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  • 1
    Online Resource
    Online Resource
    The Receptor Interacting Protein 1 Inhibits p53 Induction through NF-κB Activation and Confers a Worse Prognosis in Glioblastoma
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 7 ( 2009-04-01), p. 2809-2816
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 7 ( 2009-04-01), p. 2809-2816
    Abstract: Nuclear factor-κB (NF-κB) activation may play an important role in the pathogenesis of cancer and also in resistance to treatment. Inactivation of the p53 tumor suppressor is a key component of the multistep evolution of most cancers. Links between the NF-κB and p53 pathways are under intense investigation. In this study, we show that the receptor interacting protein 1 (RIP1), a central component of the NF-κB signaling network, negatively regulates p53 tumor suppressor signaling. Loss of RIP1 from cells results in augmented induction of p53 in response to DNA damage, whereas increased RIP1 level leads to a complete shutdown of DNA damage–induced p53 induction by enhancing levels of cellular mdm2. The key signal generated by RIP1 to up-regulate mdm2 and inhibit p53 is activation of NF-κB. The clinical implication of this finding is shown in glioblastoma, the most common primary malignant brain tumor in adults. We show that RIP1 is commonly overexpressed in glioblastoma, but not in grades II and III glioma, and increased expression of RIP1 confers a worse prognosis in glioblastoma. Importantly, RIP1 levels correlate strongly with mdm2 levels in glioblastoma. Our results show a key interaction between the NF-κB and p53 pathways that may have implications for the targeted treatment of glioblastoma. [Cancer Res 2009;69(7):2809–16]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-4079
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 2
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    Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH -Mutant Glioma
    American Society of Clinical Oncology (ASCO) ; 2016
    In:  Journal of Clinical Oncology Vol. 34, No. 33 ( 2016-11-20), p. 4030-4039
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 33 ( 2016-11-20), p. 4030-4039
    Abstract: Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. Results Quantitative 2HG MRS was technically and biologically reproducible. 2HG concentration 〉 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2016.67.1222
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
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  • 3
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    In vivo MRS measurement of 2‐hydroxyglutarate in patient‐derived IDH‐mutant xenograft mouse models versus glioma patients
    Wiley ; 2020
    In:  Magnetic Resonance in Medicine Vol. 84, No. 3 ( 2020-09), p. 1152-1160
    Details
    In: Magnetic Resonance in Medicine, Wiley, Vol. 84, No. 3 ( 2020-09), p. 1152-1160
    Abstract: To generate a preclinical model of isocitrate dehydrogenase (IDH) mutant gliomas from glioma patients and design a MRS method to test the compatibility of 2‐hydroxyglutarate (2HG) production between the preclinical model and patients. Methods Five patient‐derived xenograft (PDX) mice were generated from two glioma patients with IDH1 R132H mutation. A PRESS sequence was tailored at 9.4 T, with computer simulation and phantom analyses, for improving 2HG detection in mice. 2HG and other metabolites in the PDX mice were measured using the optimized MRS at 9.4 T and compared with 3 T MRS measurements of the metabolites in the parental‐tumor patients. Spectral fitting was performed with LCModel using in‐house basis spectra. Metabolite levels were quantified with reference to water. Results The PRESS TE was optimized to be 96 ms, at which the 2HG 2.25 ppm signal was narrow and inverted, thereby leading to unequivocal separation of the 2HG resonance from adjacent signals from other metabolites. The optimized MRS provided precise detection of 2HG in mice compared to short‐TE MRS at 9.4 T. The 2HG estimates in PDX mice were in excellent agreement with the 2HG measurements in the patients. Conclusion The similarity of 2HG production between PDX models and parental‐tumor patients indicates that PDX tumors retain the parental IDH metabolic fingerprint and can serve as a preclinical model for improving our understanding of the IDH‐mutation associated metabolic reprogramming.
    Type of Medium: Online Resource
    ISSN: 0740-3194 , 1522-2594
    URL: Issue
    URL: Article
    DOI: 10.1002/mrm.v84.3
    DOI: 10.1002/mrm.28183
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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  • 4
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    The Telomerase Antagonist, Imetelstat, Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 1 ( 2010-01-01), p. 154-163
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 1 ( 2010-01-01), p. 154-163
    Abstract: Purpose: Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo. Experimental Design: Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity, and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat. Results: Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC50 0.45 μmol/L). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation, and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood-brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg every day for three days), showed ∼70% inhibition of telomerase activity. Chronic systemic treatment produced a marked decrease in the rate of xenograft subcutaneous tumor growth. Conclusion: This preclinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies. Clin Cancer Res; 16(1); 154–63
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-09-2850
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 5
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    Metabolism of [U‐ 13 C]glucose in human brain tumors in vivo
    Wiley ; 2012
    In:  NMR in Biomedicine Vol. 25, No. 11 ( 2012-11), p. 1234-1244
    Details
    In: NMR in Biomedicine, Wiley, Vol. 25, No. 11 ( 2012-11), p. 1234-1244
    Abstract: Glioblastomas and brain metastases demonstrate avid uptake of 2‐[ 18 F]fluoro‐2‐deoxyglucose by positron emission tomography and display perturbations of intracellular metabolite pools by 1 H MRS. These observations suggest that metabolic reprogramming contributes to brain tumor growth in vivo . The Warburg effect, excess metabolism of glucose to lactate in the presence of oxygen, is a hallmark of cancer cells in culture. 2‐[ 18 F]Fluoro‐2‐deoxyglucose‐positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation relative to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo . In particular, the capacity of human brain cancers to oxidize glucose in the tricarboxylic acid cycle is unknown. Here, we studied the metabolism of human brain tumors in situ . [U‐ 13  C]Glucose (uniformly labeled glucose, i.e. d ‐glucose labeled with 13  C in all six carbons) was infused during surgical resection, and tumor samples were subsequently subjected to 13 C NMR spectroscopy. The analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the tricarboxylic acid cycle, anaplerosis and de novo glutamine and glycine synthesis contributed significantly to the ultimate disposition of glucose carbon. Surprisingly, less than 50% of the acetyl‐coenzyme A pool was derived from blood‐borne glucose, suggesting that additional substrates contribute to tumor bioenergetics. This study illustrates a convenient approach that capitalizes on the high information content of 13 C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse cancers growing in their native microenvironment. Copyright © 2012 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0952-3480 , 1099-1492
    URL: Issue
    URL: Article
    DOI: 10.1002/nbm.v25.11
    DOI: 10.1002/nbm.2794
    Language: English
    Publisher: Wiley
    Publication Date: 2012
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    detail.hit.zdb_id: 1000976-0
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  • 6
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    Measurement of 13 C turnover into glutamate and glutamine pools in brain tumor patients
    Wiley ; 2017
    In:  FEBS Letters Vol. 591, No. 21 ( 2017-11), p. 3548-3554
    Details
    In: FEBS Letters, Wiley, Vol. 591, No. 21 ( 2017-11), p. 3548-3554
    Abstract: Malignant brain tumors are known to utilize acetate as an alternate carbon source in the citric acid cycle for their bioenergetics. 13 C NMR ‐based isotopomer analysis has been used to measure turnover of 13 C‐acetate carbons into glutamate and glutamine pools in tumors. Plasma from the patients infused with [1,2‐ 13 C]acetate further revealed the presence of 13 C isotopomers of glutamine, glucose, and lactate in the circulation that were generated due to metabolism of [1,2‐ 13 C]acetate by peripheral organs. In the tumor cells, [4‐ 13 C] and [3,4‐ 13 C]glutamate and glutamine isotopomers were generated from blood‐borne 13 C‐labeled glucose and lactate which were formed due to [1,2‐ 13 C[acetate metabolism of peripheral tissues. [4,5‐ 13 C] and [3,4,5‐ 13 C]glutamate and glutamine isotopomers were produced from [1,2‐ 13 C]acetyl‐CoA that was derived from direct oxidation of [1,2‐ 13 C] acetate in the tumor. Major portion of C4 13 C fractional enrichment of glutamate (93.3 ± 0.02%) and glutamine (90.9 ± 0.03%) were derived from [1,2‐ 13 C]acetate‐derived acetyl‐CoA.
    Type of Medium: Online Resource
    ISSN: 0014-5793 , 1873-3468
    URL: Issue
    URL: Article
    DOI: 10.1002/feb2.2017.591.issue-21
    DOI: 10.1002/1873-3468.12867
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 2017
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    SSG: 12
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  • 7
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    In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 12 ( 2014-03-25), p. 4542-4547
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 12 ( 2014-03-25), p. 4542-4547
    Abstract: Glioblastoma multiforme (GBM), which account for more than 50% of all gliomas, is among the deadliest of all human cancers. Given the dismal prognosis of GBM, it would be advantageous to identify early biomarkers of a response to therapy to avoid continuing ineffective treatments and to initiate other therapeutic strategies. The present in vivo longitudinal study in an orthotopic mouse model demonstrates quantitative assessment of early treatment response during short-term chemotherapy with temozolomide (TMZ) by amide proton transfer (APT) imaging. In a GBM line, only one course of TMZ (3 d exposure and 4 d rest) at a dose of 80 mg/kg resulted in substantial reduction in APT signal compared with untreated control animals, in which the APT signal continued to increase. Although there were no detectable differences in tumor volume, cell density, or apoptosis rate between groups, levels of Ki67 (index of cell proliferation) were substantially reduced in treated tumors. In another TMZ-resistant GBM line, the APT signal and levels of Ki67 increased despite the same course of TMZ treatment. As metabolite changes are known to occur early in the time course of chemotherapy and precede morphologic changes, these results suggest that the APT signal in glioma may be a useful functional biomarker of treatment response or degree of tumor progression. Thus, APT imaging may serve as a sensitive biomarker of early treatment response and could potentially replace invasive biopsies to provide a definitive diagnosis. This would have a major impact on the clinical management of patients with glioma.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1323855111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2014
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    SSG: 11
    SSG: 12
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  • 8
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    Measurement of glycine in the human brain in vivo by 1 H‐MRS at 3 T: application in brain tumors
    Wiley ; 2011
    In:  Magnetic Resonance in Medicine Vol. 66, No. 3 ( 2011-09), p. 609-618
    Details
    In: Magnetic Resonance in Medicine, Wiley, Vol. 66, No. 3 ( 2011-09), p. 609-618
    Abstract: Glycine is a key metabolic intermediate required for the synthesis of proteins, nucleic acids, and other molecules, and its detection in cancer could, therefore, provide biologically relevant information about the growth of the tumor. Here, we report measurement of glycine in human brain and gliomas by an optimized point‐resolved spectroscopy sequence at 3 T. Echo time dependence of the major obstacle, myo ‐inositol (mI) multiplet, was investigated with numerical simulations, incorporating the 3D volume localization. The simulations indicated that a subecho pair (TE 1 , TE 2 ) = (60, 100) ms permits detection of both glycine and mI with optimum selectivity. In vivo validation of the optimized point‐resolved spectroscopy was conducted on the right parietal cortex of five healthy volunteers. Metabolite signals estimated from LCModel were normalized with respect to the brain water signal, and the concentrations were evaluated assuming the total creatine concentration at 8 mM. The glycine concentration was estimated as 0.6 ± 0.1 mM (mean ± SD, n = 5), with a mean Cramér‐Rao lower bound of 9 ± 1%. The point‐resolved spectroscopy sequence was applied to measure the glycine levels in patients with glioblastoma multiforme. Metabolite concentrations were obtained using the water signal from the tumor mass. The study revealed that a subset of human gliomas contains glycine levels elevated 1.5–8 fold relative to normal. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.
    Type of Medium: Online Resource
    ISSN: 0740-3194 , 1522-2594
    URL: Issue
    URL: Article
    DOI: 10.1002/mrm.v66.3
    DOI: 10.1002/mrm.22857
    Language: English
    Publisher: Wiley
    Publication Date: 2011
    detail.hit.zdb_id: 1493786-4
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