Abstract:
INTRODUCTION:Clinical trials directed at mechanistic target of rapamycin (mTOR) inhibition have yielded disappointing results in glioblastoma (GBM). A major mechanism of resistance involves the activation of a salvage pathway stimulating internal ribosome entry site (IRES)-mediated protein synthesis. PRMT5 activity has been implicated in the enhancement of IRES activity. METHODS:We analyzed the expression and activity of PRMT5 in response to mTOR inhibition in GBM cell lines and short-term patient cultures. To determine whether PRMT5 conferred resistance we used genetic and pharmacological approaches to ablate PRMT5 activity and assessed the effects on in vitro and in vivo sensitivity. Mutational analyses of the requisite IRES-trans-acting factor (ITAF), hnRNP A1 determined whether PRMT5-mediated methylation was necessary for ITAF RNA binding and IRES activity. RESULTS:PRMT5 activity is stimulated in response to mTOR inhibitors. Knockdown or treatment with a PRMT5 inhibitor blocked IRES activity and sensitizes GBM cells. Ectopic expression of non-methylatable hnRNP A1 mutants demonstrated that methylation of either arginine residues 218 or 225 was sufficient to maintain IRES binding and hnRNP A1-dependent cyclin D1 or c-MYC IRES activity, however a double R218K/R225K mutant was unable to do so. The PRMT5 inhibitor EPZ015666 displayed synergistic anti-GBM effects in vitro and in a xenograft mouse model in combination with PP242. CONCLUSIONS:These results demonstrate that PRMT5 activity is stimulated upon mTOR inhibition in GBM. Our data further support a signaling cascade in which PRMT5-mediated methylation of hnRNP A1 promotes IRES RNA binding and activation of IRES-mediated protein synthesis and resultant mTOR inhibitor resistance.
journal_name
J Neurooncoljournal_title
Journal of neuro-oncologyauthors
Holmes B,Benavides-Serrato A,Saunders JT,Landon KA,Schreck AJ,Nishimura RN,Gera Jdoi
10.1007/s11060-019-03274-0subject
Has Abstractpub_date
2019-10-01 00:00:00pages
11-22issue
1eissn
0167-594Xissn
1573-7373pii
10.1007/s11060-019-03274-0journal_volume
145pub_type
杂志文章abstract::Retaspimycin hydrochloride (IPI-504), an Hsp90 (heat shock protein 90) inhibitor, has shown activity in multiple preclinical cancer models, such as lung, breast and ovarian cancers. However, its biological effects in gliomas and normal brain derived cellular populations remain unknown. In this study, we profiled the e...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-014-1579-y
更新日期:2014-12-01 00:00:00
abstract::Meningiomas, when benign, are commonly treated with surgical resection alone. However, the optimal treatment for patients with subtotally resected or recurrent World Health Organization (WHO) grade I tumors, or WHO grade II and III tumors, regardless of the extent of resection, is not well defined, with both a paucity...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1007/s11060-010-0375-6
更新日期:2010-09-01 00:00:00
abstract::Aberrant activation of Akt is a common finding in adult malignant gliomas, resulting in most cases from mutations or deletions involving PTEN, which allows constitutive Akt phosphorylation. In contrast, we have previously reported that pediatric malignant gliomas, which are morphologically similar to lesions arising i...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-010-0297-3
更新日期:2010-09-01 00:00:00
abstract::Unexpected early epidural spinal metastasis in a case of osteosarcoma occurred in a patient receiving treatment with cis-diamminedichloroplatinum-II (cisplatin). The initial neurologic symptomatology manifested as paresthesias in the feet which developed 2 months after initiation of treatment (cumulative dose of cispl...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/BF00165378
更新日期:1986-01-01 00:00:00
abstract:QUESTION:Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings? Target population These recommendations apply to adults with a newly diagnosed single b...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1007/s11060-009-0061-8
更新日期:2010-01-01 00:00:00
abstract::Leptomeningeal carcinomatosis is a painful and debilitating complication of cancer. Indwelling reservoirs provide continuous assess to the subarachnoid space, making leptomeningeal cancer potentially amenable to gene therapy. Adeno-associated virus (AAV) is a defective virus not associated with any human disease. We u...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1023/a:1005702228721
更新日期:1997-09-01 00:00:00
abstract::Using the novel tissue microarray technique, we studied immunohistochemical expression of cell cycle regulators p53, p21, pRb in 42 grade II oligodendrogliomas, 16 grade III anaplastic oligodendrogliomas, 10 primary and 4 recidive grade II oligoastrocytomas, 10 grade III oligoastrocytomas and 2 other grade II mixed gl...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1023/a:1012961918848
更新日期:2001-10-01 00:00:00
abstract::High-grade gliomas release excitotoxic concentrations of glutamate which contributes to their malignant phenotype. To improve our understanding of the mechanisms by which glutamate enhances tumor growth and invasion, we examined alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-mediated signaling in glio...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-008-9552-2
更新日期:2008-06-01 00:00:00
abstract::Two main varieties of recognition disorders are distinguished in neuropsychology: agnosias and semantic disorders. The term agnosias is generally used to denote recognition defects limited to a single perceptual modality (which is itself apparently intact), whereas the term semantic disorders is used to denote recogni...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-012-0823-6
更新日期:2012-06-01 00:00:00
abstract::Gliomatosis cerebri (GC) are extensively infiltrative glial tumors classified as astrocytic tumors in the current World Health Organization (WHO) classification scheme. In investigating the tumorigenesis of GC, we reviewed 28 cases of GC immunohistochemically and carried out array-based comparative genomic hybridizati...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-008-9665-7
更新日期:2008-12-01 00:00:00
abstract::Cancer related stroke may have different phenotypes from non-cancer stroke, especially in terms of stroke progression and recurrence. We performed a case-control study to identify their incidences and risk factors in cancer related stroke. Between January 2001 and December 2009, we conducted a retrospective review of ...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-012-1011-4
更新日期:2013-02-01 00:00:00
abstract::Pituitary metastases are uncommon, ranging from 1 to 5 % of all metastases. Between 10 and 30 % of pituitary lesions are symptomatic responsible for diabetes insipidus, visual field defect or cranial nerve palsy. Primary sites are lung or breast in two-thirds of cases. There is no current reference concerning treatmen...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-015-1967-y
更新日期:2016-01-01 00:00:00
abstract::Cavernous angiomas of the spinal cord exhibit imaging characteristics that may overlap with those of hemorrhagic ependymoma. In the present study, we aimed to identify specific magnetic resonance imaging (MRI) findings that could be used to differentiate cavernous angioma from hemorrhagic ependymoma, and to evaluate s...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-016-2239-1
更新日期:2016-10-01 00:00:00
abstract::Anaplastic mixed gliomas are rare tumors that occur mostly in the cerebral hemispheres. They have a distinctive histological appearance characterized by the presence of two or more glial cellular constituents. The incidence of malignant mixed glioma of the brainstem and posterior fossa is extremely low. The authors re...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1023/a:1005969429013
更新日期:1998-04-01 00:00:00
abstract::Previous study revealed that higher expression of transforming growth factor beta induced (TGFBI) is correlated to poorer cancer-specific survival and higher proportion of tumor necrosis and Fuhrman grades III and IV in clear cell renal cell carcinomas. However, the relationships between TGFBI expression and malignant...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-017-2729-9
更新日期:2018-04-01 00:00:00
abstract::p53 mutations are the most frequently detected genetic alterations of gliomas, appearing in a similar proportion of low and high grade astrocytomas, while the amplification of epidermal growth factor receptor (EGFR) gene appears mainly in glioblastomas. Thus, these changes seem to delineate two subgroups of high grade...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/BF01054764
更新日期:1995-10-01 00:00:00
abstract::Malignant peripheral nerve sheath tumors are rare spindle-cell sarcomas derived from Schwann cells or pluripotent cells of the neural crest. They arise from the spinal roots, peripheral nerves, brachial and lumbosacral plexi, cranial nerves and terminal nerve fibers within soft tissue, intestine, lung and bone. These ...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-004-4596-4
更新日期:2005-09-01 00:00:00
abstract:INTRODUCTION:The standard treatment for primary central nervous system lymphoma (PCNSL) involves induction methotrexate-based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). As WBRT carries a substantial risk for cognitive impairment, alternative consolidation treatments have been used to re...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-019-03257-1
更新日期:2019-09-01 00:00:00
abstract::During glioma resection, 5-aminolevulinic acid (5-ALA) and fluorescein sodium (Fl-Na) are used for photodynamic tumor visualization. The objective of this study was to evaluate the pathological findings of the boundary zone between the tumor and adjacent normal brain in glioblastoma patients undergoing simultaneous do...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-017-2445-5
更新日期:2017-06-01 00:00:00
abstract::A retrospective evaluation of single agent bevacizumab in adults with recurrent glioblastoma (GBM) with an objective of determining progression free survival (PFS). There is no standard therapy for recurrent GBM after failure of alkylator-based chemotherapy. A total of 50 adults, ages 36-70 years (median 64), with rec...
journal_title:Journal of neuro-oncology
pub_type: 临床试验,杂志文章
doi:10.1007/s11060-009-9957-6
更新日期:2010-01-01 00:00:00
abstract::Bevacizumab is effective for the treatment of non-small cell lung cancer (NSCLC). Ongoing trials are exploring the safety of bevacizumab in patients with inactive, previously treated brain metastases. However, bevacizumab safety and efficacy in the treatment of active brain metastases is unknown. Bevacizumab received ...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-010-0200-2
更新日期:2010-12-01 00:00:00
abstract::Adrenomedullin is a vasoactive peptide that is upregulated in higher-grade gliomas and promotes tumor cell proliferation. Since reduced activity of the anti-oncogene PTEN seems to also correlate with higher tumor grade, this suggests an inverse association between PTEN activity and adrenomedullin expression. PC12 pheo...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-005-9035-7
更新日期:2006-09-01 00:00:00
abstract::Recurrent gliomas are most often treated by chemotherapy. However, these tumors typically acquire resistance to most drugs administered, and patients will usually die of recurrent tumor. Factors which may play a role include overexpression of putative multidrug resistance genes, such as the multidrug resistance gene 1...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/BF00182138
更新日期:1996-08-01 00:00:00
abstract:INTRODUCTION:Central nervous system (CNS) involvement, especially involvement of the cerebrospinal fluid (CSF), is common in several haematological malignancies. Intrathecal (IT) chemotherapy can be used to manage CSF involvement. METHODS:Here we evaluated the effectiveness of IT chemotherapy among 80 patients with ha...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-018-2849-x
更新日期:2018-08-01 00:00:00
abstract::Glioblastoma (GBM) is the most common malignant primary brain tumor. Although clinical presentation and brain imaging might be suggestive, histopathological evaluation by means of a brain biopsy is routinely performed to establish the diagnosis. A serum marker indicative of GBM may simplify the diagnostic work-up of p...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-015-1978-8
更新日期:2016-01-01 00:00:00
abstract::Convection-enhanced delivery (CED) of highly stable PEGylated liposomes encapsulating chemotherapeutic drugs has previously been effective against malignant glioma xenografts. We have developed a novel, convectable non-PEGylated liposomal formulation that can be used to encapsulate both the topoisomerase I inhibitor t...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-009-9917-1
更新日期:2009-11-01 00:00:00
abstract::The diagnosis of brain metastases is associated with a poor prognosis reflecting uncontrolled primary disease that has spread to the relative sanctuary of the central nervous system. 20 % of brain metastases occur in the posterior fossa and are associated with significant morbidity. The risk of acute hydrocephalus and...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-016-2254-2
更新日期:2016-12-01 00:00:00
abstract::Four cases of intracranial osteosarcoma are reported. In three cases the tumors were primary neoplasms arising from the sellar region, base of the occiput and the parieto-occipital area. One case represented osteosarcoma metastatic to the cerebellum, a site not previously described, from a primary tumor at the femur. ...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章,评审
doi:10.1023/a:1006007411312
更新日期:1998-10-01 00:00:00
abstract:OBJECT:Etoposide, a topoisomerase-II inhibitor promotes DNA damage and apoptosis of cancer cells. In this study, we have examined the ability of the histone deacetylase inhibitor, valproic acid (VPA) to modulate gene expression and sensitize glioblastoma cell lines to the cytotoxic effects of etoposide in vitro. METHO...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-007-9402-7
更新日期:2007-11-01 00:00:00
abstract::The aim of this work was to determine the accuracy and precision of stereotactic localization and treatment delivery using a helical tomotherapy based stereotactic radiosurgery (SRS) system. A tomotherapy specific radiosurgery workflow was designed that exploits the system's on board megavotage CT (MVCT) imaging syste...
journal_title:Journal of neuro-oncology
pub_type: 杂志文章
doi:10.1007/s11060-010-0227-4
更新日期:2010-06-01 00:00:00