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  • 1
    Language: English
    In: Pharmacogenomics, September 2010, Vol.11(9), pp.1189-91
    Keywords: Neoplasms -- Drug Therapy ; Protein Kinase Inhibitors -- Therapeutic Use ; Sirolimus -- Therapeutic Use ; Tor Serine-Threonine Kinases -- Antagonists & Inhibitors
    ISSN: 14622416
    E-ISSN: 1744-8042
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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...
    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: PLoS ONE, 2012, Vol.7(1), p.e29925
    Description: The phosphoinositide 3-kinase (PI3-kinase) and the mammalian target of rapamycin (mTOR) are two major signaling molecules involved in growth and activation of mast cells (MC) and basophils (BA). We examined the effects of the dual PI3-kinase/mTOR blocker NVP-BEZ235 on growth of normal and neoplastic BA and MC as well as immunoglobulin E (IgE)-dependent cell activation. Growth of MC and BA were determined by measuring 3 H-thymidine uptake and apoptosis. Cell activation was determined in histamine release experiments and by measuring upregulation of CD63 and CD203c after challenging with IgE plus anti-IgE or allergen. We found that NVP-BEZ235 exerts profound inhibitory effects on growth of primary and cloned neoplastic MC. In the MC leukemia cell line HMC-1, NVP-BEZ235 showed similar IC 50 values in the HMC-1.1 subclone lacking KIT D816V (0.025 µM) and the HMC-1.2 subclone expressing KIT D816V (0.005 µM). Moreover, NVP-BEZ235 was found to exert strong growth-inhibitory effects on neoplastic MC in a xenotransplant-mouse model employing NMR1-Foxn1 nu mice. NVP-BEZ235 also exerted inhibitory effects on cytokine-dependent differentiation of normal BA and MC, but did not induce growth inhibition or apoptosis in mature MC or normal bone marrow cells. Finally, NVP-BEZ235 was found to inhibit IgE-dependent histamine release in BA and MC (IC 50 0.5–1 µM) as well as anti-IgE-induced upregulation of CD203c in BA and IgE-dependent upregulation of CD63 in MC. In summary, NVP-BEZ235 produces growth-inhibitory effects in immature neoplastic MC and inhibits IgE-dependent activation of mature BA and MC. Whether these potentially beneficial drug effects have clinical implications is currently under investigation.
    Keywords: Research Article ; Biology ; Immunology ; Molecular Biology ; Cell Biology ; Developmental Biology
    E-ISSN: 1932-6203
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  • 5
    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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  • 6
    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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  • 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: 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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  • 9
    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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  • 10
    In: Dermatologic Surgery, 2011, Vol.37(10), pp.1456-1463
    Description: BACKGROUND AND OBJECTIVE: One of the possible complications of endovenous laser ablation (EVLA) is thrombus progression into the common femoral vein or popliteal vein with the potential risk of pulmonary embolism or stroke. We set out to investigate the effect of laser energy applied under standardized treatment conditions on biomarkers of platelet and endothelial activation and on the hemostatic system. METHODS: Twenty patients with incompetence of the great saphenous vein were included in this prospective study. Blood samples of the iliofemoral and anticubital veins were collected before, during, and after EVLA. Plasma levels of soluble (s) P-selectin, soluble thrombomodulin (sTM), prothrombin fragment F1+2 (F1+2), and d-dimer were measured. (s) P-selectin and sTM were analyzed as surrogate markers of endothelial and platelet activation. F1+2 and d-dimer were monitored to quantify the degree of surgical trauma. RESULTS: Whereas there was no immediate rise of (s) P-selectin and sTM plasma concentrations in iliofemoral or anticubital blood, plasma levels of F1+2 and d-dimer increased significantly after EVLA. CONCLUSION: Pulsed mode laser ablation with an 810-nm fiber does not induce measurable platelet and endothelium activation in the iliofemoral or systemic blood. Furthermore, the immediate surgical trauma associated with EVLA appears to be modest.The authors have indicated no significant interest with commercial supporters.
    Keywords: Medicine;
    ISSN: 1076-0512
    E-ISSN: 15244725
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