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  • 1
    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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  • 2
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(1), p.e84417
    Description: Malignant melanoma is a life-threatening skin cancer increasingly diagnosed in the western world. In advanced disease the prognosis is grave. Growth and metastasis formation in melanomas are regulated by a network of cytokines, cytokine-receptors, and adhesion molecules. However, little is known about surface antigens and target expression profiles in human melanomas. We examined the cell surface antigen profile of human skin melanoma cells by multicolor flow cytometry, and compared their phenotype with 4 melanoma cell lines (A375, 607B, Mel-Juso, SK-Mel28). Melanoma cells were defined as CD45-/CD31- cells co-expressing one or more melanoma-related antigens (CD63, CD146, CD166). In most patients, melanoma cells exhibited ErbB3/Her3, CD44/Pgp-1, ICAM-1/CD54 and IGF-1-R/CD221, but did not express CD20, ErbB2/Her2, KIT/CD117, AC133/CD133 or MDR-1/CD243. Melanoma cell lines were found to display a similar phenotype. In most patients, a distinct subpopulation of melanoma cells (4-40%) expressed the erythropoietin receptor (EPO-R) and ErbB4 together with PD-1 and NGF-R/CD271. Both the EPO-R+ and EPO-R- subpopulations produced melanoma lesions in NOD/SCID IL-2Rgamma(null) (NSG) mice in first and secondary recipients. Normal skin melanocytes did not express ErbB4 or EPO-R, but expressed a functional KIT receptor (CD117) as well as NGF-R, ErbB3/Her3, IGF-1-R and CD44. In conclusion, melanoma cells display a unique composition of surface target antigens and cytokine receptors. Malignant transformation of melanomas is accompanied by loss of KIT and acquisition of EPO-R and ErbB4, both of which are co-expressed with NGF-R and PD-1 in distinct subfractions of melanoma cells. However, expression of EPO-R/ErbB4/PD-1 is not indicative of a selective melanoma-initiating potential.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    In: PLoS ONE, 2014, Vol.9(4)
    Description: Background Endothelial progenitor cells (CEPs) and circulating endothelial cells (CECs) are potential biomarkers of response to anti-angiogenic treatment regimens. In the current study, we investigated the effect of docetaxel and sunitinib on CEP/CEC kinetics and clinical response in castration resistant prostate cancer (CRPC) patients. Patients and methods Chemonaive patients with CRPC were enrolled in this study to receive either sunitinib (37.5 mg/d), in combination with docetaxel (75 mg/m 2 ) or docetaxel alone. CEP and CEC kinetics were analyzed for every cycle. The primary objective was to compare CEP/CEC pharmacodynamics between both treatment arms. We also investigated if CEC/CEP spikes, induced by MTD docetaxel, are suppressed by sunitinib in patients treated with docetaxel/sunitinib relative to docetaxel monotherapy. Results A total of 27 patients were enrolled. We observed a significant increase of CEP/CEC (total/viable) counts over time within each cycle (coefficients 0.29233, 0.22092 and 0.26089, respectively; p〈0.001). However, no differences between the treatment groups, in terms of CEP and CEC kinetics, were detected. In the docetaxel monotherapy arm 4 (30%) patients responded to therapy with a 50% PSA decline, while 9 (64%) patients showed a PSA decline in the combination group (n.s.). The median PFS in the docetaxel monotherapy group was 3.1 months (2.6–3.6 months, 95% CI) and 6.2 months (4.9–7.4 months, 95% CI; p = 0.062) in the combination arm. Sunitinib/docetaxel was reasonably well tolerated and toxicity manageable. Conclusion In summary, no significant differences in CEC and CEP kinetics between the treatment arms were observed, although a highly significant increase of CEPs/CECs within each cycle over time was detected. These results mirror the challenge we have to face when employing anti-angiogenic strategies in CRPC. Additional preclinical research is needed to elucidate the underlying molecular mechanisms. However, docetaxel/sunitinib therapy resulted in a better response in terms of PSA decline and a trend towards improved PFS. Trial Registery clinicaltrialsregister.eu EudraCT 2007-003705-27
    Keywords: Research Article ; Medicine And Health Sciences
    E-ISSN: 1932-6203
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  • 4
    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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  • 5
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 July 2018, Vol.24(14), pp.3253-3262
    Description: The PI3K/mTOR pathway is frequently aberrated in cancer. LY3023414 is a potent and selective ATP-competitive inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Here we report the dose-escalation results of the first-in-human phase I study of LY3023414. A 3+3 dose escalation for once-daily and twice-daily oral dosing of LY3023414 was followed by an expansion cohort for CYP3A4 drug-drug interaction (DDI) assessment. The primary objective was to determine the recommended phase 2 dose (RP2D). Additional objectives included safety, pharmacokinetics/pharmacodynamics, and antitumor activity. Forty-seven patients with solid tumors received LY3023414 at once-daily (20-450 mg) or twice-daily dosing (150-250 mg). Dose-limiting toxicities were observed at 450 mg once-daily (thrombocytopenia, hypotension, hyperkalemia) in three of three patients, 250-mg twice-daily dosing (hypophosphatemia, fatigue, mucositis) in three of four patients, and in one of 15 patients at 200 mg twice-daily (nausea). Common related AEs included nausea (38%), fatigue (34%), and vomiting (32%) and were mostly mild or moderate. LY3023414 pharmacokinetics demonstrated dose-dependent increase in exposure with ≥ 90% target inhibition at doses ≥150 mg. DDI analysis demonstrated LY3023414 to be a weak inhibitor of CYP3A4. Durable partial response was observed in a patient with endometrial cancer harboring PIK3R1 and PTEN truncating mutations, and 13 additional patients (28%) had a decrease in their target lesions by up to 30%. LY3023414 has a tolerable safety profile and single-agent activity in patients with advanced cancers. The RP2D of LY3023414 monotherapy is 200 mg twice daily based on safety, tolerability, and pharmacokinetic/pharmacodynamic data. .
    Keywords: Medicine;
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 6
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 April 2017, Vol.23(8), pp.1910-1919
    Description: The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab. The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non-small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ≥ grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses 〉210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression. Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W. .
    Keywords: Antibodies, Monoclonal, Humanized -- Administration & Dosage ; Antineoplastic Agents -- Administration & Dosage ; Erlotinib Hydrochloride -- Administration & Dosage ; Neoplasms -- Drug Therapy
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 7
    In: Journal of Investigative Dermatology, 2010, Vol.131(2), p.495
    Description: The phosphatidyl inositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway has been shown to be involved in the development of melanoma. PI-103 is a kinase inhibitor blocking PI3K class IA and mTOR complex 1 and 2. Here, we studied the effect of targeting the PI3K/mTORC1/mTORC2 pathway by PI-103 and rapamycin in melanoma cells and in a melanoma mouse model. Dual targeting of PI3K and mTOR by PI-103 induced apoptosis and cell-cycle arrest, and inhibited viability of melanoma cells in vitro. Combined treatment with PI-103 and the prototypic mTORC1 inhibitor rapamycin led to the synergistic suppression of AKT and ribosomal S6 protein phosphorylation and to the induction of apoptosis. In vivo, PI-103 and rapamycin displayed only modest single-agent activity, but the combination significantly reduced the tumor growth compared with both single agents. These data show that blocking the PI3K/mTORC1/mTORC2 pathway using the combination of two distinct small-molecule inhibitors ("vertical inhibition") leads to superior efficacy against malignant melanoma in vitro and in vivo.
    Keywords: Animals–Pharmacology ; Antibiotics, Antineoplastic–Drug Effects ; Apoptosis–Physiology ; Apoptosis–Drug Effects ; Cell Cycle–Physiology ; Cell Cycle–Drug Effects ; Cell Line, Tumor–Drug Effects ; Cell Proliferation–Physiology ; Cell Survival–Pharmacology ; Cell Survival–Pharmacology ; Disease Models, Animal–Metabolism ; Enzyme Inhibitors–Pathology ; Female–Physiopathology ; Furans–Antagonists & Inhibitors ; Humans–Metabolism ; Melanoma–Antagonists & Inhibitors ; Melanoma–Metabolism ; Melanoma–Pharmacology ; Mice–Pharmacology ; Mice, Nude–Drug Effects ; Multiprotein Complexes–Physiology ; Phosphatidylinositol 3-Kinases–Pharmacology ; Phosphatidylinositol 3-Kinases–Metabolism ; Proteins–Pathology ; Proteins–Physiopathology ; Pyridines–Antagonists & Inhibitors ; Pyrimidines–Metabolism ; Signal Transduction–Metabolism ; Signal Transduction–Metabolism ; Sirolimus–Metabolism ; Skin Neoplasms–Metabolism ; Skin Neoplasms–Metabolism ; Skin Neoplasms–Metabolism ; Tor Serine-Threonine Kinases–Metabolism ; Trans-Activators–Metabolism ; Trans-Activators–Metabolism ; Transcription Factors–Metabolism ; Transplantation, Heterologous–Metabolism ; Antibiotics, Antineoplastic ; Crtc2 Protein, Mouse ; Enzyme Inhibitors ; Furans ; Multiprotein Complexes ; Pi103 ; Proteins ; Pyridines ; Pyrimidines ; Trans-Activators ; Transcription Factors ; Mechanistic Target of Rapamycin Complex 1 ; Phosphatidylinositol 3-Kinases ; Tor Serine-Threonine Kinases ; Sirolimus;
    ISSN: 0022-202X
    E-ISSN: 15231747
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  • 8
    Language: English
    In: European Journal of Nuclear Medicine and Molecular Imaging, 2012, Vol.39(1), pp.149-159
    Description: Byline: Thomas Wanek (1), Claudia Kuntner (1), Jens P. Bankstahl (2), Marion Bankstahl (2), Johann Stanek (1,3), Michael Sauberer (1), Severin Mairinger (1,3,4), Sabine Strommer (3), Volker Wacheck (3), Wolfgang Loscher (2), Thomas Erker (4), Markus Muller (3), Oliver Langer (1,3) Keywords: Multidrug resistance; P-glycoprotein; Positron emission tomography; [[.sup.11]C]Tariquidar; [[.sup.11]C]Elacridar; (R)[-[.sup.11]C]Verapamil Abstract: Purpose One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [[.sup.11]C]tariquidar and [[.sup.11]C]elacridar with the Pgp substrate radiotracer (R)[-[.sup.11]C]verapamil for discriminating tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model. Methods Murine mammary carcinoma cells (EMT6) were continuously exposed to doxorubicin to generate a Pgp-overexpressing, doxorubicin-resistant cell line (EMT6AR1.0 cells). Both cell lines were subcutaneously injected into female athymic nude mice. One week after implantation, animals underwent PET scans with [[.sup.11]C]tariquidar (n=7), [[.sup.11]C]elacridar (n=6) and (R)[-[.sup.11]C]verapamil (n=7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting. Results [11C]Tariquidar showed significantly higher retention in Pgp-overexpressing EMT6AR1.0 compared with EMT6 tumours: the mean+-SD areas under the time--activity curves in scan 1 from time 0 to 60 min (AUC.sub.0--60) were 38.8+-2.2 min and 25.0+-5.3 min (p=0.016, Wilcoxon matched pairs test). [[.sup.11]C]Elacridar and (R)[-[.sup.11]C]verapamil were not able to discriminate Pgp expression in tumour models. Following administration of unlabelled tariquidar, both EMT6Ar1.0 and EMT6 tumours showed increases in uptake of [[.sup.11]C]tariquidar, [[.sup.11]C]elacridar and (R)[-[.sup.11]C]verapamil. Conclusion Among the tested radiotracers, [[.sup.11]C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [[.sup.11]C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours. Author Affiliation: (1) Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, 2444, Seibersdorf, Austria (2) Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany (3) Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (4) Department of Medicinal Chemistry, University of Vienna, Vienna, Austria Article History: Registration Date: 09/09/2011 Received Date: 24/05/2011 Accepted Date: 09/09/2011 Online Date: 08/10/2011 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00259-011-1941-7) contains supplementary material, which is available to authorized users.
    Keywords: Multidrug resistance ; P-glycoprotein ; Positron emission tomography ; [C]Tariquidar ; [C]Elacridar ; ()-[C]Verapamil
    ISSN: 1619-7070
    E-ISSN: 1619-7089
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  • 9
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 01 December 2014, Vol.20(23), pp.6059-70
    Description: MET, the receptor for hepatocyte growth factor (HGF), has been implicated in driving tumor proliferation and metastasis. High MET expression is correlated with poor prognosis in multiple cancers. Activation of MET can be induced either by HGF-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional upregulation or by HGF-dependent autocrine or paracrine mechanisms. Here, we report on LY2875358, a novel humanized bivalent anti-MET antibody that has high neutralization and internalization activities, resulting in inhibition of both HGF-dependent and HGF-independent MET pathway activation and tumor growth. In contrast to other bivalent MET antibodies, LY2875358 exhibits no functional agonist activity and does not stimulate biologic activities such as cell proliferation, scattering, invasion, tubulogenesis, or apoptosis protection in various HGF-responsive cells and no evidence of inducing proliferation in vivo in a monkey toxicity study. LY2875358 blocks HGF binding to MET and HGF-induced MET phosphorylation and cell proliferation. In contrast to the humanized one-armed 5D5 anti-MET antibody, LY2875358 induces internalization and degradation of MET that inhibits cell proliferation and tumor growth in models where MET is constitutively activated. Moreover, LY2875358 has potent antitumor activity in both HGF-dependent and HGF-independent (MET-amplified) xenograft tumor models. Together, these findings indicate that the mechanism of action of LY2875358 is different from that of the one-armed MET antibody. LY2875358 may provide a promising therapeutic strategy for patients whose tumors are driven by both HGF-dependent and HGF-independent MET activation. LY2875358 is currently being investigated in multiple clinical studies.
    Keywords: Antibodies, Monoclonal -- Pharmacology ; Antibodies, Monoclonal, Humanized -- Pharmacology ; Antibodies, Neutralizing -- Pharmacology ; Hepatocyte Growth Factor -- Metabolism ; Neoplasms -- Metabolism ; Proto-Oncogene Proteins C-Met -- Antagonists & Inhibitors
    ISSN: 1078-0432
    E-ISSN: 15573265
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  • 10
    Language: English
    In: Investigational New Drugs, 2016, Vol.34(5), pp.584-595
    Description: Background MET is a tyrosine kinase receptor involved in the regulation of cell proliferation and migration. Reported here are the phase I dose-escalation results for LY2875358, a monoclonal antibody against MET, in Japanese patients with advanced malignancies. Methods The study comprised a 3 + 3 dose-escalation part for LY2875358 monotherapy in patients with advanced malignancies (Part A) followed by an assessment of LY2875358 in combination with erlotinib or gefitinib in patients with non-small cell lung cancer (Part B). LY2875358 was administered once every 2 weeks. The primary objective was to evaluate the safety and tolerability of LY2875358; secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, and antitumor activity. Results Eleven patients received LY2875358 monotherapy at 3 dose levels (700 mg, N  = 3; 1400 mg, N  = 3; 2000 mg, N  = 5) and 6 patients received LY2875358 2000 mg in combination with erlotinib ( N  = 3) or gefitinib ( N  = 3). No dose-limiting toxicities or serious adverse events related to LY2875358 were observed. The most frequently reported drug-related adverse events were hypoalbuminemia (2 patients) in Part A and dermatitis acneiform (4 patients) in Part B. LY2875358 area under the curve (AUC) and maximum concentration (C max ) increased with dose over the dose range of 700 mg to 2000 mg. A best response of stable disease was achieved by 2/11 patients in Part A and 4/6 patients in Part B (disease control rate: 35 %). Conclusions LY2875358 at doses up to 2000 mg demonstrated a favorable safety and tolerability profile as monotherapy or in combination with erlotinib or gefitinib in Japanese patients with advanced malignancies.
    Keywords: Antibodies, monoclonal ; Epidermal growth factor receptor ; LY2875358 ; MET ; Pharmacokinetics ; Solid tumors
    ISSN: 0167-6997
    E-ISSN: 1573-0646
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