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  • Hoeflmayer, Doris  (8)
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  • 1
    In: BMC Pharmacology, 2010, Vol.10(Suppl 1), p.A41-A41
    Description: Gastric cancer at advanced stage of disease is a major health problem and the prognosis with the current therapeutic treatment strategies remains poor. PI3K/mTOR pathway mutations, especially PTEN, PI3K3C and AKT mutations and pS6 overexpression, are found frequently in gastric cancer patients and are linked with poor outcome. Thus, we evaluated the dual PI3K and mTOR inhibitor BEZ235 against gastric cancer in vitro and in vivo.
    Keywords: Meeting Abstract
    E-ISSN: 1471-2210
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  • 2
    Language: English
    In: Cancer Research, 04/15/2010, Vol.70(8 Supplement), pp.4470-4470
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 3
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 August 2011, Vol.17(16), pp.5322-32
    Description: In this study, we tested the antitumor activity of the dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor BEZ235 against gastric cancer in vitro and in vivo. Gastric cancer cell lines (N87, MKN45, and MKN28) were incubated with BEZ235 and assessed for cell viability, cell cycle, and PI3K/mTOR target inhibition. In vivo, athymic nude mice were inoculated with N87, MKN28, or MKN45 cells and treated daily with BEZ235. 3'-Deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) uptake was measured via small animal positron emission tomography (PET). In vitro, BEZ235 dose dependently decreased the cell viability of gastric cancer cell lines. The antiproliferative activity of BEZ235 was linked to a G(1) cell-cycle arrest. In vivo, BEZ235 treatment resulted in PI3K/mTOR target inhibition as shown by dephosphorylation of AKT and S6 protein in all xenograft models. However, BEZ235 treatment only inhibited tumor growth of N87 xenografts, whereas no antitumor effect was observed in the MKN28 and MKN45 xenograft models. Sensitivity to BEZ235 in vivo correlated with downregulation of the proliferation marker thymidine kinase 1. Accordingly, [(18)F]FLT uptake was only significantly reduced in the BEZ235-sensitive N87 xenograft model as measured by PET. In conclusion, in vivo sensitivity of gastric cancer xenografts to BEZ235 did not correlate with in vitro antiproliferative activity or in vivo PI3K/mTOR target inhibition by BEZ235. In contrast, [(18)F]FLT uptake was linked to BEZ235 in vivo sensitivity. Noninvasive [(18)F]FLT PET imaging might qualify as a novel marker for optimizing future clinical testing of dual PI3K/mTOR inhibitors.
    Keywords: Xenograft Model Antitumor Assays ; Imidazoles -- Pharmacology ; Phosphatidylinositol 3-Kinases -- Antagonists & Inhibitors ; Quinolines -- Pharmacology ; Stomach Neoplasms -- Drug Therapy ; Tor Serine-Threonine Kinases -- Antagonists & Inhibitors
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 4
    Language: English
    In: The Journal of infectious diseases, 01 February 2010, Vol.201(3), pp.354-62
    Description: BACKGROUND. The nonstructural protein NS1 of influenza virus counteracts the interferon-mediated immune response of the host. By deleting the open reading frame of NS1, we have generated a novel type of influenza vaccine. We studied the safety and immunogenicity of an influenza strain lacking the NS1 gene (DeltaNS1-H1N1) in healthy volunteers. METHODS. Healthy seronegative adult volunteers were randomized to receive either a single intranasal dose of the DeltaNS1-H1N1 A/New Caledonia vaccine at 1 of 5 dose levels (6.4, 6.7, 7.0, 7.4, and 7.7 log(10) median tissue culture infective dose) (n = 36 recipients) or placebo (n = 12 recipients). RESULTS. Intranasal vaccination with the replication-deficient DeltaNS1-H1N1 vaccine was well tolerated. Rhinitis-like symptoms and headache were the most common adverse events identified during the 28-day observation period. Adverse events were similarly distributed between the treatment and placebo groups. Vaccine-specific local and serum antibodies were induced in a dose-dependent manner. In the highest dose group, vaccine-specific antibodies were detected in 10 of 12 volunteers. Importantly, the vaccine also induced neutralizing antibodies against heterologous drift variants. CONCLUSIONS. We show that vaccination with an influenza virus strain lacking the viral interferon antagonist NS1 induces statistically significant levels of strain-specific and cross-neutralizing antibodies despite the highly attenuated replication-deficient phenotype. Further studies are warranted to determine whether these results translate into protection from influenza virus infection. TRIAL REGISTRATION. ClinicalTrials.gov identifier: NCT00724997 .
    Keywords: Influenza A Virus, H1n1 Subtype -- Immunology ; Influenza Vaccines -- Immunology ; Influenza, Human -- Prevention & Control ; Vaccines, Attenuated -- Immunology ; Viral Nonstructural Proteins -- Genetics
    ISSN: 00221899
    E-ISSN: 1537-6613
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  • 5
    In: Anti-Cancer Drugs, 2011, Vol.22(3), pp.245-252
    Description: Sphingosine kinase 1 (Sphk1), a lipid kinase implicated in cell transformation and tumor growth, is overexpressed in gastric cancer and is linked with a poor prognosis. The biological relevance of Sphk1 expression in gastric cancer is unclear. Here, we studied the functional significance of Sphk1 as a novel molecular target for gastric cancer by using an antisense oligonucleotide approach in vitro and in vivo.Gastric cancer cell lines (MKN28 and N87) were treated with Sphk1 with locked nucleic acid–antisense oligonucleotides (LNA–ASO). Sphk1 target regulation, cell growth, and apoptosis were assessed for single-agent Sphk1 LNA–ASO and for combinations with doxorubicin. Athymic nude mice xenografted with gastric cancer cells were treated with Sphk1 LNA and assessed for tumor growth and Sphk1 target regulation, in vivo.In vitro, nanomolar concentrations of Sphk1 LNA–ASO induced an approximately two-fold reduction in Sphk1 mRNA in both the cell lines. This resulted in a 1.6-fold increase in apoptosis and inhibited the growth of gastric cancer cells by more than 50% (P〈0.05). The combination of Sphk1 LNA–ASO with doxorubicin resulted in significant chemosensitization. In vivo, Sphk1 LNA–ASO displayed neither mRNA target regulation in xenografts nor antitumor activity in two independent nude mouse xenograft models.In conclusion, the potent single-agent activity and the synergistic effect of Sphk1 LNA–ASO in combination with chemotherapy in vitro highlight Sphk1 as a biologically relevant molecular target for gastric cancer. Further studies are warranted to overcome the challenge of delivering Sphk1-targeting RNA-therapeutics to solid tumors in vivo.
    Keywords: Molecular Targeted Therapy ; Apoptosis -- Drug Effects ; Cell Proliferation -- Drug Effects ; Oligonucleotides, Antisense -- Pharmacology ; Phosphotransferases (Alcohol Group Acceptor) -- Genetics ; Stomach Neoplasms -- Drug Therapy;
    ISSN: 0959-4973
    E-ISSN: 14735741
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  • 6
    Language: English
    In: Cancer Biology & Therapy, 01 June 2010, Vol.9(11), pp.919-927
    Description: The vascular endothelial growth factor (VEGF) is a central mediator of tumor-induced angiogenesis. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, decreases VEGF-secretion of cancer cells. Vatalanib is a selective inhibitor of...
    Keywords: Medicine
    ISSN: 1538-4047
    E-ISSN: 1555-8576
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  • 7
    Language: English
    In: Cancer Letters, 2010, Vol.296(2), pp.249-256
    Description: VEGF receptor blockage has been reported to increase serum VEGF. We hypothesized that mTOR inhibition by everolimus counteracts VEGF induction by sunitinib resulting in an improved anti-tumor activity of sunitinib. , sunitinib in combination with everolimus did not outperform the respective monotherapies. monotherapies reduced tumor growth by 60%, whereas the combination of sunitinib and everolimus led to an almost complete tumor growth inhibition. This superior anti-tumor activity coincided with attenuation of VEGF peaks. In conclusion mTOR inhibition by everolimus counteracts VEGF induction by sunitinib and results in significant reduction of tumor burden and long-lasting tumor growth control.
    Keywords: Angiogenesis ; Gastric Cancer ; Mtor ; Sunitinib ; Vegf ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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  • 8
    In: BMC Pharmacology, 2008, Vol.8(Suppl 1), p.A51
    Description: Gastric cancer is the fourth most common cancer worldwide. Despite advances in diagnosis of gastric cancer, the prognosis at advanced stage of disease with the current chemotherapeutic treatment strategies remains poor. Hence, new agents and molecular targets for gastric cancer therapy are desperately needed. Sphingosine kinase 1 represents a promising novel target for anti-cancer therapy. However, the most common used small molecule inhibitors of SphK are unspecific inhibitors of SphK1. Here we investigated the effect of targeted downregulation of SphK1 by locked nucleic acid antisense oligonucleotides (LNA-ASO) in gastric cancer cell lines.
    Keywords: Pharmacy, Therapeutics, & Pharmacology;
    ISSN: 1471-2210
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