A5034541719- Angiogenesis and VEGF in Cancer
- Cancer, Hypoxia, and Metabolism
- Fibroblast Growth Factor Research
- Phagocytosis and Immune Regulation
- Developmental Biology and Gene Regulation
- Cancer Treatment and Pharmacology
- Microtubule and mitosis dynamics
- Renal cell carcinoma treatment
- Cancer Genomics and Diagnostics
- HER2/EGFR in Cancer Research
- Hepatocellular Carcinoma Treatment and Prognosis
- Thyroid Cancer Diagnosis and Treatment
- Cancer Immunotherapy and Biomarkers
- Cell Adhesion Molecules Research
- Cancer Cells and Metastasis
- Metabolism, Diabetes, and Cancer
- Cancer-related gene regulation
- Pancreatic function and diabetes
- Cancer-related Molecular Pathways
- PI3K/AKT/mTOR signaling in cancer
- Adipose Tissue and Metabolism
- Kruppel-like factors research
- RNA Research and Splicing
- Regulation of Appetite and Obesity
- Cholesterol and Lipid Metabolism
Eisai (Japan)
2014-2025
Eisai (United States)
2018-2024
University of Tsukuba
2018
Takeda (Japan)
2014-2017
Mount Sinai Hospital
2014
Icahn School of Medicine at Mount Sinai
2014
The University of Tokyo
2001-2007
Nara Institute of Science and Technology
2003
Osaka University
1999-2000
Osaka University of Pharmaceutical Sciences
1998-1999
The adipocyte-derived hormone adiponectin has been proposed to play important roles in the regulation of energy homeostasis and insulin sensitivity, it reported exhibit putative antiatherogenic properties <i>in vitro</i>. In this study we generated adiponectin-deficient mice directly investigate whether a physiological protective role against diabetes atherosclerosis vivo</i>. Heterozygous (<i>adipo</i> <sup>+/−</sup>) showed mild resistance, while homozygous <sup>−/−</sup>) moderate...
The adipocyte-derived hormone adiponectin has been shown to play important roles in the regulation of energy homeostasis and insulin sensitivity. In this study, we analyzed globular domain (gAd) transgenic (Tg) mice crossed with leptin-deficient ob/ob or apoE-deficient mice. Interestingly, despite an unexpected similar body weight, gAd Tg showed amelioration resistance β-cell degranulation as well diabetes, indicating that leptin appeared have both distinct overlapping functions....
E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity against SCF-induced angiogenesis in vitro tumor growth SCF-producing human small cell lung carcinoma H146 cells vivo. inhibits SCF-driven tube formation HUVEC, which express receptor, KIT at IC(50) value 5.2 nM it was almost identical for VEGF-driven one (IC(50) = 5.1 nM). To assess role SCF/KIT signaling angiogenesis, evaluated...
Abstract Purpose: Vascular endothelial growth factor (VEGF)-C/VEGF-receptor 3 (VEGF-R3) signal plays a significant role in lymphangiogenesis and tumor metastasis based on its effects lymphatic vessels. However, little is known about the effect of inhibiting VEGF-R3 lymph node metastases using small-molecule kinase inhibitor. Experimental Design: We evaluated E7080, potent inhibitor both VEGF-R2 kinase, bevacizumab angiogenesis mammary fat pad xenograft model human breast cancer MDA-MB-231...
Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor (VEGF) signaling pathway is a promising therapeutic strategy for thyroid cancer. Lenvatinib mesilate (lenvatinib) potent inhibitor VEGF receptors (VEGFR1-3) and other prooncogenic receptor tyrosine kinases, including fibroblast (FGFR1-4), platelet derived α (PDGFRα), KIT, RET. We examined antitumor activity lenvatinib against human cancer xenograft models in nude mice. Orally administered showed significant...
Lenvatinib is an oral inhibitor of multiple receptor tyrosine kinases (RTKs) targeting vascular endothelial growth factor (VEGFR1-3), fibroblast (FGFR1-4), platelet α (PDGFR α), RET and KIT. Antiangiogenesis activity lenvatinib in VEGF- FGF-driven angiogenesis models both vitro vivo was determined. Roles tumor vasculature (microvessel density (MVD) pericyte coverage) as biomarkers for were also examined this study.We evaluated antiangiogenesis against proliferation tube formation HUVECs...
Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast (FGF) receptors. We investigated the immunomodulatory activities of lenvatinib in tumor microenvironment its mechanisms enhanced antitumor activity when combined with programmed cell death-1 (PD-1) blockade. Antitumor was examined immunodeficient immunocompetent mouse models. Single-cell analysis, flow cytometric immunohistochemistry were used to analyze...
Glucokinase (Gck) functions as a glucose sensor for insulin secretion, and in mice fed standard chow, haploinsufficiency of β cell–specific Gck (Gck+/–) causes impaired secretion to glucose, although the animals have normal cell mass. When high-fat (HF) diet, wild-type showed marked hyperplasia, whereas Gck+/– demonstrated decreased replication insufficient hyperplasia despite showing similar degree resistance. DNA chip analysis revealed receptor substrate 2 (Irs2) expression HF diet–fed...
Abstract Angiogenesis inhibitors such as lenvatinib and sorafenib, an immune checkpoint inhibitor ( ICI ), nivolumab, are used for anticancer therapies against advanced hepatocellular carcinoma HCC ). Combination treatments comprising angiogenesis plus s promising options improving clinical benefits in patients, trials ongoing. Here, we investigated the antitumor immunomodulatory activities of (a multiple receptor tyrosine kinase targeting vascular endothelial growth factor 1‐3, fibroblast...
Eribulin mesylate is a synthetic macrocyclic ketone analog of the marine sponge natural product halichondrin B and an inhibitor microtubule dynamics. Some tubulin-binding drugs are known to have antivascular (antiangiogenesis or vascular-disrupting) activities that can target abnormal tumor vessels. Using dynamic contrast-enhanced MRI analyses, here we show eribulin induces remodeling vasculature through novel activity in MX-1 MDA-MB-231 human breast cancer xenograft models. Vascular...
Lenvatinib is an oral multikinase inhibitor that selectively inhibits vascular endothelial growth factor (VEGF) receptors 1 to 3 and other proangiogenic oncogenic pathway-related receptor tyrosine kinases. To elucidate the origin of potency lenvatinib in VEGF 2 (VEGFR2) inhibition, we conducted a kinetic interaction analysis with VEGFR2 X-ray crystal structure VEGFR2-lenvatinib complexes. Kinetic revealed had rapid association rate constant relatively slow dissociation complex VEGFR2....
Abstract Unresectable hepatocellular carcinoma ( uHCC ) is one of the most lethal and prevalent cancers worldwide, current systemic therapeutic options for are limited. Lenvatinib, a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors VEGFR s) fibroblast FGFR s), recently demonstrated treatment effect on overall survival by statistical confirmation noninferiority to sorafenib in phase 3 study . Here, we investigated mechanisms underlying...
c-kit receptor tyrosine kinase is a marker of progenitor cells, which differentiate into blood and/or vascular endothelial and has an important role in the amplification/mobilization cells. expressed mature but its there unclear. Stem cell factor, ligand, dose-dependently promoted survival, migration, capillary tube formation human umbilical vein These effects mimicked those growth except that stem factor did not sufficiently support proliferation these After exposing cells to this Akt,...
AbstractTo investigate the role of insulin receptor substrate 1 (IRS-1) and IRS-2, two ubiquitously expressed IRS proteins, in adipocyte differentiation, we established embryonic fibroblast cells with four different genotypes, i.e., wild-type, IRS-1 deficient (IRS-1−/−), IRS-2 (IRS-2−/−), double (IRS-1−/−IRS-2−/−), from mouse embryos corresponding genotypes. The abilities IRS-1−/− IRS-2−/− to differentiate into adipocytes are approximately 60 15%, respectively, lower than that wild-type...
Insulin receptor substrate (IRS)-2<sup>−/−</sup> mice develop diabetes because of insulin resistance in the liver and failure to undergo β-cell hyperplasia. Here we show by DNA chip microarray analysis that expression sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target insulin, was paradoxically increased 16-week-old IRS-2<sup>−/−</sup> mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The SREBP-1 genes, such as spot...
The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state resultant transcriptional output. enzymes that catalyze these often contained within multiprotein complexes in nature. Two such complexes, polycomb repressive complex 2 (PRC2) methyltransferase SWItch/Sucrose Non-Fermentable (SWI/SNF) remodeler have been reported act opposition each other during development homeostasis. An imbalance their induced by...
Lenvatinib inhibits VEGF- and FGF-driven angiogenesis, proliferation of tumor cells with activated FGF signaling pathways in preclinical models, we previously demonstrated antitumor activity human HCC xenograft models. Here, examined the inhibitory lenvatinib against survival cell lines. First, conducted a histological analysis FGF19-overexpressing Hep3B2.1-7 tumors collected from mice treated lenvatinib. Second, effects pharmacological inhibition on cultured an pathway under...
We previously reported that eribulin mesylate (eribulin), a tubulin‐binding drug ( TBD ), could remodel tumor vasculature (i.e. increase vessels and perfusion) in human breast cancer xenograft models. However, the role of this vascular remodeling antitumor effects is not fully understood. Here, we investigated eribulin‐induced on activities multiple Microvessel densities MVD ) were evaluated by immunohistochemistry CD 31 staining), examined 10 Eribulin significantly increased compared to...
Abstract The Wnt/β-catenin signaling pathway plays crucial roles in embryonic development and the of multiple types cancer, its aberrant activation provides cancer cells with escape mechanisms from immune checkpoint inhibitors. E7386, an orally active selective inhibitor interaction between β-catenin CREB binding protein, which is part pathway, disrupts HEK293 adenomatous polyposis coli (APC)-mutated human gastric ECC10 cells. It also inhibited tumor growth xenograft model suppressed polyp...
Background Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma Study 111/KEYNOTE-146 ( NCT02501096 ). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores descriptively summarized response biomarker subpopulations defined by tumor mutational burden (TMB) DNA variants for individual genes of interest. Methods Patients...
Heterozygous peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-deficient (PPARgamma(+/-)) mice were protected from high-fat diet-induced insulin resistance. To determine the impact of systemic reduction PPAR-gamma activity on beta-cell function, we investigated secretion in PPARgamma(+/-) a diet. Glucose-induced was impaired vitro. The tissue triglyceride (TG) content white adipose tissue, skeletal muscle, and liver decreased mice, but it unexpectedly increased islets, TG islets...
The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, plus everolimus, mammalian target rapamycin ( mTOR ) significantly improved clinical outcomes versus everolimus monotherapy in phase II study metastatic renal cell carcinoma RCC ). We investigated potential mechanisms underlying the antitumor activity treatment preclinical models. Lenvatinib showed greater than either three human xenograft mouse models (A‐498, Caki‐1, and Caki‐2). In particular, led to tumor...