Emerging Therapies for Glioblastoma

Thomas, Alissa A.; Brennan, Cameron; DeAngelis, Lisa M.; Omuro, Antonio

doi:10.1001/jamaneurol.2014.1701

Cited by 164 publications

(115 citation statements)

References 74 publications

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“…Interestingly, the third cluster had much lower survival times than both G1 and non-G1. This difference was observed in spite of the dramatic known differences in median survival for different tumor types (i.e., GBM vs. KIRC) [36,37]. Together these data indicate that mitotic trait classifications within single tumor types ( Figure 3A and 3B) or across a diverse set of tumors ( Figure 3D) correlate with patient outcome and mutation status, again demarcating the importance of cell cycle regulation in tumor biology.…”

Section: Pan-cancer Classification Of Tumors By Mitotic Traitmentioning

confidence: 82%

A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer

et al. 2016

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Progression through the cell cycle is largely dependent on waves of periodic gene expression, and the regulatory networks for these transcriptome dynamics have emerged as critical points of vulnerability in various aspects of tumor biology. Through RNA-sequencing of human cells during two continuous cell cycles (>2.3 billion paired reads), we identified over 1 000 mRNAs, non-coding RNAs and pseudogenes with periodic expression. Periodic transcripts are enriched in functions related to DNA metabolism, mitosis, and DNA damage response, indicating these genes likely represent putative cell cycle regulators. Using our set of periodic genes, we developed a new approach termed "mitotic trait" that can classify primary tumors and normal tissues by their transcriptome similarity to different cell cycle stages. By analyzing >4 000 tumor samples in The Cancer Genome Atlas (TCGA) and other expression data sets, we found that mitotic trait significantly correlates with genetic alterations, tumor subtype and, notably, patient survival. We further defined a core set of 67 genes with robust periodic expression in multiple cell types. Proteins encoded by these genes function as major hubs of protein-protein interaction and are mostly required for cell cycle progression. The core genes also have unique chromatin features including increased levels of CTCF/RAD21 binding and H3K36me3. Loss of these features in uterine and kidney cancers is associated with altered expression of the core 67 genes. Our study suggests new chromatin-associated mechanisms for periodic gene regulation and offers a predictor of cancer patient outcomes.

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Section: Pan-cancer Classification Of Tumors By Mitotic Traitmentioning

confidence: 82%

A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer

et al. 2016

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“…Grade III astrocytomas are also known as anaplastic astrocytomas, whereas grade IV astrocytomas, commonly referred to as glioblastoma, are the most aggressive of all gliomas. GBMs are also the most common type of glioma with an annual incident rate of 3.19/100,000 in the USA (5,6).…”

Section: Introductionmentioning

confidence: 99%

High expression of MMP9 in glioma affects cell proliferation and is associated with patient survival rates

et al. 2017

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Abstract. Human gliomas are a heterogeneous group of primary malignant brain tumors, which most commonly occur in the central nervous system of children and adults. Previous studies have suggested a prognostic role of matrix metalloproteinase 9 (MMP9) in glioma, however, the frequency and significance of the protein expression of MMP9 in glioma remain to be fully elucidated. In the present study, the expression of MMP9 was detected by reverse transcription-quantitative polymerase chain reaction (qPCR), western blotting and immunohistochemical staining. MTT and colony-forming assays were used to detect the role of MMP9 in the proliferation of glioma cells. MMP9 copy numbers in glioma were examined using qPCR. The results indicated that the expression level of MMP9 was significantly increased in glioma and was associated with World Health Organization (WHO) glioma grades. The high expression of MMP9 in tissues was an independent predictor of survival rates in patients with WHO grade III tumors. The overexpression of MMP9 promoted cell growth and induced a significant increase in clonogenic potential in U87 glioblastoma cell lines. These experimental data suggested that the overexpression of MMP9 in glioblastoma cells may occur primarily through an increase in gene copy number. The results of the present study suggested that the overexpression of MMP9 may be necessary for the transition to the more aggressive phenotype typical of WHO grade III gliomas, suggesting the likely involvement of the MMP9 gene in gliomagenesis and disease progression. IntroductionHuman gliomas are a heterogeneous group of primary malignant brain tumors, which most commonly occur in the central nervous system of children and adults (1). Glioblastoma multiforme (GBM), the most aggressive form of glioma, exhibits advanced features of malignancy, including rapid tumor cell proliferation, apoptosis resistance, florid necrosis and angiogenesis (2). These tumor properties are associated with poor clinical outcome by conferring resistance to chemotherapy and radiotherapy, and by promoting neurological debilitation leading to individuals succumbing to mortality within 12-18 months of diagnosis (3).Gliomas can be categorized based on the type of glial cell, which they are most histologically similar to, the location of the tumor and the aggressiveness of the cancer cells. Tumors, which are most similar to astrocytes are specifically termed astrocytomas and can be further classified into grades I-IV based on the criteria set by the World Health Organization (WHO) (4), with higher grades corresponding to more aggressive tumors. Grade I and II astrocytomas correspond to low-grade tumors, which are predominantly non-malignant. Grade III and IV astrocytomas are high-grade, malignant tumors. Grade III astrocytomas are also known as anaplastic astrocytomas, whereas grade IV astrocytomas, commonly referred to as glioblastoma, are the most aggressive of all gliomas. GBMs are also the most common type of glioma with an annual incident rate of 3.19/100,000 in ...

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“…Glioblastoma multiforme is the most common, malignant form of primary brain tumor with poor prognosis and 1-year survival rate of only 35.7% (1). Surgical resection combined with radiotherapy and adjuvant temozolomide is the current standard of care therapy, which extends survival but is not curative (2). Glioblastoma multiforme is more common in adults but can also arise in children.…”

Section: Introductionmentioning

confidence: 99%

Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus

Ramachandran

Dyczynski

et al. 2017

Clinical Cancer Research

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Background: Glioblastoma multiforme and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic approach for these malignancies. Here we evaluate the oncolytic capacity of the neurovirulent and partly IFNb-resistant Semliki Forest virus (SFV)-4 in glioblastoma multiformes and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal central nervous system (CNS) cells through insertion of microRNA target sequences for miR124, miR125, miR134.Methods: Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and glioblastoma multiforme cell lines and in patient-derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT-2A, GL261) and a syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFNb in inhibiting therapeutic efficacy was investigated.

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Emerging Therapies for Glioblastoma

Cited by 164 publications

References 74 publications

A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer

A high-resolution transcriptome map of cell cycle reveals novel connections between periodic genes and cancer

High expression of MMP9 in glioma affects cell proliferation and is associated with patient survival rates

Safe and Effective Treatment of Experimental Neuroblastoma and Glioblastoma Using Systemically Delivered Triple MicroRNA-Detargeted Oncolytic Semliki Forest Virus

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