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Berlin Brandenburg

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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    Language: English
    In: Clinical cancer research : an official journal of the American Association for Cancer Research, 15 June 2004, Vol.10(12 Pt 1), pp.4185-91
    Description: Little is known about the role that Mcl-1, an antiapoptotic Bcl-2 family member, plays in solid tumor biology and susceptibility to anticancer therapy. We observed that the Mcl-1 protein is widely expressed in human sarcoma cell lines of different histological origin (n = 7). Because the expression of antiapoptotic Bcl-2 family proteins can significantly contribute to the chemoresistance of human malignancies, we used an antisense strategy to address this issue in sarcoma. SCID mice (n = 6/group) received s.c. injections of SW872 liposarcoma cells. After development of palpable tumors, mice were treated by s.c.-implanted miniosmotic pumps prefilled with saline or antisense or universal control oligonucleotides (20 mg/kg/day for 2 weeks). On days 2, 6, and 10, mice were treated with low-dose cyclophosphamide (35 mg/kg i.p) or saline control. During the experiments, tumor weight was assessed twice weekly by caliper measurements. On day 14, animals were sacrificed. Tumors were weighed and fixed in formalin for immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling analysis. Mcl-1 antisense oligonucleotides specifically reduced Mcl-1 protein expression but produced no reduction in tumor weight compared with saline-treated control animals. Cyclophosphamide monotreatment caused only modest tumor weight reduction compared with saline control. However, use of Mcl-1 antisense oligonucleotides combined with cyclophosphamide clearly enhanced tumor cell apoptosis and significantly reduced tumor weight by more than two-thirds compared with respective control treatments. A combination of Mcl-1 antisense oligonucleotides with low-dose cyclophosphamide provides a synergistic antitumor effect and might qualify as a promising strategy to overcome chemoresistance in human sarcoma.
    Keywords: Drug Resistance, Neoplasm ; Cyclophosphamide -- Therapeutic Use ; Neoplasm Proteins -- Metabolism ; Oligonucleotides, Antisense -- Therapeutic Use ; Proto-Oncogene Proteins C-Bcl-2 -- Metabolism ; Sarcoma -- Drug Therapy
    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, 01 September 2019, Vol.25(17), pp.5202-5211
    Description: Inhibition of the VEGFR-2 blocks angiogenesis and attenuates tumor growth, but cancers may evade this effect through activation of the hepatocyte growth factor receptor MET. Here we report results of the phase Ib/II study of ramucirumab, a monoclonal anti-VEGFR-2 antibody, plus the anti-MET mAb emibetuzumab. A 3+3 dose escalation of emibetuzumab plus ramucirumab (phase Ib) was followed by tumor-specific expansion cohorts. Primary objectives were to determine the recommended phase II dose and to evaluate antitumor activity. Secondary objectives included safety, pharmacokinetics, and immunogenicity. Tumoral MET expression was explored by immunohistochemistry (IHC). A total of 97 patients with solid tumor [6 phase Ib, 16 gastric or gastroesophageal junction adenocarcinoma, 45 hepatocellular carcinoma (HCC), 15 renal cell carcinoma, and 15 non-small lung cancer] received emibetuzumab at 750 or 2,000 mg flat dosing plus ramucirumab at 8 mg/kg every 2 weeks. No dose-limiting toxicities were observed. Common adverse events were primarily mild or moderate and included fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). Emibetuzumab exposures were similar as in previous studies with no apparent drug-drug interactions. Five partial responses (5.2%) were observed across all tumor types. The greatest antitumor activity was noted in HCC with a 6.7% overall response rate, 60% disease control rate, and 5.42 months (95% confidence interval, 1.64-8.12) progression-free survival (PFS). HCC with high MET expression showed improved PFS with approximately 3-fold increase in PFS (8.1 vs. 2.8 months) relative to low MET expression. Ramucirumab plus emibetuzumab was safe and exhibited cytostatic antitumor activity. MET expression may help to select patients benefitting most from this combination treatment in select tumor types.
    ISSN: 1078-0432
    E-ISSN: 15573265
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