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  • 1
    Keywords: EXPRESSION ; CELL ; Germany ; KINASE ; GENE ; GENES ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; transcription ; DRUG ; TUMORS ; PATIENT ; treatment ; ALPHA ; culture ; AMPLIFICATION ; COPY NUMBER ; NUMBER ; REGION ; FUTURE ; gene amplification ; OVEREXPRESSION ; ASTROCYTOMAS ; GLIOMAS ; targeting ; ONCOLOGY ; SUBSET ; GLIOMA ; GRADE ; TRANSLATION ; FACTOR VEGF ; LEVEL ; SIZE ; KINASES ; oligodendroglioma ; glioblastoma multiforme ; GLIOBLASTOMA-MULTIFORME ; KIT ; USA ; DRUGS ; GENE AMPLIFICATIONS ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; SET ; KDR ; AUTOCRINE LOOP ; HUMAN-MALIGNANT GLIOMAS ; PDGFRA
    Abstract: A subset of glioblastomas (GBMs) carry gene amplifications on chromosomal segment 4q12. To characterize this amplicon in detail, we analyzed a set of 100 samples consisting of 65 GBMs, 10 WHO grade III astrocytomas, 12 oligodendrogliomas, and 13 glioma cell cultures. We applied multiplex ligation-dependent probe amplification to determine the gene dosage of PDGFRA, KIT, and KDR and the flanking genes USP46, RASL11B, LNX1, CHIC2, SEC3L1, and IGFBP7. The amplicon was highly variable in size and copy number and extended over a region of up to 5 Mb. Amplifications on 4q12 were observed in 15% of GBMs and 23% of GBM cell cultures but not in 22 other gliomas. We analyzed transcription and translation of some genes within this amplicon. Gene amplification generally correlated with high transcript levels but did not necessarily result in increased protein levels. However, we detected frequent expression of proteins encoded by PDGFRA, KIT, and KDR in GBMs and GBM cell cultures independent of the amplification status. Future treatment of GBM patients may include drugs targeting multiple kinases that are encoded by genes on chromosomal segment 4q12
    Type of Publication: Journal article published
    PubMed ID: 17504929
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  • 2
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; proliferation ; tumor ; CELL ; CELL-PROLIFERATION ; FACTOR RECEPTOR ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; THERAPY ; TYROSINE KINASE ; GENE ; GENES ; HYBRIDIZATION ; PROTEIN ; DRUG ; TUMORS ; LINES ; PATIENT ; LIGAND ; prognosis ; REDUCTION ; CONTRAST ; CELL-LINES ; GROWTH-FACTOR RECEPTOR ; PHOSPHORYLATION ; chromosome ; TARGET ; NO ; IN-SITU ; LESIONS ; AMPLIFICATION ; MUTATION ; METASTASIS ; PROSTATE-CANCER ; CELL-LINE ; LINE ; MUTATIONS ; HOMOLOG ; US ; LIGANDS ; TARGETS ; FLUORESCENCE ; POOR-PROGNOSIS ; SARCOMA ; fluorescence in situ hybridization ; PTEN ; TP53 ; EPIDERMAL-GROWTH-FACTOR ; ONCOLOGY ; TUMOR-SUPPRESSOR ; THERAPIES ; INCREASE ; EGFR ; cell proliferation ; LEVEL ; analysis ; SUPPRESSOR ; tumor suppressor gene ; NERVE ; USA ; DRUGS ; KINASE INHIBITOR ; epidermal growth factor receptor ; GROWTH-FACTOR-RECEPTOR ; receptor tyrosine kinase ; SOMATIC MUTATIONS ; comparison ; ErbB2 ; neurofibromatosis ; TARGETED THERAPY ; tumor suppressor ; EGF ; TRASTUZUMAB ; FACTOR-RECEPTOR ; growth factor ; MPNST ; NEU PROTOONCOGENE ; SCHWANN-CELLS
    Abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n=37). Multiplex ligation-dependent probe amplification and fluorescence in situ hybridization analysis revealed increased EGFR dosage in 28% of MPNSTs. ERBB2 and three tumor suppressor genes (PTEN [phosphatase and tensin homolog deleted on chromosome 10], CDKN2A [cyclin-dependent kinase inhibitor 2A], and TP53 [tumor protein p53]) were frequently lost or reduced. Reduction of CDKN2A was linked to appearance of metastasis. Comparison of corresponding neurofibromas and MPNSTs revealed an increase in genetic lesions in MPNSTs. No somatic mutations were found within tyrosine-kinase-encoding exons of EGFR and ERBB2. However, at the protein level, expression of EGFR and erbB2 was frequently detected in MPNSTs. EGFR expression was significantly associated with increased EGFR gene dosage. The EGFR ligands transforming growth factor a and EGF were more strongly expressed in MPNSTs than in neurofibromas. The effects of the drugs erlotinib and trastuzumab, which target EGFR and erbB2, were determined on MPNST cell lines. In contrast to trastuzumab, erlotinib mediated dose-dependent inhibition of cell proliferation. EGF-induced EGFR phosphorylation was attenuated by erlotinib. Summarized, our data indicate that EGFR and erbB2 are potential targets in treatment of MPNST patients. Neuro-Oncology 10, 946-957, 2008 (Posted to Neuro-Oncology [serial online], Doc. D07-00250, July 23, 2008. URL http://neuro-oncology.dukejournals.org; DOI: 10.1215/15228517-2008-053)
    Type of Publication: Journal article published
    PubMed ID: 18650488
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  • 3
    Keywords: RECEPTOR ; ANGIOGENESIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INHIBITOR ; proliferation ; CELL ; Germany ; IN-VIVO ; INHIBITION ; KINASE ; MODEL ; THERAPY ; TYROSINE KINASE ; VITRO ; VIVO ; DRUG ; MICE ; COMPLEX ; COMPLEXES ; TYPE-1 ; TYROSINE KINASE INHIBITOR ; ALPHA ; TARGET ; MOUSE ; PATTERNS ; EFFICACY ; PLEXIFORM NEUROFIBROMAS ; TARGETS ; inflammation ; NERVE SHEATH TUMORS ; FEATURES ; ONCOLOGY ; PATTERN ; XENOGRAFTS ; IMATINIB MESYLATE ; SIZE ; KIT ; FRAGMENT ; INHIBIT ; PDGFR ; neurofibromatosis ; tumours ; Type ; RECEPTOR-TYROSINE-KINASE ; Glivec
    Abstract: Plexiform neurofibromas (PNF), one of the major features of neurofibromatosis type 1 (NF1), are characterized by complex cellular composition and mostly slow but variable growth patterns. In this study, we examined the effect of imatinib mesylate, a receptor tyrosine kinase inhibitor, on PNF-derived Schwann cells and PNF tumour growth in vitro and in vivo. In vitro, PNF-derived primary Schwann cells express platelet-derived growth factors receptors (PDGFR) alpha and beta, both targets of imatinib, and cell viability was reduced by imatinib mesylate, with 50% inhibition concentration (IC50) of 10 mu M. For in vivo studies, PNF tumour fragments xenografted onto the sciatic nerve of athymic nude mice were first characterized. The tumours persisted for at least 63 days and maintained typical characteristics of PNFs such as complex cellular composition, low proliferation rate and angiogenesis. A transient enlargement of the graft size was due to inflammation by host cells. Treatment with imatinib mesylate at a daily dose of 75 mg/kg for 4 weeks reduced the graft size by an average of 80% (n = 8), significantly different from the original sizes within the group and from sizes of the grafts in 11 untreated mice in the control group (P 〈 0.001). We demonstrated that grafting human PNF tumour fragments into nude mice provides an adequate in vivo model for drug testing. Our results provide in vivo and in vitro evidence for efficacy of imatinib mesylate for PNF
    Type of Publication: Journal article published
    PubMed ID: 19921098
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  • 4
    Keywords: CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; Germany ; GENE-EXPRESSION ; PROTEIN ; TUMORS ; PATIENT ; MARKER ; prognosis ; CONTRAST ; treatment ; TYPE-1 ; ASSOCIATION ; polymorphism ; TARGET ; MUTANT ; NO ; IDENTIFICATION ; NEOPLASIA ; PROGRESSION ; MUTATION ; TUMOR PROGRESSION ; METASTASIS ; p53 ; MUTATIONS ; SOFT-TISSUE SARCOMAS ; CARCINOMAS ; RECURRENT ; POOR-PROGNOSIS ; TP53 ; MMP ; WILD-TYPE P53 ; MATRIX ; ONCOLOGY ; GRADE ; MALIGNANT PROGRESSION ; LEVEL ; NEUROFIBROMATOSIS TYPE-1 ; USA ; matrix metalloproteinase ; METALLOPROTEINASE ; MATRIX-METALLOPROTEINASE ; malignant peripheral nerve sheath tumor ; neurofibromatosis type 1 ; HUMAN COLLAGENASE-3 MMP-13 ; matrix metalloproteinase 13 ; POLYMORPHIC VARIANTS ; TP53 MUTATIONS
    Abstract: Malignant peripheral nerve sheath tumors ( MPNST) are sarcomas with poor prognosis and limited treatment options. Factors contributing to tumor progression are largely unknown. We therefore examined MPNST from 22 neurofibromatosis type 1 (NF1) patients, 14 non-NF1 patients, and 14 neurofibroma patients for matrix metalloproteinase 13 (MMP-13) expression. Because wild-type and mutant p53 were shown to differentially regulate MMP-13 expression, TP53 status and protein levels were also determined. MMP-13 expression was detected in 58% of MPNST and was significantly associated with recurrent MPNST (P =.019). p53 was observed in 78% of MPNST and was found to be strongly associated with MMP- 13 expression ( P =.005). In contrast, 14 neurofibromas lacked MMP- 13 and p53 expressions. TP53 mutations were found in only 11% of MPNST and were associated with high tumor grades (P=.029). No significant association between mutant TP53 and MMP- 13 was observed, indicating that other factors drive MMP- 13 expression in MPNST. The presence of metastasis was linked to p53Pro(72) polymorphism (P=.041) and shorter survival. In summary, our data suggest that MMP-13 expression in nerve sheath tumors is coupled with malignant progression. Therefore, MMP- 13 may serve as a marker for progression and as a therapeutic target
    Type of Publication: Journal article published
    PubMed ID: 17786186
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  • 5
  • 6
    Keywords: CANCER ; IN-VIVO ; INHIBITION ; MUTATION ; MOUSE MODEL ; SUPPRESSOR GENE ; MAMMALIAN TARGET ; NEUROFIBROMATOSIS TYPE-1 ; LHERMITTE-DUCLOS-DISEASE ; SOMA SIZE
    Abstract: Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that develop in about 10% of patients with the genetic disease neurofibromatosis type 1 (NF1). Molecular alterations contributing to MPNST formation have only partially been resolved. Here we examined the role of Pten, a key regulator of the Pi3k/Akt/mTOR pathway, in human MPNST and benign neurofibromas. Immunohistochemistry showed that Pten expression was significantly lower in MPNST (n = 16) than in neurofibromas (n = 16) and normal nervous tissue. To elucidate potential mechanisms for Pten down-regulation or Akt/mTOR activation in MPNST we performed further experiments. Mutation analysis revealed absence of somatic mutations in PTEN (n = 31) and PIK3CA (n = 38). However, we found frequent PTEN promotor methylation in primary MPNST (11/26) and MPNST cell lines (7/8) but not in benign nerve sheath tumours. PTEN methylation was significantly associated with early metastasis. Moreover, we detected an inverse correlation of Pten-regulating miR-21 and Pten protein levels in MPNST cell lines. The examination of NF1-/- and NF1+/+ Schwann cells and fibroblasts showed that Pten expression is not regulated by NF1. To determine the significance of Pten status for treatment with the mTOR inhibitor rapamycin we treated 5 MPNST cell lines with rapamycin. All cell lines were sensitive to rapamycin without a significant correlation to Pten levels. When rapamycin was combined with simvastatin a synergistic anti-proliferative effect was achieved. Taken together we show frequent loss/reduction of Pten expression in MPNST and provide evidence for the involvement of multiple Pten regulating mechanisms.
    Type of Publication: Journal article published
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  • 7
    Keywords: brain ; RECEPTOR ; CELLS ; EXPRESSION ; GROWTH-FACTOR ; INVASION ; tumor ; CELL ; Germany ; human ; RNA ; METABOLISM ; cell line ; TUMORS ; LINES ; ACTIVATION ; MECHANISM ; RECEPTOR EXPRESSION ; prognosis ; INDUCTION ; mechanisms ; CELL-LINES ; treatment ; ASSAY ; UP-REGULATION ; CELL-LINE ; LINE ; CANCER-CELLS ; PHENOTYPE ; DEGRADATION ; INVOLVEMENT ; NETHERLANDS ; POOR-PROGNOSIS ; REPRESSION ; cell lines ; PLASMINOGEN-ACTIVATOR ; MATRIX ; ONCOLOGY ; BRAIN-TUMORS ; TUMOR-GROWTH ; GLIOMA ; GLIOMA-CELLS ; ACTIVATOR ; IRON ; ASSAYS ; hypoxia-inducible factor-1 ; urokinase ; DEPLETION ; HIF-1 ; GLIOBLASTOMA ; matrix metalloproteinase ; METALLOPROTEINASE ; MATRIX-METALLOPROTEINASE ; DEPENDENT INHIBITION ; DFO ; HYPOXIA-INDUCIBLE FACTOR ; IRON CHELATORS ; UROKINASE-PLASMINOGEN-ACTIVATOR
    Abstract: Glioblastoma multiforme are highly invasive brain tumors. Experimental approaches focus on unravelling the mechanisms of invasion, this being a major reason for the poor prognosis of these tumors. Our previous results hinted towards involvement of the iron metabolism in invasion. In this study, we examined the effect of iron depletion on the invasive phenotype of glioblastoma cells. Transwell Matrigel invasion assays were used to monitor iron-dependent invasion of human glioblastoma cell lines U373MG and DBTRG05MG. Intracellular iron concentrations were modulated by applying desferrioxamine (DFO) and ferric ammonium citrate (FAC). We detected enhanced invasion of glioblastoma cells upon DFO-induced iron depletion. Treatment of cells with FAC strongly inhibited invasion. DFO treatment resulted in hypoxia-inducible factor 1 (Hif-1)-mediated induction of urokinase plasminogen activator receptor and matrix metalloproteinase 2. Further, RNA interference-mediated repression of urokinase plasminogen activator receptor inhibited DFO-induced invasion. Our data demonstrate a direct effect of DFO on Hif-1 expression resulting in activation of factors associated with ECM degradation and invasion of glioma cells. These findings caution on utilization of DFO and other iron chelators in the treatment of tumors with invasive potential
    Type of Publication: Journal article published
    PubMed ID: 17357815
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  • 8
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; IN-VIVO ; KINASE ; PATHWAY ; THERAPY ; TYROSINE KINASE ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; DRUG ; TUMORS ; LINES ; TRANSDUCTION ; PATIENT ; MARKER ; BIOLOGY ; CELL-LINES ; signal transduction ; TYPE-1 ; TYROSINE KINASE INHIBITOR ; ALPHA ; PROGRESSION ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; COPY NUMBER ; gene expression ; INDUCED APOPTOSIS ; NUMBER ; EFFICACY ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; MARKERS ; REGION ; RECEPTORS ; IMBALANCES ; OVEREXPRESSION ; cell lines ; VEGF ; C-KIT ; NERVE SHEATH TUMORS ; signaling ; MAPK ; SCIENCE ; drug targeting ; KIT ; receptor tyrosine kinase ; RECEPTOR TYROSINE KINASES ; PDGFR ; neurofibromatosis ; CONSEQUENCES ; SU11248 ; COEXPRESSION ; Type ; LOOP ; RECEPTOR-TYROSINE-KINASE ; VEGFR-2 ; MAPK PATHWAY
    Abstract: Background: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive tumors which originate from Schwann cells and develop in about 10% of neurofibromatosis type 1 (NF1) patients. The five year survival rate is poor and more effective therapies are needed. Sunitinib is a drug targeting receptor tyrosine kinases (RTK) like PDGFR alpha, c-Kit and VEGFR-2. These genes are structurally related and cluster on chromosomal segment 4q12. Methodology/Principal Findings: Here we characterize this region by multiplex ligation-dependent probe amplification (MLPA) in MPNST. Our probe set encompasses the 3 adjacent RTK genes (PDGFRA, KIT, KDR) and 6 flanking genes. We found amplification of several genes within this region in a subset of MPNST and MPNST cell lines. Transcript and protein expression of PDGFRA matched well with its increased copy number suggesting a central role of PDGFRA within the amplicon. Studying the effect of sunitinib on 5 MPNST cell lines revealed that cell line S462 harboring the 4q12 amplicon was extremely sensitive to the drug with an IC50 below 1.0 mu M. Moreover, sunitinib induced apoptosis and prevented PDGFAA induced signaling via PDGFR alpha as determined by western blotting. Co-expression of VEGF and its receptor VEGFR-2 (KDR) was present in MPNST cell lines suggesting an autocrine loop. We show that VEGF triggered signal transduction via the MAPK pathway, which could be blocked by sunitinib. Conclusions/Significance: Since multiple receptors targeted by sunitinib are expressed or over-expressed by MPNST cells sunitinib appears as an attractive drug for treatment of MPNST patients. Presence of the 4q12 amplicon and subsequent over-expression of PDGFRA might serve as predictive markers for efficacy of sunitinib
    Type of Publication: Journal article published
    PubMed ID: 20686603
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  • 9
    Keywords: EXPRESSION ; GROWTH ; CELL ; DISEASE ; GENE ; PROTEIN ; DIFFERENTIATION ; BIOMARKERS ; IN-SITU ; MALIGNANT-MELANOMA ; ORIGIN ; SERUM ; BURDEN ; MELANOMA INHIBITORY-ACTIVITY
    Abstract: Background: Neurofibromatosis type 1 (NF1) is a frequent genetic disease characterized by multiple benign tumours with increased risk for malignancy. There is currently no biomarker for tumour load in NF1 patients. Methods: In situ hybridization and quantitative real-time polymerase reaction were applied to investigate expression of cartilage-specific genes in mice bearing conditional inactivation of NF1 in the developing limbs. These mice do not develop tumours but recapitulate aspects of NF1 bone dysplasia, including deregulation of cartilage differentiation. It has been recently shown that NF1 tumours require for their growth the master regulator of cartilage differentiation SOX9. We thus hypothesized that some of the cartilage-specific genes deregulated in an Nf1Prx1 mouse model might prove to be relevant biomarkers of NF1 tumours. We tested this hypothesis by analyzing expression of the SOX9 target gene product melanoma-inhibitory activity/cd-rap (MIA) in tumour and serum samples of NF1 patients. Results: Increased expression of Mia was found in Nf1-deficient cartilage in mice. In humans, MIA was expressed in all NF1-related tumours and its serum levels were significantly higher in NF1 patients than in healthy controls. Among NF1 patients, MIA serum levels were significantly higher in those with plexiform neurofibromas and in those with large number of cutaneous (〉 1,000) or subcutaneous (〉 100) neurofibromas than in patients without such tumours. Most notably, MIA serum levels correlated significantly with internal tumour burden. Conclusions: MIA is a potential serum biomarker of tumour load in NF1 patients which could be useful in following the disease course and monitoring the efficacy of therapies
    Type of Publication: Journal article published
    PubMed ID: 21726432
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  • 10
    Keywords: pathology ; THERAPIES ; FAMILIES ; MEMBER ; NEW-YORK ; FAMILY ; EXPRESSION ; THERAPY ; EGFR ; GENETIC ALTERATION ; USA
    Type of Publication: Meeting abstract published
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