The mTOR signaling pathway as a treatment target for intracranial neoplasms

Pachow, Doreen; Wick, Wolfgang; Gutmann, David H.; Mawrin, Christian

doi:10.1093/neuonc/nou164

Cited by 49 publications

(38 citation statements)

References 151 publications

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“…Rapamycin is an allosteric inhibitor of mTOR, which has been shown to dramatically reduce the self-renewal and tumorigenic activity of glioma cells and GSCs ( 53 ). In agreement with these results, several phase I and II clinical trials, with some of its rapalogs, such as everolimus or temsirolimus, alone or in combination, showed radiographic and symptomatic evidence of improvement in delaying tumor progression without provoking high toxicity in patients with newly diagnosed or recurrent glioblastoma ( 54 ). It has recently been demonstrated that mTOR regulates the expression of SOX2.…”

Section: Therapeutic Approaches Toward Sox2 Reduction In Gbmsupporting

confidence: 57%

Targeting SOX2 as a Therapeutic Strategy in Glioblastoma

et al. 2016

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Glioblastoma is the most common and malignant brain cancer in adults. Current therapy consisting of surgery followed by radiation and temozolomide has a moderate success rate and the tumor reappears. Among the features that a cancer cell must have to survive the therapeutic treatment and reconstitute the tumor is the ability of self-renewal. Therefore, it is vital to identify the molecular mechanisms that regulate this activity. Sex-determining region Y (SRY)-box 2 (SOX2) is a transcription factor whose activity has been associated with the maintenance of the undifferentiated state of cancer stem cells in several tissues, including the brain. Several groups have detected increased SOX2 levels in biopsies of glioblastoma patients, with the highest levels associated with poor outcome. Therefore, SOX2 silencing might be a novel therapeutic approach to combat cancer and particularly brain tumors. In this review, we will summarize the current knowledge about SOX2 in glioblastoma and recapitulate several strategies that have recently been described targeting SOX2 in this malignancy.

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Section: Therapeutic Approaches Toward Sox2 Reduction In Gbmsupporting

confidence: 57%

Targeting SOX2 as a Therapeutic Strategy in Glioblastoma

et al. 2016

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“…The protein codified by this gene shows similarity with NOTCH2 [29], so it is possible that neural tube defects might be caused also by mutations in other genes coding for proteins that belong to the Notch signaling pathway. This mechanism had been already described in many other genetic conditions such as Rasopathies [30], coesinopathy [31], and mTOR related conditions [32]. Consequently, other genes associated with neural tube defects [11], including spina bifida, were sequenced, with negative results.…”

Section: Discussionmentioning

confidence: 91%

Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome

Micaglio

Andronache

Carrera

et al. 2019

IJMS

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A.A.A.); Mario.carminati@grupposandonato.it (M.C.);Abstract: Alagille syndrome (AGS) is an autosomal-dominant disorder characterized by various degrees of abnormalities in the liver, heart, eyes, vertebrae, kidneys, face, vasculature, skeleton, and pancreas. This case report describes a newborn child exhibiting a congenital neural tube defect and peculiar craniofacial appearance characterized by a prominent forehead, deep-set eyes, bulbous nasal tip, and subtle upper lip. Just a few hours after birth, congenital heart disease was suspected for cyanosis and confirmed by heart evaluation. In particular, echocardiography indicated pulmonary atresia with ventricular septal defect with severe hypoplasia of the pulmonary branches (1.5 mm), large patent ductus arteriosus and several major aortopulmonary collateral arteries. Due to the association of peculiar craniofacial appearance and congenital heart disease, a form of Alagille syndrome was suspected. In addition, on the fifth day after birth, the patient developed jaundice, had acholic stools, and high levels of conjugated bilirubin and gamma-glutamyltransferase (GGT) were detected in the blood. Genetic testing revealed the novel variant c.802del in a single copy of the JAG1 gene. No variants in the NOTCH2 gene were detected. To the best of our knowledge, this is the first clinical description of a congenital neural tube defect in a molecularly confirmed Alagille patient. This work demonstrates a novel pathogenic heterozygous JAG1 mutation is associated with an atypical form of Alagille syndrome, suggesting an increased risk for neural tube defects compared to other Alagille patients.

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“…There are approximately twenty current clinical studies using mTOR inhibitors for the treatment of gliomas [ 55 ]. However, phase II studies with recurrent glioblastoma reported no efficacy of TEM in the combination with TMZ, sorafenib, bevacizumab, or erlotinib [ 55 ]. Although we used a clinically relevant TEM concentration [ 56 ], the discrepancy between cell culture responses (Fig.…”

Section: Discussionmentioning

confidence: 99%

Temozolomide promotes genomic and phenotypic changes in glioblastoma cells

et al. 2016

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BackgroundTemozolomide (TMZ) is a first-line drug for the treatment of glioblastoma. Long-term TMZ-treated tumour cells acquire TMZ resistance by profound reprogramming of the transcriptome, proteome, kinome, metabolism, and demonstrate versatile and opposite changes in proliferation, invasion, in vivo growth, and drug cross-resistance. We hypothesized that chromosomal instability (CIN) may be implicated in the generation of TMZ-driven molecular and phenotype diversity. CIN refers to the rate (cell-to-cell variability) with which whole chromosomes or portions of chromosomes are gained or lost.MethodsThe long-term TMZ-treated cell lines were established in vitro (U251TMZ1, U251TMZ2, T98GTMZ and C6TMZ) and in vivo (C6R2TMZ). A glioma model was achieved by the intracerebral stereotactic implantation of C6 cells into the striatum region of rats. Genomic and phenotypic changes were analyzed by conventional cytogenetics, array CGH, trypan blue exclusion assay, soft agar colony formation assay, scratch wound healing assay, transwell invasion assay, quantitative polymerase chain reaction, and Western blotting.ResultsLong-term TMZ treatment increased CIN-mediated genomic diversity in U251TMZ1, U251TMZ2 and T98GTMZ cells but reduced it in C6TMZ and C6R2TMZ cells. U251TMZ1 and U251TMZ2 cell lines, established in parallel with a similar treatment procedure with the only difference in the duration of treatment, underwent individual phenotypic changes. U251TMZ1 had a reduced proliferation and invasion but increased migration, whereas U251TMZ2 had an enhanced proliferation and invasion but no changes in migration. U251TMZ1 and U251TMZ2 cells demonstrated individual patterns in expression/activation of signal transduction proteins (e.g., MDM2, p53, ERK, AKT, and ASK). C6TMZ and C6R2TMZ cells had lower proliferation, colony formation efficiency and migration, whereas T98GTMZ cells had increased colony formation efficiency without any changes in proliferation, migration, and invasion. TMZ-treated lines demonstrated a differential response to a reduction in glucose concentration and an increased resistance to TMZ re-challenge but not temsirolimus (mTOR inhibitor) or U0126 (MEK1/2 inhibitor) treatment.ConclusionLong-term TMZ treatment selected resistant genotype-phenotype variants or generated novel versatile phenotypes by increasing CIN. An increase of resistance to TMZ re-challenge seems to be the only predictable trait intrinsic to all long-term TMZ-treated tumour cells. Changes in genomic diversity may be responsible for heterogeneous phenotypes of TMZ-treated cell lines.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0311-8) contains supplementary material, which is available to authorized users.

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The mTOR signaling pathway as a treatment target for intracranial neoplasms

Cited by 49 publications

References 151 publications

Targeting SOX2 as a Therapeutic Strategy in Glioblastoma

Targeting SOX2 as a Therapeutic Strategy in Glioblastoma

Novel JAG1 Deletion Variant in Patient with Atypical Alagille Syndrome

Temozolomide promotes genomic and phenotypic changes in glioblastoma cells

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