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  • American Association for Cancer Research (AACR)  (6)
  • 1
    Online Resource
    Online Resource
    Dual targeting of AKT and mammalian target of rapamycin: A potential therapeutic approach for malignant peripheral nerve sheath tumor
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 5 ( 2009-05-01), p. 1157-1168
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 5 ( 2009-05-01), p. 1157-1168
    Abstract: The mammalian target of rapamycin (mTOR) pathway may constitute a potential target for the treatment of malignant peripheral nerve sheath tumors (MPNST). However, investigations of other cancers suggest that mTOR blockade can paradoxically induce activation of prosurvival, protumorigenic signaling molecules, especially upstream AKT. Consequently, we hypothesized that dual phosphatidylinositol 3-kinase (PI3K)/AKT-mTOR blockade might be applicable for MPNST treatment. Expression of activated mTOR downstream targets (p4EBP1 and pS6RP) and pAKT was evaluated immunohistochemically in a tissue microarray of human MPNSTs (n = 96) and benign neurofibromas (n = 31). Results were analyzed by Wilcoxon rank-sum tests. mTOR and AKT pathways in human MPNST cell lines, and the effects of rapamycin (mTOR inhibitor), LY294002 (dual PI3K/mTOR inhibitor), and PI-103 (potent dual PI3K/AKT-mTOR inhibitor) on pathway activation were evaluated by Western blot. Effects on cell growth were evaluated via MTS and colony formation assays. Cell cycle progression and apoptosis were assessed by propidium iodide/fluorescence-activated cell sorting staining and Annexin V assays. Acridine orange staining/fluorescence-activated cell sorting analysis, electron microscopy, and Western blot evaluated autophagy induction. p4EBP1, pS6Rp, and pAKT levels were found to be significantly higher in MPNST versus neurofibroma (P & lt; 0.05 for all markers). mTOR and AKT pathways were found to be highly activated in MPNST cell lines. MPNST cells were sensitive to rapamycin; however, rapamycin enhanced pAKT and peIF4E expression. PI-103 abrogated MPNST cell growth and induced G1 cell cycle arrest potentially through repression of cyclin D1. PI-103 did not elicit apoptosis but significantly induced autophagy in MPNST cells. These results suggest further study of combined PI3K/AKT and mTOR inhibition as a novel therapy for patients harboring MPNST. [Mol Cancer Ther 2009;8(5):OF1–12]
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-08-1008
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 2062135-8
    SSG: 12
    Location Call Number Limitation Availability
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  • 2
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    Online Resource
    Abstract 1248: DNA methylation biomarkers for MPNST detection in patients with neurofibromatosis type 1
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1248-1248
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 1248-1248
    Abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are a highly aggressive soft tissue sarcoma affecting approximately 10-15% of individuals with neurofibromatosis type 1 (NF1). MPNST development is characterized by an altered DNA methylation landscape and presents a promising area for developing MPNST-specific biomarkers for screening NF1 patients in the clinic. Here, using genome-wide DNA methylation profiling of a cohort of 13 matched pairs of MPNSTs and adjacent neurofibroma tissues, along with MPNST cell lines and control samples, we conducted intensive DNA methylation analysis towards identification and validation of candidate MPNST specific CpG sites. We utilized a logistic regression model with LASSO regularization to identify the best candidate biomarkers for MPNST detection in patient tissue and/or blood samples. For model fitting, we used TCGA data along with an independent, publicly available dataset. The selected candidate biomarkers were validated on an independent cohort of 22 tissue samples using bisulfite sequencing as well as optimized droplet digital PCR (ddPCR). Our comprehensive analysis revealed the presence of a unique hypermethylation pattern during MPNST development that is also recapitulated within the in vitro MPNST model. Further, based on application of stringent feature selection criteria among an MPNST and NF comparison, together with building a prediction model, we provide a list of candidate MPNST-specific CpGs. Moreover, we successfully applied a ddPCR method to measure the DNA level of five selected candidate biomarkers, all of which showed high performance for MPNST detection (sensitivity: & gt;88%, specificity: & gt;91%) in tissue samples. Overall, our findings confirmed the appearance of a unique hypermethylation pattern during malignant transformation that is also maintained across an in vitro MPNST model. Importantly, we provide a panel of candidate CpGs that have great potential to be further applied as biomarkers in clinical settings for MPNST detection in NF1 patients' tissue and/or liquid biopsy samples. Citation Format: Katarzyna J. Tomczak, Christine B. Peterson, S Carson Callahan, Sharon M. Landers, Christopher J. Terranova, Gabryella S. Serrao, Angela D. Bhalla, Jace P. Landry, Zachary A. Mulder, Michelle G. Yeagley, Ayush T. Raman, Erica L. Gardenhire, Davis R. Ingram, Alexander Lazar, Wei-Lien Wang, Ian E. McCutcheon, John M. Slopis, Kunal Rai, Keila E. Torres. DNA methylation biomarkers for MPNST detection in patients with neurofibromatosis type 1 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1248.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-1248
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Combining Curcumin (Diferuloylmethane) and Heat Shock Protein Inhibition for Neurofibromatosis 2 Treatment: Analysis of Response and Resistance Pathways
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11 ( 2011-11-01), p. 2094-2103
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11 ( 2011-11-01), p. 2094-2103
    Abstract: Neurofibromatosis type 2 (NF2) is a genetic condition characterized by inactivation of the NF2 tumor suppressor gene and the development of schwannomas. The NF2 gene product, merlin, is activated (dephosphorylated) by contact inhibition and promotes growth suppression. We investigated the effect of curcumin (diferuloylmethane), a molecule with anti-inflammatory and antitumorigenic properties, on human schwannoma cell growth and the regulation of merlin by curcumin in both NF2 cells and neuroblastoma (non-NF2) cells. Curcumin inhibited the growth of HEI-193 schwannoma cells in vitro and downregulated the phosphorylation of Akt and extracellular signal–regulated kinase 1/2. Curcumin also activated MYPT1-pp1δ (a merlin phosphatase), which was associated with dephosphorylation of merlin on serine 518, an event that results in the folding of merlin to its active conformation. In addition, curcumin induced apoptosis and generated reactive oxygen species in HEI-193 cells. Consequently, hsp70 was upregulated at the mRNA and protein levels, possibly serving as a mechanism of escape from curcumin-induced apoptosis and growth inhibition. Endogenous merlin and hsp70 proteins interacted in HEI-193 schwannoma and SK-N-AS neuroblastoma cells. The combination of curcumin and an hsp inhibitor synergistically suppressed schwannoma cell growth. Our results provide a rationale for combining curcumin and KNK437 in the treatment of NF2. Mol Cancer Ther; 10(11); 2094–103. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-11-0243
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 4
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    Online Resource
    HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 19 ( 2017-10-01), p. 5313-5326
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 19 ( 2017-10-01), p. 5313-5326
    Abstract: Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression. Here, we report that the transcription factor HNF1B is downregulated in the majority of ChRCC and that the magnitude of HNF1B loss is unique to ChRCC. We also observed a strong correlation between reduced HNF1B expression and aneuploidy in ChRCC patients. In murine embryonic fibroblasts or ACHN cells, HNF1B deficiency reduced expression of the spindle checkpoint proteins MAD2L1 and BUB1B, and the cell-cycle checkpoint proteins RB1 and p27. Furthermore, it altered the chromatin accessibility of Mad2l1, Bub1b, and Rb1 genes and triggered aneuploidy development. Analysis of The Cancer Genome Atlas database revealed TP53 mutations in 33% of ChRCC where HNF1B expression was repressed. In clinical specimens, combining HNF1B loss with TP53 mutation produced an association with poor patient prognosis. In cells, combining HNF1B loss and TP53 mutation increased cell proliferation and aneuploidy. Our results show how HNF1B loss leads to abnormal mitotic protein regulation and induction of aneuploidy. We propose that coordinate loss of HNF1B and TP53 may enhance cellular survival and confer an aggressive phenotype in ChRCC. Cancer Res; 77(19); 5313–26. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-17-0986
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Induction of Apoptosis in Primary Meningioma Cultures by Fenretinide
    American Association for Cancer Research (AACR) ; 2005
    In:  Cancer Research Vol. 65, No. 4 ( 2005-02-15), p. 1547-1553
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 65, No. 4 ( 2005-02-15), p. 1547-1553
    Abstract: Fenretinide, a synthetic retinoid that induces apoptosis in tumor cells in vitro, is being evaluated in clinical trials as a chemotherapeutic agent against several malignancies. Due to its ease of administration, long-term tolerability, and low incidence of long-term side effects, we explored its potential as a therapeutic agent against meningiomas by examining its efficacy in vitro against such cells in primary culture. Cells, cultured from freshly resected benign, atypical, or malignant meningiomas, were exposed to fenretinide (10 μmol/L). Treatment effects were assessed using flow cytometry, Western blot analysis, semiquantitative reverse transcription-PCR for retinoid receptor expression, and changes in insulin-like growth factor-I (IGF-I)–induced proliferation. Fenretinide induced apoptosis in the three grades of meningioma primary cells tested, as shown by the appearance of a sub-G1 fraction in flow cytometric analysis and by the detection of poly-adenosyl ribonucleotidyl phosphorylase cleavage indicating caspase activation. Fenretinide treatment also increased levels of the death receptor DR5 and caused mitochondrial membrane depolarization. The levels of the retinoid receptors, retinoic acid receptor α and retinoid X receptor γ, were up-regulated in response to fenretinide, suggestive of ligand-induced receptor up-regulation. IGF-I-induced proliferation in the meningioma cells was abolished by fenretinide. We conclude that fenretinide induces apoptosis in all three histologic subtypes of meningioma and exerts diverse cellular effects, including DR5 up-regulation, modulation of retinoid receptor levels, and inhibition of IGF-I-induced proliferation. These results provide preliminary evidence that fenretinide has activity against meningiomas and suggest that further studies are warranted to explore its potential as a therapeutic agent against meningiomas.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-04-0786
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2005
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Online Resource
    Autophagic Survival in Resistance to Histone Deacetylase Inhibitors: Novel Strategies to Treat Malignant Peripheral Nerve Sheath Tumors
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 1 ( 2011-01-01), p. 185-196
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 1 ( 2011-01-01), p. 185-196
    Abstract: Histone deacetylase inhibitors (HDACi) show promise as cancer therapeutics; however, the full scope of their utility remains unknown. Here we report findings that strongly rationalize clinical evaluation of HDACis in malignant peripheral nerve sheath tumors (MPNST), a class of highly aggressive, therapeutically resistant, and commonly fatal malignancies that occur sporadically or in patients with the inherited neurofibromatosis type-1 (NF1) syndrome. We evaluated the effects of the chemical HDACis PCI-24781, suberoylanilide hydroxamic acid, and MS-275 on a panel of human NF1-associated and sporadic MPNSTs in vitro and in vivo. A subset of MPNSTs was found to be highly sensitive to HDACis, especially to PCI-24781. All cell lines in this group were NF1-associated. Significant proapoptotic effects were noted in vitro and in vivo and were independent of p53 mutational status. In contrast, as a group the sporadic–MPNST cells were markedly resistant to HDACi treatment. HDACis were found to induce productive autophagy in MPNST cells. Genetic and/or pharmacologic autophagy blockade resulted in significant HDACi-induced apoptosis in cells defined as resistant or sensitive, leading to abrogated growth of primary tumors and lung metastases in tumor xenograft assays. Among autophagy-associated genes expressed in response to HDACi, the immunity-related GTPase family, M was validated as a critical target in mediating HDACi-induced autophagy and enhanced apoptosis. Taken together, our findings strongly support the evaluation of HDACi currently in clinical trials as an important new therapeutic strategy to treat MPNST, including in combination with autophagy blocking combination regimens in particular for patients with sporadic MPNST. Cancer Res; 71(1); 185–96. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-2799
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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