presented a generalized tonic-clonic seizure. Cerebral MRI showed patchy lesions in the subcortical white matter with infiltration of the internal table of the skull with elevated serum lactate dehydrogenase (LDH). Calvarial biopsy revealed an intravascular large B-cell lymphoma. Treatment with cyclophosphamide and high-dose corticosteroids was initiated but the patient developed impaired consciousness and died of respiratory and circulatory failure six weeks after his readmission. Intravascular large B cell lymphoma should be considered in patients with a rapidly progressive severe encephalomyeloradiculoneuropathy. A biopsy of involved organs including the brain should not be delayed when IVLBCL is suspected, to initiate prompt systemic therapy.

Methylene blue and ifosfamide-induced encephalopathy: Myth or reality?

BACKGROUND: Ifosfamide-induced encephalopathy (IIE) is a rare and serious adverse reaction. Thus far, no standard medication has been documentedto be efficient in the reversal of IIE, and while ifosfamide infusion interruption and hydration are recommended, methylene blue (MB) administration remains controversial. METHODS: We retrospectively reviewed medical records to assess cases with IIE after ifosfamide infusion. We included all patients having received an ifosfamide infusion during their hospitalization in the medical oncology unit of the National Institute of Oncology in Rabat, Morocco, between September 2016 and September 2017. We subsequently conducted a literature review to determine the role of MB in IIE by searching PubMed using the terms "Methylene Blue" and "Ifosfamide". RESULTS: A total of 88 patients received ifosfamide, and four patients had IIE. Ifosfamide infusion was stopped immediately after the IIE occurrence, and patients underwent renal function correction with hydration. All patients received MB infusion, and three patients had an improvement of their neurological status. As regards the literature review, 34 articles were reviewed and 16 items were included in the review. Overall, 38 (65.5%) patients received MB infusion and 28 (75.6%) patients responded favorably to the treatment. CONCLUSIONS: Methylene blue can be used as a treatment for IIE owing to the severity of the IIE as well as absence of standard medication. Nonetheless, side effects such as serotonergic syndrome should be investigated. More broadly, prospective studies and controlled trials are needed to explore the contribution of MB in IIE management and encourage its use.

Virus-associated human cancers in Moroccan population: From epidemiology to prospective research.

Eight human viruses have been classified by the International Agency for Research on Cancer as carcinogenic or probably carcinogenic for humans. Infection with high risk human papillomaviruses, hepatitis B and C viruses, Epstein-Barr virus (EBV), human T-Cell Lymphotropic Virus Type 1 (HTLV-1), Human herpesvirus 8 (HHV-8), Merkel cell polyomavirus and human immunodeficiency virus-1 (HIV1) alone or in combination with other agents are the main etiologic factors of many cancers. This review highlights some aspects of virus-associated human cancers, potentially responsible for >14,000 malignancies per year in Morocco. Given that not all individuals infected with these viruses develop cancer, somatic alterations, genetic predisposition, and lifestyle or environmental factors obviously play potentializing roles modulating viral activity. These viral, host genetic signatures and lifestyle interactions may represent a reservoir of biomarkers for early detection, prevention of cancer and rationale-based therapy.

Chemotherapy-Induced Distal Enhancers Drive Transcriptional Programs to Maintain the Chemoresistant State in Ovarian Cancer.

Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharmacologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity in vitro and in vivo. In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers. SIGNIFICANCE: Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.

Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma.

PURPOSE: Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. The receptor tyrosine kinase MET is frequently upregulated or overactivated in GBM. Although clinically applicable MET inhibitors have been developed, resistance to single modality anti-MET drugs frequently occurs, rendering these agents ineffective. We aimed to determine the mechanisms of MET inhibitor resistance in GBM and use the acquired information to develop novel therapeutic approaches to overcome resistance.Experimental Design: We investigated two clinically applicable MET inhibitors: crizotinib, an ATP-competitive small molecule inhibitor of MET, and onartuzumab, a monovalent monoclonal antibody that binds to the extracellular domain of the MET receptor. We developed new MET inhibitor-resistant cells lines and animal models and used reverse phase protein arrays (RPPA) and functional assays to uncover the compensatory pathways in MET inhibitor-resistant GBM. RESULTS: We identified critical proteins that were altered in MET inhibitor-resistant GBM including mTOR, FGFR1, EGFR, STAT3, and COX-2. Simultaneous inhibition of MET and one of these upregulated proteins led to increased cell death and inhibition of cell proliferation in resistant cells compared with either agent alone. In addition, in vivo treatment of mice bearing MET-resistant orthotopic xenografts with COX-2 or FGFR pharmacological inhibitors in combination with MET inhibitor restored sensitivity to MET inhibition and significantly inhibited tumor growth. CONCLUSIONS: These data uncover the molecular basis of adaptive resistance to MET inhibitors and identify new FDA-approved multidrug therapeutic combinations that can overcome resistance.

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors.

The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virus-negative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments. Mol Cancer Ther; 17(2); 368-80. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."

Inactivation of the CRL4-CDT2-SET8/p21 ubiquitylation and degradation axis underlies the therapeutic efficacy of pevonedistat in melanoma.

The cullin-based CRL4-CDT2 ubiquitin ligase is emerging as a master regulator of cell proliferation. CRL4-CDT2 prevents re-initiation of DNA replication during the same cell cycle "rereplication" through targeted degradation of CDT1, SET8 and p21 during S-phase of the cell cycle. We show that CDT2 is overexpressed in cutaneous melanoma and predicts poor overall and disease-free survival. CDT2 ablation inhibited a panel of melanoma cell lines through the induction of SET8- and p21-dependent DNA rereplication and senescence. Pevonedistat (MLN4924), a specific inhibitor of the NEDD8 activating enzyme (NAE), inhibits the activity of cullin E3 ligases, thereby stabilizing a vast number of cullin substrates and resulting in cancer cell inhibition in vitro and tumor suppression in nude mice. We demonstrate that pevonedistat is effective at inhibiting the proliferation of melanoma cell lines in vitro through the induction of rereplication-dependent permanent growth arrest as well as through a transient, non-rereplication-dependent mechanism. CRISPR/Cas9-mediated heterozygous deletion of CDKN1A (encoding p21) or SET8 in melanoma cells demonstrated that the rereplication-mediated cytotoxicity of pevonedistat is mediated through preventing the degradation of p21 and SET8 and is essential for melanoma suppression in nude mice. By contrast, pevonedistat-induced transient growth suppression was independent of p21 or SET8, and insufficient to inhibit tumor growth in vivo. Pevonedistat additionally synergized with the BRAF kinase inhibitor PLX4720 to inhibit BRAF melanoma, and suppressed PLX4720-resistant melanoma cells. These findings demonstrate that the CRL4-CDT2-SET8/p21 degradation axis is the primary target of inhibition by pevonedistat in melanoma and suggest that a broad patient population may benefit from pevonedistat therapy. RESEARCH IN CONTEXT: The identification of new molecular targets and effective inhibitors is of utmost significance for the clinical management of melanoma. This study identifies CDT2, a substrate receptor for the CRL4 ubiquitin ligase, as a prognostic marker and therapeutic target in melanoma. CDT2 is required for melanoma cell proliferation and inhibition of CRL4(CDT2) by pevonedistat suppresses melanoma in vitro and in vivo through the induction of DNA rereplication and senescence through the stabilization of the CRL4(CDT2) substrates p21 and SET8. Pevonedistat also synergizes with vemurafenib in vivo and suppresses vemurafenib-resistant melanoma cells. These findings show a significant promise for targeting CRL4(CDT2) therapeutically.

A miR-297/hypoxia/DGK-α axis regulating glioblastoma survival.

BACKGROUND: Despite advances in the treatment of the most aggressive form of brain tumor, glioblastoma, patient prognosis remains disappointing. This failure in treatment has been attributed to dysregulated oncogenic pathways, as observed in other tumors. We and others have suggested the use of microRNAs (miRs) as therapeutic tools able to target multiple pathways in glioblastoma. METHODS: This work features PCR quantification of miRs and transient transfection of many glioblastoma cell lines with miRs, followed by cell number analysis, trypan blue staining, alamarBlue assay of cell viability, caspase-3/-7 activity assay, immunoblot of cleaved poly(ADP-ribose) polymerase and fluorescence activated cell sorting and imaging of apoptotic nuclei, cell invasion assays, MRIs of glioblastoma xenografts in mice using transiently transfected cells as well as posttumor treatment with lentiviral vector encoding miR-297, and analysis of miR-297 target diacylglycerol kinase (DGK)-α including immunoblot, 3'UTR luciferase activity, and rescue with DGK-α overexpression. Cell counts and DGK-α immunoblot were also analyzed in the context of hypoxia and with overexpression of heterogeneous ribonucleoprotein L (hnRNPL). RESULTS: We identified miR-297 as a highly cytotoxic microRNA in glioblastoma, with minimal cytotoxicity to normal astrocytes. miR-297 overexpression reduced in vitro invasiveness and in vivo tumor formation. DGK-α is shown to be a miR-297 target with a critical role in miR-297 toxicity. In addition, hypoxia and its mediator hnRNPL upregulated DGK-α and buffered the cytotoxic effects of miR-297. CONCLUSION: This work shows miR-297 as a novel and physiologic regulator of cancer cell survival, largely through targeting of DGK-α, and also indicates that hypoxia ameliorates miR-297 toxicity to cancer cells.

A novel PTEN/mutant p53/c-Myc/Bcl-XL axis mediates context-dependent oncogenic effects of PTEN with implications for cancer prognosis and therapy.

Phosphatase and tensin homolog located on chromosome 10 (PTEN) is one of the most frequently mutated tumor suppressors in human cancer including in glioblastoma. Here, we show that PTEN exerts unconventional oncogenic effects in glioblastoma through a novel PTEN/mutant p53/c-Myc/Bcl-XL molecular and functional axis. Using a wide array of molecular, genetic, and functional approaches, we demonstrate that PTEN enhances a transcriptional complex containing gain-of-function mutant p53, CBP, and NFY in human glioblastoma cells and tumor tissues. The mutant p53/CBP/NFY complex transcriptionally activates the oncogenes c-Myc and Bcl-XL, leading to increased cell proliferation, survival, invasion, and clonogenicity. Disruption of the mutant p53/c-Myc/Bcl-XL axis or mutant p53/CBP/NFY complex reverses the transcriptional and oncogenic effects of PTEN and unmasks its tumor-suppressive function. Consistent with these data, we find that PTEN expression is associated with worse patient survival than PTEN loss in tumors harboring mutant p53 and that a small molecule modulator of p53 exerts greater antitumor effects in PTEN-expressing cancer cells. Altogether, our study describes a new signaling pathway that mediates context-dependent oncogenic/tumor-suppressive role of PTEN. The data also indicate that the combined mutational status of PTEN and p53 influences cancer prognosis and anticancer therapies that target PTEN and p53.

Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition.

PURPOSE: The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors. EXPERIMENTAL DESIGN: We investigated the molecular factors and pathway activation signatures that determine sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells, and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor volume measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo. RESULTS: We found that HGF coexpression is a key predictor of response to c-MET inhibition among the examined factors and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and nonresponsive cells. Surprisingly, we also found that short pretreatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the antitumor effects of c-MET inhibition. We observed a similar ligand-induced sensitization effect to an EGF receptor small-molecule kinase inhibitor. CONCLUSIONS: These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition and propose ligand pretreatment as a potential new strategy for improving the anticancer efficacy of RTK inhibitors.

Oncogenic effects of miR-10b in glioblastoma stem cells.

MicroRNAs and cancer stem cells have emerged as critical players in glioblastoma, one of the deadliest human cancers. In this study, we investigated the expression and function of microRNA-10b in glioblastoma cells and stem cells. An analysis of The Cancer Genome Atlas data revealed a correlation between high miR-10b levels and poor prognosis in glioblastoma patients. We measured the levels of miR-10b and found that it is upregulated in human glioblastoma tissues, glioblastoma cell and stem cell lines as compared to normal human tissues or astrocytes. Inhibition of miR-10b with a specific antagomir inhibited the proliferation of glioblastoma established and stem cell lines. Inhibition of miR-10b strongly reduced cell invasion and migration in glioblastoma cell and stem cell lines while overexpression of miR-10b induced cell migration and invasion. We also investigated several predicted targets of miR-10b but could not verify any of them experimentally. Additionally, miR-10b inhibition significantly decreased the in vivo growth of stem cell-derived orthotopic GBM xenografts. Altogether, our findings confirm the oncogenic effects of miR-10b in GBM cells and show for the first time a role of this microRNA in GBM stem cells. Targeting miR-10b might therefore inhibit glioblastoma stem cells, which are thought to be at the origin of glioblastoma and to contribute its recurrence and resistance to therapy.

Cooperation between c-Met and focal adhesion kinase family members in medulloblastoma and implications for therapy.

We previously showed the involvement of the tyrosine kinase receptor c-Met in medulloblastoma malignancy. The nonreceptor tyrosine kinases focal adhesion kinase (FAK) and Pyk2 are key players in the progression of different cancers. However, their role in medulloblastoma malignancy is not well understood. In this study, using a protein array approach, we found that c-Met induces FAK and Pyk2 phosphorylation in medulloblastoma cells. We therefore studied the interactions between c-Met and FAK/Pyk2 and their implications for medulloblastoma therapy. We found that c-Met activates FAK and Pyk2 in several medulloblastoma cell lines. We also found that FAK and Pyk2 mediate the malignant effects of c-Met on medulloblastoma cell proliferation, migration, and invasion. On the basis of these findings, we hypothesized that combined c-Met and FAK inhibitions would have additive effects on the inhibition of medulloblastoma malignancy. To test this hypothesis, we assessed the effects on medulloblastoma malignancy parameters of single or combined treatments of medulloblastoma cells with c-Met and FAK small-molecule kinase inhibitors. We found a significant increase in the inhibitory effect of both inhibitors on medulloblastoma cell migration and cell invasion as compared with single inhibitions (P < 0.05). In addition, oral gavage treatment with c-Met inhibitor of mice bearing medulloblastoma xenografts significantly reduced in vivo tumor growth. Therefore, combining c-Met inhibitors with FAK inhibitors constitutes a new potential strategy for medulloblastoma therapy. Altogether, our study describes a role for FAK and Pyk2 in medulloblastoma malignancy, uncovers new interactions between c-Met and FAK/Pyk2, and proposes for the first time combining anti-c-Met and anti-FAK inhibitors as a new strategy for medulloblastoma therapy.

microRNA-34a is tumor suppressive in brain tumors and glioma stem cells.

We recently found that microRNA-34a (miR-34a) is downregulated in human glioma tumors as compared to normal brain, and that miR-34a levels in mutant-p53 gliomas were lower than in wildtype-p53 tumors. We showed that miR-34a expression in glioma and medulloblastoma cells inhibits cell proliferation, G1/S cell cycle progression, cell survival, cell migration and cell invasion, but that miR-34a expression in human astrocytes does not affect cell survival and cell cycle. We uncovered the oncogenes c-Met, Notch-1 and Notch-2 as direct targets of miR-34a that are inhibited by miR-34a transfection. We found that c-Met levels in human glioma specimens inversely correlate with miR-34a levels. We showed that c-Met and Notch partially mediate the inhibitory effects of miR-34a on cell proliferation and cell death. We also found that mir-34a expression inhibits in vivo glioma xenograft growth. We concluded that miR-34a is a potential tumor suppressor in brain tumors that acts by targeting multiple oncogenes. In this extra view, we briefly review and discuss the implications of these findings and present new data on the effects of miR-34a in glioma stem cells. The new data show that miR-34a expression inhibits various malignancy endpoints in glioma stem cells. Importantly, they also show for the first time that miR-34a expression induces glioma stem cell differentiation. Altogether, the data suggest that miR-34a is a tumor suppressor and a potential potent therapeutic agent that acts by targeting multiple oncogenic pathways in brain tumors and by inducing the differentiation of cancer stem cells.

XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC.

XL-184 (BMS-907351), under development by Exelixis Inc and Bristol-Myers Squibb Co, is a pan-tyrosine kinase inhibitor for the potential oral treatment of medullary thyroid cancer, glioblastoma multiforme and NSCLC. The prinicipal targets of XL-184 are MET, VEGFR-2 and RET, but the drug is also reported to display inhibitory activity against KIT, FLT3 and TEK. Preclinical studies demonstrated that XL-184 potently inhibited multiple receptor tyrosine kinases in various cancer cell lines and animal xenograft models, and that the drug exhibited significant oral bioavailability and blood-brain barrier penetration. A phase I clinical trial in patients with advanced solid malignancies indicated that XL-184 accumulated dose-dependently in the plasma and had a long terminal half-life. A phase II trial in patients with progressive or recurrent glioblastoma revealed modest but promising median progression-free survival. Toxicity and side effects for the drug have generally been of low-to-moderate severity. At the time of publication, three additional trials of XL-184 were recruiting patients, including a phase I trial in combination with standard of care in patients with glioblastoma, a phase I/II trial in combination with erlotinib in patients with NSCLC, and a phase III trial in patients with medullary thyroid cancer.

An orally bioavailable c-Met kinase inhibitor potently inhibits brain tumor malignancy and growth.

The receptor tyrosine kinase, c-Met and its ligand hepatocyte growth factor (HGF) are important regulators of malignancy in human cancer including brain tumors. c-Met is frequently activated in brain tumors and has emerged as a promising target for molecular therapies. Recently, an orally bioavailable small molecule kinase inhibitor of c-Met (SGX523) was developed by SGX Pharmaceuticals. We tested the effects of this inhibitor on c-Met brain tumor cell activation, c-Met-dependent malignancy, and in vivo glioma xenograft growth. SGX523 potently inhibited c-Met activation and c-Met-dependent signaling at nanomolar concentrations in glioma cells, primary gliomas, glioma stem cells and medulloblastoma cells. SGX523 treatment inhibited c-Met-dependent brain tumor cell proliferation and G1/S cell cycle progression. SGX523 also inhibited brain tumor cell migration and invasion. Furthermore, systemic delivery of SGX523 via oral gavage to mice bearing orthotopic human glioblastoma xenografts led to a significant decrease of in vivo tumor growth. These studies show that c-Met activation and c-Met-dependent brain tumor cell and stem cell malignancy can be inhibited by small molecules. The study also shows for the first time that oral delivery of a small molecule kinase inhibitor of c-Met inhibits intracranial tumor growth. These findings suggest that targeting c-Met with small molecule kinase inhibitors is a promising approach for brain tumor therapy.