A5089444669- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Breast Cancer Treatment Studies
- Radiopharmaceutical Chemistry and Applications
- PI3K/AKT/mTOR signaling in cancer
- Lung Cancer Treatments and Mutations
- Cancer Cells and Metastasis
- Growth Hormone and Insulin-like Growth Factors
- Peptidase Inhibition and Analysis
- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Advanced Breast Cancer Therapies
- Metabolism, Diabetes, and Cancer
- Chronic Lymphocytic Leukemia Research
- Estrogen and related hormone effects
- Glycosylation and Glycoproteins Research
- Cancer Treatment and Pharmacology
- Cancer, Hypoxia, and Metabolism
- Cancer-related Molecular Pathways
- Chronic Myeloid Leukemia Treatments
- CAR-T cell therapy research
- Neuroendocrine Tumor Research Advances
- Platelet Disorders and Treatments
- Synthesis and Biological Evaluation
- Advanced Biosensing Techniques and Applications
University of the West Indies
2021
Genentech
1999-2019
University of East Anglia
2019
Molecular Oncology (United States)
2014-2017
Bruce W. Carter VA Medical Center
2016
Institut Curie
2013
Sarah Cannon
2013
Indiana University Health
2013
Indiana University – Purdue University Indianapolis
2013
Kaiser Permanente South San Francisco Medical Center
2012
HER2 is a validated target in breast cancer therapy. Two drugs are currently approved for HER2-positive cancer: trastuzumab (Herceptin), introduced 1998, and lapatinib (Tykerb), 2007. Despite these advances, some patients progress through therapy succumb to their disease. A variation on antibody-targeted utilization of antibodies deliver cytotoxic agents specifically antigen-expressing tumors. We determined vitro vivo efficacy, pharmacokinetics, toxicity trastuzumab-maytansinoid...
The proto-oncogene designated erb B2 or HER2 encodes a 185-kilodalton transmembrane tyrosine kinase (p185 ), whose overexpression has been correlated with poor prognosis in several human malignancies. A 45-kilodalton protein heregulin-α (HRG-α) that specifically induced phosphorylation of p185 was purified from the conditioned medium breast tumor cell line. Several complementary DNA clones encoding related HRGs were identified, all which are similar to proteins epidermal growth factor...
The HER2/c-erbB-2 gene encodes the epidermal growth factor receptorlike human homolog of rat neu oncogene. Amplification this in primary breast carcinomas has been show to correlate with poor clinical prognosis for certain cancer patients. We here that a monoclonal antibody directed against extracellular domain p185HER2 specifically inhibits tumor-derived cell lines overexpressing product and prevents HER2/c-erbB-2-transformed NIH 3T3 cells from forming colonies soft agar. Furthermore,...
The vascular endothelium was once thought to function primarily in nutrient and oxygen delivery, but recent evidence suggests that it may play a broader role tissue homeostasis. To explore the of sinusoidal endothelial cells (LSECs) adult liver, we studied effects growth factor (VEGF) receptor activation on mouse hepatocyte growth. Delivery VEGF-A increased liver mass mice did not stimulate hepatocytes vitro, unless LSECs were also present culture. Hepatocyte (HGF) identified as one...
We report on the production of tumor necrosis factor (TNF)-alpha and TNF-beta by mitogen-activated peripheral blood lymphocytes or enriched monocyte subpopulations from human leukocyte antigen (HLA)-typed healthy subjects. The results indicate that HLA-DR2- DQw1-positive donors frequently exhibit low TNF-alpha, whereas DR3- DR4-positive subjects show high levels TNF-alpha production. No correlation between HLA-A, -B, -C genotype was found. relevance this quantitative polymorphism to genetic...
The HER2/c-erbB-2 gene encodes the epidermal growth factor receptorlike human homolog of rat neu oncogene. Amplification this in primary breast carcinomas has been show to correlate with poor clinical prognosis for certain cancer patients. We here that a monoclonal antibody directed against extracellular domain p185HER2 specifically inhibits tumor-derived cell lines overexpressing product and prevents HER2/c-erbB-2-transformed NIH 3T3 cells from forming colonies soft agar. Furthermore,...
We investigated the ability of cyclosporin A (CsA) and transforming growth factor beta (TGF-beta) to modulate production TNF-alpha TNF-beta IFN-gamma by unseparated, nonadherent, adherent PBMC. Treatment unseparated PBMC with CsA resulted in a significant dose-dependent inhibition all three cytokines ranging from greater than 90% for TNF-beta, approximately 70% TNF-alpha. Pretreatment or nonadherent TGF-beta inhibited 60-70%. However, these cells was only minimally affected, at 0.1-1 ng/ml...
Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytotoxic drugs by targeting potent to antigen-expressing tumor cells, thereby enhancing their antitumor activity. Successful ADC development for a given target antigen depends on optimization antibody selection, linker stability, potency, mode linker-drug conjugation antibody. Here, we systematically examined in vitro potency as well vivo preclinical efficacy safety profiles heterogeneous preparation...
Abstract Introduction The human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate mechanisms to each drug alone, or their combination using a large panel of cell lines made resistant these drugs. Methods Response L + T treatment was characterized 13 identify that were de novo resistant. Acquired then established by long-term exposure...
Abstract Recent single-cell studies of cancer in both mice and humans have identified the emergence a myofibroblast population specifically marked by highly restricted leucine-rich-repeat-containing protein 15 (LRRC15) 1–3 . However, molecular signals that underlie development LRRC15 + cancer-associated fibroblasts (CAFs) their direct impact on anti-tumour immunity are uncharacterized. Here mouse models pancreatic cancer, we provide vivo genetic evidence TGFβ receptor type 2 signalling...
Abstract Purpose: HER2-positive breast cancer is heterogeneous. Some tumors express mutations, like activating PIK3CA mutations or reduced PTEN expression, that negatively correlate with response to HER2-targeted therapies. In this exploratory analysis, we investigated whether the efficacy of trastuzumab emtansine (T-DM1), an antibody–drug conjugate comprised cytotoxic agent DM1 linked antibody trastuzumab, was correlated expression specific biomarkers in phase III EMILIA study. Experimental...
Abstract Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with or pertuzumab binding, conjugated to reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents alkylate cross-link DNA. In our study, the is modified alkylate, but This DHES0815A, demonstrates in vivo efficacy models of HER2-low cancers...
The effect of a variety cytokines on lipid metabolism in 3T3 L1 mouse fibroblasts and adipocytes was studied. Uptake [3H]acetate by heparin-releasable lipoprotein lipase activity inhibited after treatments the cells with picomolar concentrations recombinant human tumor necrosis factor alpha (rHuTNF-alpha), beta (rHuTNF-beta, also called lymphotoxin), murine interferon-gamma (rMuIFN-gamma), hybrid interferon-alpha [rHuIFN-alpha 2/alpha 1 (Bgl II)]. Recombinant (rHuIFN-gamma), natural...
The interaction of highly purified recombinant human tumor necrosis factor-alpha (rTNF-alpha) with polymorphonuclear neutrophils (PMNs) was investigated. Binding 125I-rTNF-alpha to PMN reached maximum levels in 30 min at 37 degrees C and 2 h 4 C. Scatchard analysis competitive binding data indicated approximately 6000 receptor sites per cell a Kd 1.37 nM. rapid internalization rTNF-alpha. Following this receptor-mediated interaction, TNF-alpha found inhibit the migration PMNs under agarose...
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a nonreducible thioether linker to maytansinoid antitubulin agent DM1. T-DM1 has shown favorable safety and efficacy in patients with HER2-positive metastatic breast cancer. In previous animal studies, exhibited better pharmacokinetics (PK) slightly more than several disulfide-linked versions. The findings are unique, as other conjugates (ADC) have greater thioether-linked...
Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the antibody-drug conjugate trastuzumab emtansine (T-DM1) dimerization inhibitor pertuzumab (Perjeta).Drug combination studies T-DM1 and were performed on cultured tumor cells in mouse xenograft models HER2-amplified cancer. In patients locally advanced or metastatic breast cancer (mBC), was dose-escalated fixed standard dose 3+3 phase Ib/II study...