Preclinical efficacy of the c-Met inhibitor CE-355621 in a U87 MG mouse xenograft model evaluated by 18F-FDG small-animal PET

Molecular Imaging Program at Stanford, Bio-X Program, and Department of Radiology, Stanford University, Stanford, California 94305-5427, USA.
Journal of Nuclear Medicine (Impact Factor: 6.16). 02/2008; 49(1):129-34. DOI: 10.2967/jnumed.106.038836
Source: PubMed


The purpose of this study was to evaluate the efficacy of CE-355621, a novel antibody against c-Met, in a subcutaneous U87 MG xenograft mouse model using (18)F-FDG small-animal PET.
CE-355621 or control vehicle was administered intraperitoneally into nude mice (drug-treated group, n = 12; control group, n = 14) with U87 MG subcutaneous tumor xenografts. Drug efficacy was evaluated over 2 wk using (18)F-FDG small-animal PET and compared with tumor volume growth curves.
The maximum %ID/g (percentage injected dose per gram of tissue) of (18)F-FDG accumulation in mice treated with CE-355621 remained essentially unchanged over 2 wk, whereas the %ID/g of the control tumors increased 66% compared with the baseline. Significant inhibition of (18)F-FDG accumulation was seen 3 d after drug treatment, which was earlier than the inhibition of tumor volume growth seen at 7 d after drug treatment.
CE-355621 is an efficacious novel antineoplastic chemotherapeutic agent that inhibits (18)F-FDG accumulation earlier than tumor volume changes in a mouse xenograft model. These results support the use of (18)F-FDG PET to assess early tumor response for CE-355621.

Download full-text


Available from: Mangal Dandekar,
56 Reads
  • Source
    • "Deregulation of MET is associated with transformation and metastatic progression in many cancers, and this has led to research of the MET pathway as a therapeutic target [3] [4]. Anti-MET strategies have been investigated using antibodies [5], decoy receptors [6], and a variety of tyrosine kinase inhibitors (TKIs) [7] [8] [9] [10]. MET is expressed in a variety of tissues including canine osteosarcoma (OS) tumors and cell lines [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: This investigation sought to elucidate the relationship between hepatocyte growth factor (HGF)-induced metastatic behavior and the tyrosine kinase inhibitors (TKIs) crizotinib and dasatinib in canine osteosarcoma (OS). Preliminary evidence of an apparent clinical benefit from adjuvant therapy with dasatinib in four dogs is described. The inhibitors were assessed for their ability to block phosphorylation of MET; reduce HGF-induced production of matrix metalloproteinase (MMP); and prevent invasion, migration, and cell viability in canine OS cell lines. Oral dasatinib (0.75 mg/kg) was tested as an adjuvant therapy in four dogs with OS. Constitutive phosphorylation of MET was detected in two cell lines, and this was unaffected by 20-nM incubation with either dasatinib or crizotinib. Incubation of cell lines with HGF (MET ligand) increased cell migration and invasion in both cell lines and increased MMP-9 activity in one. Dasatinib suppressed OS cell viability and HGF-induced invasion and migration, whereas crizotinib reduced migration and MMP-9 production but did not inhibit invasion or viability. Invasion, migration, and viability of canine OS cell lines are increased by exogenous HGF. HGF induces secretion of different forms of MMP in different cell lines. The HGF-driven increase in viability and metastatic behaviors we observed are more uniformly inhibited by dasatinib. These observations suggest a potential clinical benefit of adjuvant dasatinib treatment for dogs with OS. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Translational oncology 08/2015; 8(4):231-8. DOI:10.1016/j.tranon.2015.03.006 · 2.88 Impact Factor
  • Source
    • "Since many patients will have to high background levels, response monitoring by fluorodeoxyglucose positron emission tomography (FDG-PET) is a good alternative to detect responders. The feasibility of FDG-PET imaging for response monitoring for MET inhibitors was described (Tseng et al., 2008), and recently, we also confirmed for BAY-853474 where we could also show the suitability of FDG as well as fluoro-L-thymidine positron emission tomography in the HS746T xenografts model (Wiehr et al., submitted). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The receptor tyrosine kinase MET contributes to a wide range of biological activities, including survival, proliferation, and metastasis, which play an important role in cancer progression. MET is frequently overexpressed or amplified in a range of malignancies. Therefore, MET is an attractive therapeutic target for treatment of cancer. BAY-853474 is a novel specific MET inhibitor highly effective in preclinical tumor models. For response monitoring in clinical studies, soluble plasma biomarkers are the most convenient and least invasive choice. Therefore, we sought to identify such biomarkers in xenograft models. We show that BAY-853474 reduces the tumor burden in U87MG glioblastoma, NCI-H1993 nonsmall cell lung cancer, and HS746T gastric cancer xenograft models. We demonstrate that the dose dependence is reflected by inhibition of MET phosphorylation and that the soluble plasma biomarkers hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 as well as the MET-ectodomain can be used to monitor the tumor size and response to treatment. Clinical samples, however, show only moderately elevated levels of these biomarker candidates in cancer patients even with MET amplification. We, therefore, established an immunohistochemistry (IHC) protocol to detect MET phosphorylation that is suitable to monitor the effect of BAY-853474 in tumor biopsies. IHC-based analysis of target phosphorylation in tumor biopsies is recommended in addition to testing plasma biomarkers for response monitoring.
    Biomarkers 03/2012; 17(4):325-35. DOI:10.3109/1354750X.2012.670865 · 2.26 Impact Factor
  • Source
    • "Several authors have used small animal FDG PET to assess various therapies in mouse tumor xenograft models with FDG and the proliferation tracer 3′-deoxy-3′-[ 18 F]fluorothymidine (FLT) [10] [11] [12] [13] [14] [15] [16] [17]. We have recently shown that small animal PET studies are reproducible with moderately low variability, such that serial studies on mouse tumor xenografts are reliable in assessing therapy response [18] [19]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Positron emission tomography (PET) imaging has become a useful tool for assessing early biologic response to cancer therapy and may be particularly useful in the development of new cancer therapeutics. RAF265, a novel B-Raf/vascular endothelial growth factor receptor-2 inhibitor, was evaluated in the preclinical setting for its ability to inhibit the uptake of PET tracers in the A375M(B-Raf(V600E)) human melanoma cell line. RAF265 inhibited 2-deoxy-2-[(18)F]fluoro-d-glucose (FDG) accumulation in cell culture at 28 hours in a dose-dependent manner. RAF265 also inhibited FDG accumulation in tumor xenografts after 1 day of drug treatment. This decrease persisted for the remaining 2 weeks of treatment. DNA microarray analysis of treated tumor xenografts revealed significantly decreased expression of genes regulating glucose and thymidine metabolism and revealed changes in apoptotic genes, suggesting that the imaging tracers FDG, 3-deoxy-3-[(18)F]fluorothymidine, and annexin V could serve as potential imaging biomarkers for RAF265 therapy monitoring. We concluded that RAF265 is highly efficacious in this xenograft model of human melanoma and decreases glucose metabolism as measured by DNA microarray analysis, cell culture assays, and small animal FDG PET scans as early as 1 day after treatment. Our results support the use of FDG PET in clinical trials with RAF265 to assess early tumor response. DNA microarray analysis and small animal PET studies may be used as complementary technologies in drug development. DNA microarray analysis allows for analysis of drug effects on multiple pathways linked to cancer and can suggest corresponding imaging tracers for further analysis as biomarkers of tumor response.
    Neoplasia (New York, N.Y.) 03/2011; 13(3):266-75. DOI:10.1593/neo.101466 · 4.25 Impact Factor
Show more