Peptide-based inhibition of the HOXA9/PBX interaction retards the growth of human meningioma.

BACKGROUND: Meningiomas are the most common type of intracranial tumor, accounting for between 24 and 30 % of primary intracranial tumors. Thus far, no biomarkers exist to reliably predict the clinical outcome of meningiomas. A previous genome-wide methylation analysis revealed that HOXA9 is one of the most functionally relevant biomarkers. In this study, we have examined whether HOXA9 is a potential therapeutic target in meningiomas, using HXR9, a peptide inhibitor of the interaction between HOXA9 and its cofactor PBX. METHODS: We determined the expression level of HOXA9 in human meningiomas, meningioma cell lines, and normal brain tissue. Meningioma in culture and in subcutaneous tumors was treated with HXR9. We also examined the disruption of HOXA9/PBX dimers. RESULTS: We first confirmed that HOXA9 is highly expressed in meningiomas, but not in normal brain tissue. The HXR9 peptide blocks the binding of HOXA9 to PBX, leading to an alteration of DNA binding, and subsequent regulation of their target genes. HXR9 markedly inhibited the growth of meningioma cells and subcutaneous meningeal tumors. CONCLUSION: There is no effective chemotherapy for meningiomas at present, and targeting the HOXA9/PBX interaction may represent a novel treatment option for this disease.

A novel method of intracranial injection via the postglenoid foramen for brain tumor mouse models.

OBJECT: Mouse models have been widely used in developing therapies for human brain tumors. However, surgical techniques such as bone drilling and skin suturing to create brain tumors in adult mice are still complicated. The aim of this study was to establish a simple and accurate method for intracranial injection of cells or other materials into mice. METHODS: The authors performed micro CT scans and skull dissection to assess the anatomical characteristics of the mouse postglenoid foramen. They then used xenograft and genetically engineered mouse models to evaluate a novel technique of percutaneous intracranial injection via the postglenoid foramen. They injected green fluorescent protein-labeled U87MG cells or virus-producing cells into adult mouse brains via the postglenoid foramen and identified the location of the created tumors by using bioluminescence imaging and histological analysis. RESULTS: The postglenoid foramen was found to be a well-conserved anatomical structure that allows percutaneous injection into the cerebrum, cerebellum, brainstem, and basal cistern in mice. The mean (± SD) time for the postglenoid foramen injection technique was 88 ± 15 seconds. The incidence of in-target tumor formation in the xenograft model ranged from 80% to 100%, depending on the target site. High-grade gliomas were successfully developed by postglenoid foramen injection in the adult genetically engineered mouse using virus-mediated platelet-derived growth factor B gene transfer. There were no procedure-related complications. CONCLUSIONS: The postglenoid foramen can be used as a needle entry site into the brain of the adult mouse. Postglenoid foramen injection is a less invasive, safe, precise, and rapid method of implanting cells into the adult mouse brain. This method can be applied to both orthotopic xenograft and genetically engineered mouse models and may have further applications in mice for the development of therapies for human brain tumors.

Glioma-initiating cells and molecular pathology: implications for therapy.

There is now compelling evidence that gliomas harbor a small population of cells, termed glioma-initiating cells (GICs), characterized by their ability to undergo self-renewal and initiate tumorigenesis. The development of therapeutic strategies targeted toward GIC signaling may improve the treatment of malignant gliomas. The characterization of GICs provides a clue to elucidating histological heterogeneity and treatment failure. The role of the stem cell marker CD133 in the initiation and progression of brain tumors is still uncertain. Here, we review some of the signaling mechanisms involved in GIC biology, such as phosphatase and tensin homolog (PTEN), sonic hedgehog, Notch, and WNT signaling pathways, maternal embryonic leucine-zipper kinase (MELK), BMI1, and Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling. In addition, we discuss the role of microRNAs in GICs by focusing on microRNA-21 regulation by type I interferon.

The global DNA methylation surrogate LINE-1 methylation is correlated with MGMT promoter methylation and is a better prognostic factor for glioma.

Gliomas are the most frequently occurring primary brain tumor in the central nervous system of adults. Glioblastoma multiformes (GBMs, WHO grade 4) have a dismal prognosis despite the use of the alkylating agent, temozolomide (TMZ), and even low grade gliomas (LGGs, WHO grade 2) eventually transform to malignant secondary GBMs. Although GBM patients benefit from promoter hypermethylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) that is the main determinant of resistance to TMZ, recent studies suggested that MGMT promoter methylation is of prognostic as well as predictive significance for the efficacy of TMZ. Glioma-CpG island methylator phenotype (G-CIMP) in the global genome was shown to be a significant predictor of improved survival in patients with GBM. Collectively, we hypothesized that MGMT promoter methylation might reflect global DNA methylation. Additionally in LGGs, the significance of MGMT promoter methylation is still undetermined. In the current study, we aimed to determine the correlation between clinical, genetic, and epigenetic profiles including LINE-1 and different cancer-related genes and the clinical outcome in newly diagnosed 57 LGG and 54 GBM patients. Here, we demonstrated that (1) IDH1/2 mutation is closely correlated with MGMT promoter methylation and 1p/19q codeletion in LGGs, (2) LINE-1 methylation levels in primary and secondary GBMs are lower than those in LGGs and normal brain tissues, (3) LINE-1 methylation is proportional to MGMT promoter methylation in gliomas, and (4) higher LINE-1 methylation is a favorable prognostic factor in primary GBMs, even compared to MGMT promoter methylation. As a global DNA methylation marker, LINE-1 may be a promising marker in gliomas.