A5063550429- Cancer Cells and Metastasis
- Colorectal Cancer Treatments and Studies
- Lung Cancer Treatments and Mutations
- Cancer Immunotherapy and Biomarkers
- Pancreatic and Hepatic Oncology Research
- HER2/EGFR in Cancer Research
- Cancer Treatment and Pharmacology
- Cancer-related gene regulation
- Wnt/β-catenin signaling in development and cancer
- Cancer, Hypoxia, and Metabolism
- Advanced Breast Cancer Therapies
- Peptidase Inhibition and Analysis
- Neuroendocrine Tumor Research Advances
- Cancer Research and Treatments
- Cancer-related Molecular Pathways
- Lung Cancer Research Studies
- Cancer Genomics and Diagnostics
- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- CAR-T cell therapy research
- Angiogenesis and VEGF in Cancer
- Immune Cell Function and Interaction
- Melanoma and MAPK Pathways
- Developmental Biology and Gene Regulation
- TGF-β signaling in diseases
OncoMed (United States)
2013-2023
South Texas Accelerated Research Therapeutics
2017
University of Michigan
2012
Scion
2000-2008
Pfizer (United States)
2007
University of Tübingen
2007
Hertie Institute for Clinical Brain Research
2007
Beth Israel Deaconess Medical Center
2007
Harvard University
2007
Hadassah Medical Center
2007
The Wnt/β-catenin pathway, which signals through the Frizzled (Fzd) receptor family and several coreceptors, has long been implicated in cancer. Here we demonstrate a therapeutic approach to targeting Wnt pathway with monoclonal antibody, OMP-18R5. This initially identified by binding 7, interacts five Fzd receptors conserved epitope within extracellular domain blocks canonical signaling induced multiple members. In xenograft studies minimally passaged human tumors, this antibody inhibits...
The Notch pathway plays an important role in both stem cell biology and cancer. Dysregulation of signaling has been reported several human tumor types. In this report, we describe the development antibody, OMP-59R5 (tarextumab), which blocks Notch2 Notch3 signaling.We utilized patient-derived xenograft tumors to evaluate antitumor effect OMP-59R5. Immunohistochemistry, RNA microarray, real-time PCR, vivo serial transplantation assays were employed investigate mechanisms action...
Purpose Adenoid cystic carcinomas (ACCs) represent a heterogeneous group of chemotherapy refractory tumors, with subset demonstrating an aggressive phenotype. We investigated the molecular underpinnings this phenotype and assessed Notch1 pathway as potential therapeutic target. Methods genotyped 102 ACCs that had available pathologic clinical data. activation was by immunohistochemistry for intracellular domain. Luciferase reporter assays were used to confirm target gene expression in vitro....
Purpose: Wnt signaling is implicated in tumor cell dedifferentiation and cancer stem function. Ipafricept (OMP-54F28) a first-in-class recombinant fusion protein with the extracellular part of human frizzled 8 receptor fused to IgG1 Fc fragment that binds ligands. This trial evaluated ipafricept patients solid tumors.Experimental design: A 3+3 design was used; given intravenously every 3 weeks. The objectives were determination dose-limiting toxicities (DLTs), recommended phase 2 dose...
The use of cDNA microarrays has made it possible to simultaneously analyze gene expression for thousands genes. Microarray technology was used evaluate the >4000 genes in a rat model myocardial infarction. More than 200 were identified that showed differential response Gene changes monitored from 2 16 weeks after infarction regions heart, left ventricle free wall and interventricular septum. A novel clustering program identify patterns within this large set data. Unique revealed...
The natriuretic peptides, including human B-type peptide (BNP), have been implicated in the regulation of cardiac remodeling. Because transforming growth factor-β (TGF-β) is associated with profibrotic processes heart failure, we tested whether BNP could inhibit TGF-β–induced effects on primary fibroblasts. inhibited cell proliferation as well production collagen 1 and fibronectin proteins measured by Western blot analysis. cDNA microarray analysis was performed RNA from fibroblasts...
Inhibitors of angiogenic factors are known to be upregulated, and their levels increase in the maternal circulation before onset preeclampsia. We reproduced a previously characterized model preeclampsia by adenoviral overexpression soluble vascular endothelial growth factor (VEGF) receptor sFlt-1 (also referred as sVEGFR-1) pregnant nonpregnant Sprague-Dawley rats. Animals were treated with VEGF121 at 0, 100, 200, or 400 μg/kg once twice daily (n=8 per group; 64 total) compared normal...
Pulmonary fibrosis is characterized by chronic scar formation and deposition of extracellular matrix, resulting in impaired lung function respiratory failure. Idiopathic pulmonary (IPF) associated with pronounced morbidity mortality responds poorly to known therapeutic interventions; there are no drugs that effectively block or reverse progressive fibrosis. Transforming growth factor beta (TGF-beta) mediate matrix gene regulation appears be a major player both the initiation progression IPF....
Abstract Purpose: This phase I trial evaluated the safety, pharmacokinetics, and pharmacodynamics of demcizumab (OMP-21M18), a humanized IgG2 mAb targeting Notch ligand DLL4 in adult patients with advanced malignancies. Experimental Design: Standard 3+3 design, 0.5, 1, 2.5, or 5 mg/kg weekly 5, 10 every other week, an expansion cohort at week. Dose-limiting toxicities (DLT) were assessed during first 28 days. Results: Fifty-five received (15 weekly, 18 21 cohort, 1 loading dose). No more...
WNT antagonism displays marked synergy with taxane chemotherapy and reverses taxane-induced enrichment of cancer stem cells.
Brontictuzumab is a monoclonal antibody that targets Notch1 and inhibits pathway activation. The purpose of this first-in-human study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, immunogenicity preliminary efficacy brontictuzumab in patients with solid tumors.Subjects selected refractory tumors were eligible. administered intravenously at various levels schedule during escalation, 1.5 mg/kg every 3 weeks (Q3W) expansion. Evidence activation as determined by an...
Deregulation of the β-catenin signaling has long been associated with cancer. Intracellular components this pathway, including axin, APC, and β-catenin, are frequently mutated in a range human tumors, but contribution specific extracellular ligands that promote cancer development through axis remains unclear. We conducted reporter-based screen panel tumors to identify secreted factors stimulate signaling. Through further molecular characterization, we found R-spondin (RSPO) proteins...
Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel gemcitabine patients untreated metastatic pancreatic adenocarcinoma. Patients received at escalating doses standard dosing of according to 3 + design. A total 31 were treated 5 cohorts. Fragility fractures attributed occurred 2 Cohort (7 mg/kg every weeks), this maximum administered...
TIGIT (T-cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain) is a co-inhibitory receptor of T-cell natural killer cell activity. Targeting or without PD-1/PD-L1 checkpoint inhibition may enhance antitumor immunity.This Phase 1a/b trial was first-in-human, open-label, multicenter, dose-escalation -expansion study in patients locally advanced metastatic solid tumors. Using 3 + design, underwent 14-day treatment cycles anti-TIGIT antibody etigilimab alone (Phase...
Transforming growth factor beta (TGFbeta) is a pleiotropic that regulates cell proliferation, angiogenesis, metastasis, and immune suppression. Dysregulation of the TGFbeta pathway in tumor cells often leads to resistance antiproliferative effects while supporting other cellular processes promote invasiveness growth. In present study, SD-208, 2,4-disubstituted pteridine, ATP-competitive inhibitor receptor I kinase (TGFbetaRI), was used inhibit activities progression PANC-1, human pancreatic...
KRAS mutations are frequent in colorectal cancer (CRC) and associated with clinical resistance to treatment the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies. Delta-like 4 ligand (DLL4) is an important component of Notch signaling pathway mediates stem cell self-renewal vascular development. DLL4 inhibition colon tumor cells reduces frequency. Considering need for new drugs treat cancers oncogenic mutations, we examined this study efficacy anti-DLL4 antibodies mutant...
Myocardial Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition improves cardiac function following myocardial infarction (MI), but the CaMKII-dependent pathways that participate in stress responses are incompletely understood. To address this issue, we sought to determine transcriptional consequences of CaMKII after MI. We performed gene expression profiling mouse hearts with cardiomyocyte-delimited transgenic either a inhibitory peptide (AC3-I) or scrambled control (AC3-C) Of...
Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab a fully human IgG2 antibody that inhibits Notch2/3 receptors.Aphase 2, randomized, placebo-controlled, multicenter trial evaluated activity tarextumab combination with nab-paclitaxel and gemcitabine patients metastatic PDAC. Patients were stratified based on ECOG performance score Ca 19-9 level randomized 1:1 to nab-paclitaxel, either or placebo. Based preclinical phase Ib results...
2540 Background: The WNT pathway is a key oncologic in numerous tumor types. Vantictumab first-in-class anti-Cancer Stem Cell (CSC) antibody that interacts with the extracellular domain of 5 Frizzled receptors (1, 2, 5, 7, 8) and blocks canonical Wnt signaling (PNAS 109, 11717). In patient-derived xenograft models, vantictumab inhibits growth many types, reduces CSC frequency, promotes differentiation cells, synergizes chemotherapeutic agents. Methods: Using 3+3 design, was given...
Summary Purpose This Phase I trial evaluated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics and preliminary efficacy of tarextumab (OMP-5948), a novel cross-reactive antibody which binds selectively inhibits signaling via both Notch2 Notch3, in adult patients with advanced malignancies. Methods Standard 3 + design 0.5, 1, 2.5, or 5 mg/kg weekly, 5, 7.5, 10 every other week, 7.5 mg weeks. Dose-limiting toxicities (DLT) were assessed during first 28 days. Results...