A5057758171- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Advanced Biosensing Techniques and Applications
- Glycosylation and Glycoproteins Research
- Peptidase Inhibition and Analysis
- Radiopharmaceutical Chemistry and Applications
- Cell Adhesion Molecules Research
- Estrogen and related hormone effects
- Colorectal Cancer Treatments and Studies
- Lung Cancer Treatments and Mutations
- Cancer therapeutics and mechanisms
- PARP inhibition in cancer therapy
- Cancer Cells and Metastasis
- Cell death mechanisms and regulation
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Receptor Mechanisms and Signaling
- ATP Synthase and ATPases Research
- Medical Imaging Techniques and Applications
- Drug Transport and Resistance Mechanisms
- CAR-T cell therapy research
- Cytokine Signaling Pathways and Interactions
- Cancer, Hypoxia, and Metabolism
- Calcium signaling and nucleotide metabolism
- Toxin Mechanisms and Immunotoxins
Roche Pharma AG (Germany)
2012-2023
Western General Hospital
2009-2023
University of Edinburgh
2009-2023
Roche (Switzerland)
2008-2017
Roche (United Kingdom)
2005-2017
National Center for Tumor Diseases
2017
Heidelberg University
2017
University Hospital Heidelberg
2017
Roche (Spain)
2017
CS Diagnostics
2007-2013
The human epidermal growth factor receptor (HER) family plays an important role in cell survival and proliferation, is implicated oncogenesis. Overexpression of HER2 associated with aggressive disease poor prognosis. Trastuzumab a humanized monoclonal antibody targeting has proven benefit for women HER2-positive early metastatic breast cancer. Pertuzumab, another antibody, dimerization inhibitor that binds to different epitope on than trastuzumab inhibits dimer formation other HER members...
The therapeutic potential of anticancer antibodies is limited by the resistance tumor cells to complement‐mediated attack, primarily through over‐expression membrane complement regulatory proteins (mCRPs: CD46, CD55 and CD59). Trastuzumab, an anti‐ HER2 monoclonal antibody, approved for treatment HER2‐positive breast gastric cancers, exerts only minor cytotoxicity (CDC). Pertuzumab a novel anti‐HER2 which blocks dimerization with other ligand‐activated HER family members. Here, we explored...
Increasing the efficacy of targeted cancer therapies requires identification robust biomarkers suitable for patient stratification. This study focused on molecular mechanisms causing resistance against anti-ERBB2-directed therapeutic antibodies trastuzumab and pertuzumab presently used to treat patients with ERBB2-amplified breast cancer. Immunohistochemistry clinical data were evaluated yielded evidence existence high-level epidermal growth-factor receptor (EGFR) expression as a separate...
Summary Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family inhibition using lumretuzumab (anti-HER3) pertuzumab (anti-HER2) in combination with paclitaxel patients metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC (first line or higher) HER3-positive HER2-low (immunohistochemistry 1+ to 2+ in-situ hybridization negative) tumors. Patients received (1000 mg Cohort 1; 500 Cohorts 2 3) plus (840...
The quality control testing of chemical degradations in the bio-pharmaceutical industry is currently under controversial debate. Here we have systematically applied vitro and vivo stress conditions to investigate influence protein degradation on structure-function. Extensive purification characterization enabled identification functional assessment physiological modification sites variable complementarity-determining regions (CDRs) conserved region trastuzumab. We demonstrate that...
Antibody-dependent cell-mediated cytotoxicity (ADCC) is one mechanism of action the monoclonal antibody (mAb) therapies trastuzumab and pertuzumab. Tyrosine kinase inhibitors (TKIs), like lapatinib, may have added therapeutic value in combination with mAbs through enhanced ADCC activity. Using clinical data, we examined impact lapatinib on HER2/EGFR expression levels natural killer (NK) cell gene signatures. We investigated ability three TKIs (lapatinib, afatinib, neratinib) to alter...
In many solid tumors, overexpression of human epidermal growth factor receptors (e.g., HER1/EGFR and HER2) correlates with poor prognosis. Erlotinib (Tarceva) is a potent tyrosine kinase inhibitor. Pertuzumab (Omnitarg), novel HER2-specific, recombinant, humanized monoclonal antibody, prevents heterodimerization HER2 other HERs. Both mechanisms disrupt signaling pathways, resulting in tumor inhibition. We evaluated whether inhibition both superior to monotherapy cell lines expressing...
Abstract Purpose: Attempts to selectively initiate tumor cell death through inducible apoptotic pathways are increasingly being exploited as a potential anticancer strategy. Inhibition of NAD+ synthesis by novel agent FK866 has been recently reported induce apoptosis in human leukemia, hepatocarcinoma cells vitro, and various types xenografts vivo. In the present study, we used 1H-decoupled phosphorus (31P) magnetic resonance spectroscopy (MRS) examine metabolic changes associated with...
Abstract Purpose: The aim of this study was to investigate the antitumor effects HER2-directed combination therapy in ovarian cancer xenograft models evaluate their potential. combinations trastuzumab and pertuzumab, aromatase inhibitor were investigated. Experimental Design: trastuzumab, letrozole on growth response, apoptosis, morphology, gene protein expression evaluated SKOV3 cell line a panel five human xenografts derived directly from clinical specimens. Results: antibodies showed...
Bidirectional cross talk between members of the human epidermal growth factor family receptors (HER) and estrogen receptor (ER) is believed to underlie resistance mechanisms that develop in response treatment with anti-HER agents endocrine therapy. We investigated interaction HER2, HER3 ER vitro using embryonic kidney cells transfected HER3, ERα. also additive efficacy combination regimens consisting anti-HER3 (lumretuzumab), anti-HER2 (pertuzumab), (fulvestrant) therapy vivo. Our data show...
Abstract Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response agent model cancer. A panel 13 cancer cell lines was treated with heregulin β1 (HRGβ1) or transforming growth factor-α, and proliferation assessed. Both agents increased number the majority studied, both being similar (r = 0.83; P 0.0004, Pearson test). HRGβ1...
Abstract Epidermal growth factor receptor (EGFR) and ErbB2 readily form heterodimers when both are expressed in the same cell EGFR is activated by one of its ligands. Our data show that such constitutively formed also a ligand-independent manner on overexpression porcine aortic endothelial cells. Interestingly, cross-linking experiments showed incubation with antibody pertuzumab, which has been shown to bind dimerization arm ErbB2, resulted dissolution EGFR-ErbB2 heterodimers. Incubation...
Trastuzumab and pertuzumab target the Human Epidermal growth factor Receptor 2 (HER2). Combination therapy has been shown to provide enhanced antitumour activity; however, downstream signalling explain how these drugs mediate their response is not clearly understood. Transcriptome profiling was performed after 4 days of trastuzumab, combination treatment in human ovarian cancer vivo. Signalling pathways identified were validated investigated primary xenografts at protein level across a...
Abstract Recently, it was reported that the anti‐estrogen tamoxifen not only inhibits estradiol‐stimulated growth of MCF‐7 cells but also significantly reduces proliferation rate stimulated by factors. We have confirmed this finding and shown new droloxifene epidermal factor (EGF) insulin‐like factor‐I (IGF‐I)‐stimulated cells. The growth‐factor‐induced inhibited in a dose‐dependent manner anti‐estrogens complete absence estrogen FCS. Of anti‐estrogens, considerably more potent than...
This study was designed to evaluate the expression of HER receptors as a marker sensitivity humanized anti-HER2 monoclonal antibody pertuzumab in ovarian cancer cells. In recent clinical trial, low levels HER3 mRNA have been shown associate with response when combined gemcitabine. We sought define how modulated using cell line models better understand differential and dynamic receptor therapeutic response. Changes were also assessed pertuzumab-treated xenografts. and, lesser extent, HER2,...
Abstract HER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes of AKT and ERK1/2, contributing to tumour progression therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, although they have shown favorable tolerability, their activity as a single agent has proven be limited. Here we show phosphorylation cells occurs paracrine manner mediated cancer-associated fibroblasts (CAFs). Moreover,...