Molecular Targets in Glioblastoma

Zorzan, Maira; Giordan, Enrico; Redaelli, Marco; Caretta, Antonio; Mucignat‐Caretta, Carla

doi:10.2217/fon.15.22

Cited by 34 publications

(35 citation statements)

References 140 publications

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“…In adults, components of the RTK/Ras/PI3K pathway are mutated in 88% of GBMs, those of the p53 pathway in 87%, and those of the Rb pathway in 78%. Mutations such as amplification of the epidermal growth factor receptor (EGFR) can be found in 45% of GBMs, gain of PI3K function in 15%, and loss of phosphatase and tensin homolog (PTEN) in 36% [23, 24]. These discoveries have led to a better understanding of the molecular signature of GBM and have revealed numerous consistent changes in genes and pathways [4, 16, 22, 25, 26].…”

Section: Glioblastoma Multiformementioning

confidence: 99%

“…The methylation status of MGMT (O 6 -methylguanine-DNA methyltransferase), a DNA-repair gene, is used as a GBM predictor because it is the major relevant biomarker for the response to temozolomide treatment [24]. Silencing of MGMT expression by promoter methylation impairs the ability of tumor cells to repair the DNA damage induced by temozolomide, further decreasing tumor cell survival [30].…”

Section: Current Standard Treatmentmentioning

confidence: 99%

“…Thus, combined treatment with temozolomide and radiation remains the standard regimen for all patients with GBM [19, 31]. However, the improved 2-year survival with temozolomide treatment is only in 27% [24], which is still unsatisfactory.…”

Section: Current Standard Treatmentmentioning

confidence: 99%

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Advances in epigenetic glioblastoma therapy

et al. 2017

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Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults despite contemporary gold-standard first-line treatment strategies. This type of tumor recurs in virtually all patients and no commonly accepted standard treatment exists for the recurrent disease. Therefore, advances in all scientific and clinical aspects of GBM are urgently needed. Epigenetic mechanisms are one of the major factors contributing to the pathogenesis of cancers, including glioblastoma. Epigenetic modulators that regulate gene expression by altering the epigenome and non-histone proteins are being exploited as therapeutic drug targets. Over the last decade, numerous preclinical and clinical studies on histone deacetylase (HDAC) inhibitors have shown promising results in various cancers. This article provides an overview of the anticancer mechanisms of HDAC inhibitors and the role of HDAC isoforms in GBM. We also summarize current knowledge on HDAC inhibitors on the basis of preclinical studies and emerging clinical data.

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Section: Glioblastoma Multiformementioning

confidence: 99%

Section: Current Standard Treatmentmentioning

confidence: 99%

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Advances in epigenetic glioblastoma therapy

et al. 2017

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“…The siRNAs-based RNAi technology has brought potential promises for patients to fight against this deadly disease by gene therapy approach (Gan et al, 2016). Great efforts have been made by the medicine research community to seek effective gene targets for treating glioblastoma and several strategies have been proposed and identified (Zorzan et al, 2015). In this study, anti-tumor therapeutics targeting TERT was employed as a unique therapy strategy due to the high prevalence of telomerase in most of the tumor cells (Ruden and Puri, 2013).…”

Section: Discussionmentioning

confidence: 99%

Quantum Dots-siRNA Nanoplexes for Gene Silencing in Central Nervous System Tumor Cells

et al. 2017

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RNA interfering (RNAi) using short interfering RNA (siRNA) is becoming a promising approach for cancer gene therapy. However, owing to the lack of safe and efficient carriers, the application of RNAi for clinical use is still very limited. In this study, we have developed cadmium sulphoselenide/Zinc sulfide quantum dots (CdSSe/ZnS QDs)-based nanocarriers for in vitro gene delivery. These CdSSe/ZnS QDs are functionalized with polyethyleneimine (PEI) to form stable nanoplex (QD-PEI) and subsequently they are used for siRNA loading which specially targets human telomerase reverse transcriptase (TERT). High gene transfection efficiency (>80%) was achieved on two glioblastoma cell lines, U87 and U251. The gene expression level (49.99 ± 10.23% for U87, 43.28 ± 9.66% for U251) and protein expression level (51.58 ± 7.88% for U87, 50.69 ± 7.59% for U251) of TERT is observed to decrease substantially after transfecting the tumor cells for 48 h. More importantly, the silencing of TERT gene expression significantly suppressed the proliferation of glioblastoma cells. No obvious cytotoxicity from these QD-PEI nanoplexes were observed over at 10 times of the transfected doses. Based on these results, we envision that QDs engineered here can be used as a safe and efficient gene nanocarrier for siRNA delivery and a promising tool for future cancer gene therapy applications.

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“…GBs are classified as primary or secondary according to their formation [3,4]. The two GB types are characterized by different genetic alterations, and mutations in isocitrate dehydrogenase (IDH) genes are most commonly used to discriminate between primary and secondary GBs [5][6][7]. Many studies showed that IDH mutations are more frequent in secondary GB (>80%) than in primary GB (<5%) and that they correlate with a better prognosis [8,9].…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas

Argadal

Mutlu

Aksoy

et al. 2019

Bosn J of Basic Med Sci

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Primary glioblastoma (GB) is the most aggressive type of brain tumors. While mutations in isocitrate dehydrogenase (IDH) genes are frequent in secondary GBs and correlate with a better prognosis, most primary GBs are IDH wild-type. Recent studies have shown that the long noncoding RNA metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is associated with aggressive tumor phenotypes in different cancers. Our aim was to clarify the prognostic significance of MALAT1 in IDH1/2 wild-type primary GB tumors. We analyzed IDH1/2 mutation status in 75 patients with primary GB by DNA sequencing. The expression of MALAT1 was detected in the 75 primary GB tissues and 5 normal brain tissues using reverse transcription quantitative PCR (RT-qPCR). The associations between MALAT1 expression, IDH1/2 mutation status, and clinicopathological variables of patients were determined. IDH1 (R132H) mutation was observed in 5/75 primary GBs. IDH2 (R172H) mutation was not detected in any of our cases. MALAT1 expression was significantly upregulated in primary GB vs. normal brain tissues (p = 0.025). Increased MALAT1 expression in IDH1/2 wild-type primary GBs correlated with patient age and tumor localization (p = 0.032 and p = 0.025, respectively). A multivariate analysis showed that high MALAT1 expression was an unfavorable prognostic factor for overall survival (p = 0.034) in IDH1/2 wild-type primary GBs. High MALAT1 expression may have a prognostic role in primary GBs independent of IDH mutations.

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Molecular Targets in Glioblastoma

Cited by 34 publications

References 140 publications

Advances in epigenetic glioblastoma therapy

Advances in epigenetic glioblastoma therapy

Quantum Dots-siRNA Nanoplexes for Gene Silencing in Central Nervous System Tumor Cells

Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas

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