Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

JNJ-28871063 is a potent and highly selective pan-ErbB kinase inhibitor from a novel aminopyrimidine oxime structural class that blocks the proliferation of epidermal growth factor receptor (EGFR; ErbB1)- and ErbB2-overexpressing cells but does not affect the growth of non-ErbB-overexpressing cells. Treatment of human cancer cells with JNJ-28871063 inhibited phosphorylation of functionally important tyrosine residues in both EGFR and ErbB2 and blocked downstream signal transduction pathways responsible for proliferation and survival. A single dose of compound reduced phosphorylation of ErbB2 receptors in tumor-bearing mice, demonstrating target suppression in vivo. Tissue distribution studies show that JNJ-28871063 crosses the blood-brain barrier and penetrates into tumors, where it is able to accumulate to higher levels than those found in the plasma. JNJ-28871063 showed oral antitumor activity in human tumor xenograft models that overexpress EGFR and ErbB2. In an intracranial ErbB2-overexpressing tumor model, JNJ-28871063 extended survival relative to untreated animals. The brain is a primary site of metastasis for EGFR-overexpressing lung cancers and ErbB2-overexpressing breast cancers. Therefore, the ability to penetrate into the brain could be an advantage over existing therapies such as trastuzumab (Herceptin) and cetuximab (Erbitux), which are antibodies and do not cross the blood-brain barrier. These results show that JNJ-28871063 is orally bioavailable, has activity against EGFR and ErbB2-dependent tumor xenografts, and can penetrate into the brain and inhibit ErbB2-overexpressing tumor growth.
Mol Pharmacol 2008 Feb
PMID:Cellular and in vivo activity of JNJ-28871063, a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brain barrier and displays efficacy against intracranial tumors. 1798 94

Pharmacologic agents developed for cancer therapy have traditionally relied on a therapeutic ratio of effects between tumors and normal tissue. Over the past decade, this concept has been refined through the development of agents that are intended to specifically target tumor cells. The epidermal growth factor receptor (EGFR) (ErbB) family of receptor tyrosine kinases is an intensely studied target in many cancer cell types, and several successful therapeutic agents have been developed to block the growth promoting functions of these receptors. However, with their success has come the evolution of novel clinical scenarios by which tumor cells can evade these targeted therapies. Trastuzumab, a monoclonal antibody to Her2/ErbB2 that is used in breast cancer, has been shown to provide a survival benefit for patients whose tumors express this receptor but it does not have activity in the central nervous system because of the blood-brain barrier. In this issue of Molecular Pharmacology, Emanuel et al. (p. 328) report on a tyrosine kinase inhibitor that targets Her2/neu and also crosses the blood-brain barrier. Efforts to improve current strategies of targeting this receptor may lead not only to benefits in the treatment of breast cancer but also to advances in the treatment of other central nervous system malignancies, such as gliomas and medulloblastoma.
Mol Pharmacol 2008 Feb
PMID:Revoking the privilege: targeting HER2 in the central nervous system. 1797 7

The CCNG2 gene that encodes the unconventional cyclin G2 was one of the few genes up-regulated on anti-human epidermal growth factor receptor 2 (HER2) antibody-mediated inhibition of HER2 signaling. The purpose of this study was to explore how HER2 signaling modulates cyclin G2 expression and the effect of elevated cyclin G2 on breast cancer cell growth. Treatment of breast cancer cells that overexpress HER2 (BT474, SKBr3, and MDAMB453) with the anti-HER2 antibody trastuzumab or its precursor 4D5 markedly up-regulated cyclin G2 mRNA in vitro and in vivo, as shown by real-time PCR. Immunoblot and immunofluorescence analysis with specific antibodies against cyclin G2 showed that anti-HER2 antibody significantly increased cyclin G2 protein expression and translocated the protein to the nucleus. Trastuzumab was not able to induce cyclin G2 expression in cells weakly expressing HER2 (MCF7) or in cells that had developed resistance to trastuzumab. Enforced expression of HER2 in T47D and MDAMB435 breast cancer cells reduced cyclin G2 levels. Collectively, these data suggest that HER2-mediated signaling negatively regulates cyclin G2 expression. Inhibition of phosphoinositide 3-kinase (LY294002), c-jun NH(2)-terminal kinase (SP600125), and mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K; rapamycin) increased cyclin G2 expression. In contrast, treatment with inhibitors of p38 mitogen-activated protein kinase (SB203580), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (U0126), or phospholipase Cgamma (U73122) did not affect cyclin G2 expression. Anti-HER2 antibody in combination with LY294002, rapamycin, or SP600125 induced greater cyclin G2 expression than either agent alone. Ectopic expression of cyclin G2 inhibited cyclin-dependent kinase 2 activity, Rb phosphorylation, cell cycle progression, and cellular proliferation without affecting p27(Kip1) expression. Thus, cyclin G2 expression is modulated by HER2 signaling through multiple pathways including phosphoinositide 3-kinase, c-jun NH(2)-terminal kinase, and mTOR signaling. The negative effects of cyclin G2 on cell cycle and cell proliferation, which occur without altering p27(Kip1) levels, may contribute to the ability of trastuzumab to inhibit breast cancer cell growth.
Mol Cancer Ther 2007 Nov
PMID:Roles of human epidermal growth factor receptor 2, c-jun NH2-terminal kinase, phosphoinositide 3-kinase, and p70 S6 kinase pathways in regulation of cyclin G2 expression in human breast cancer cells. 1802 71

Salivary duct carcinoma (SDC) shares significant morphologic and immunophenotypic overlap with ductal carcinoma of the breast, including HER-2/neu expression. Previous studies have detected HER-2/neu at the protein level in SDCs; however, no study, to date, has assayed whether this expression is related to gene amplification detected by chromogenic in situ hybridization (CISH). Formalin-fixed, paraffin-embedded tissue sections from 12 previously diagnosed SDCs were evaluated by immunohistochemistry (IHC) and CISH for HER-2/neu status. Result concordance was seen in all 12 cases. A total of 4 SDCs were positive by IHC; all 4 cases showed amplification with CISH. The remaining 8 cases were negative by IHC and showed no gene amplification with CISH. SDCs in this study show HER-2/neu overexpression on both the protein and gene levels in approximately 30% of cases. These findings suggest a role may exist for Herceptin (trastuzumab) based therapy in some SDC patients.
Appl Immunohistochem Mol Morphol 2008 Jan
PMID:Her-2/neu expression in salivary duct carcinoma: an immunohistochemical and chromogenic in situ hybridization study. 1809 19

EGF receptor (EGFR) represents an attractive target for anticancer therapies in a variety of malignant neoplasms, including colorectal, non-small-cell lung, head and neck carcinomas and gliomas. Monoclonal antibodies, such as cetuximab, are directed against the extracellular EGFR domain, whereas small molecules are targeting the intracellular tyrosine kinase domain. Particularly for application of drugs against extracellular EGFR parts, knowledge about EGFR levels within the cell membrane is of high import, because only EGFR-depending tumors respond to these therapeutic approaches. Immunohistochemical investigation of tissue slides of the primary tumor are performed to screen for EGFR occurrence in tumor cells. Since 2004, the combination of 'EGFR PharmDx kit', a diagnostic test for EGFR, and subsequent application of cetuximab in EGFR-positive colon carcinomas has been approved by the US FDA. It represents the second approved combination of diagnostic tools and dependent application of monoclonal antibody therapies after the successful HercepTest/Herceptin for breast carcinomas. This proceeding represents an important step toward a personalized cancer therapy with major advantages for patients, mainly reduction of toxic side effects and dramatically increased efficiency.
Expert Rev Mol Diagn 2008 Mar
PMID:Implications of EGFR PharmDx kit for cetuximab eligibility. 1836 1

The epidermal growth factor (EGF) receptor (or ErbB1) and the related ErbB4 are transmembrane receptor protein tyrosine kinases which bind extracellular ligands of the EGF family. ErbB2 and ErbB3 are "co-receptors" structurally related to ErbB1/ErbB4, but ErbB2 is an "orphan" receptor and ErbB3 lacks tyrosine kinase activity. However, both are important in transmembrane signalling. All ErbB receptors/ligands are intimately involved in the regulation of cell growth, differentiation and survival, and their dysregulation contributes to some human malignancies. After extracellular ligand binding, receptor dimerisation and transautophosphorylation of intracellular C-terminal tyrosine residues, they bind signalling proteins which recognise specific tyrosine-phosphorylated motifs. This leads to activation of multiple signalling pathways, notably the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade and the phosphoinositide 3-kinase (PI3K)/protein kinase B [PKB/(Akt)] pathway. In heart, targeted deletion of ErbB2, ErbB3, ErbB4 and some ErbB receptor extracellular ligands leads to embryonic lethality resulting from cardiovascular defects. ErbB receptor ligands improve cardiac myocyte viability and are hypertrophic, partly because of activation of ERK1/2 and/or PI3K/PKB(Akt). Furthermore, ErbB transactivation by Gq protein-coupled receptor (GqPCR) signalling may mediate the hypertrophic effects of GqPCR agonists. The utility of anthracyclines in cancer chemotherapy can be limited by their cardiotoxic side effects and these may be counteracted by ErbB receptor ligands. ErbB2 is the target of anti-cancer monoclonal antibody trastuzumab (Herceptin), and its myocardial downregulation may account for the occasional cardiotoxicity of this therapy. Here, we review the basic biochemistry of ErbB receptors/ligands, and emphasise their particular roles in the myocardium.
J Mol Cell Cardiol 2008 May
PMID:ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium. 1843 Apr 38

It is important to understand how knowledge of genomics can be translated from research into clinical practice and health policies. This review examines existing evidence on three key factors in the adoption of personalized medicine: utilization, preferences, and economic value, using two cancer examples: HER2/neu antigen testing and trastuzumab (Herceptin) treatment and genetic testing for Lynch syndrome. Our findings highlight areas in which additional research is required to build an evidence base addressing utilization of, preferences for, and the potential costs and benefits of personalized medicine. Major challenges include a lack of linked data, the need for relevant research frameworks and methodologies, and the clinical complexities of genomic-based diagnostics and treatment.
Curr Opin Mol Ther 2008 Jun
PMID:Challenges to the translation of genomic information into clinical practice and health policy: Utilization, preferences and economic value. 1853 33

ERBB2 overexpression in estrogen receptor (ER)-positive breast cancer cells such as BT474 (BT) cells has been found to confer resistance to tamoxifen, and suppression of ERBB2 improves the antiproliferative effects of tamoxifen. In this study, the responsiveness to tamoxifen in the BT/HerR, Herceptin-resistant BT cell lines established through constant Herceptin exposure, was evaluated. Compared with BT cells, improvement of sensitivity to tamoxifen in BT/HerR was demonstrated by ER functional analysis and cell proliferation assay. Tamoxifen in the resistant cell line was found to inhibit 17beta-estradiol-stimulating estrogen-responsive gene pS2 expression more effectively than in BT cells in real-time PCR assay. Western blot analysis showed that cross-phosphorylation between ER and downstream components of ERBB2 was attenuated in BT/HerR cells. ER redistribution from cytoplasm to nucleus could be found in these cells through immunofluorescence and confocal studies, and importantly, chromatin immunoprecipitation studies demonstrated that tamoxifen induced occupancy of the pS2 promoter by ER and nuclear receptor corepressor (NCOR1) instead of coactivator NCOA3 in these cells. Finally, combination of tamoxifen and Herceptin was found to improve the sensitivity of BT/HerR cells to Herceptin. Our results suggest that the ER genomic pathway in the ER-positive and Herceptin-resistant breast cancer cells may be reactivated, allowing tamoxifen therapy to be effective again, and a combination of tamoxifen and Herceptin can be a potential therapeutic strategy for ER-positive and Herceptin-resistant human breast cancer.
J Mol Endocrinol 2008 Nov
PMID:Improvement of sensitivity to tamoxifen in estrogen receptor-positive and Herceptin-resistant breast cancer cells. 1876 63

All four members of the human epidermal growth factor (EGF) receptor (HER) family are implicated in human cancers. Although efficacious in a subset of patients, resistance to single-targeted anti-HER therapy [i.e., cetuximab (Erbitux) and trastuzumab (Herceptin)] is often associated with coexpression of other HER family members. This may be overcome by a HER ligand binding molecule that sequesters multiple EGF-like ligands, preventing ligand-dependent receptor activation. Toward this end, we have combined the HER-1/EGFR and HER-3 ligand binding domains, dimerized with fusion of an Fc fragment of human IgG1. This resulted in a mixture of HER-1/Fc homodimer (HFD100), HER-3/Fc homodimer (HFD300), and HER-1/Fc:HER-3/Fc heterodimer (RB200), also termed Hermodulins. The purified first-generation RB200 bound EGF and neuregulin 1 (NRG1)-beta1 ligands, determined by cross-linking and direct binding studies. The binding affinity for both was approximately 10 nmol/L by dissociation-enhanced lanthanide fluorescence immunoassay using europium (Eu)-labeled ligands. Competition studies with RB200 using Eu-EGF or Eu-NRG1-beta1 revealed that RB200 bound HER-1 ligands, including transforming growth factor-alpha and heparin-binding EGF, and HER-3 ligands NRG1-alpha and NRG1-beta3. RB200 inhibited EGF- and NRG1-beta1-stimulated tyrosine phosphorylation of HER family proteins, proliferation of a diverse range of tumor cells in monolayer cell growth assays, tumor cell proliferation as a single agent and in synergy with tyrosine kinase inhibitors, lysophosphatidic acid-stimulated cell proliferation, and tumor growth in two human tumor xenograft nude mouse models. Taken together, the data reveal that RB200 has the potential to sequester multiple HER ligands and interfere with signaling by HER-1, HER-2, and HER-3.
Mol Cancer Ther 2008 Oct
PMID:Human epidermal growth factor receptor (HER-1:HER-3) Fc-mediated heterodimer has broad antiproliferative activity in vitro and in human tumor xenografts. 1885 26

Antibody-based therapeutics currently enjoy unprecedented success, growth in research and revenues, and recognition of their potential. It appears that the promise of the "magic bullet" has largely been realized. There are currently 22 monoclonal antibodies (mAbs) approved by the United States Food and Drug Administration (FDA) for clinical use and hundreds are in clinical trials for treatment of various diseases including cancers, immune disorders, and infections. The revenues from the top five therapeutic antibodies (Rituxan, Remicade, Herceptin, Humira, and Avastin) nearly doubled from $6.4 billion in 2004 to $11.7 billion in 2006. During the last several years major pharmaceutical companies raced to acquire antibody companies, with a recent example of MedImmune being purchased for $15.6 billion by AstraZeneca. These therapeutic and business successes reflect the major advances in antibody engineering which have resulted in the generation of safe, specific, high-affinity, and non-immunogenic antibodies during the last three decades. Currently, second and third generations of antibodies are under development, mostly to improve already existing antibody specificities. However, although the refinement of already known methodologies is certainly of great importance for potential clinical use, there are no conceptually new developments in the last decade comparable, for example, to the development of antibody libraries, phage display, domain antibodies (dAbs), and antibody humanization to name a few. A fundamental question is then whether there will be another change in the paradigm of research as happened 1-2 decades ago or the current trend of gradual improvement of already developed methodologies and therapeutic antibodies will continue. Although any prediction could prove incorrect, it appears that conceptually new methodologies are needed to overcome the fundamental problems of drug (antibody) resistance due to genetic or/and epigenetic alterations in cancer and chronic infections, as well as problems related to access to targets and complexity of biological systems. If new methodologies are not developed, it is likely that gradual saturation will occur in the pipeline of conceptually new antibody therapeutics. In this scenario we will witness an increase in combination of targets and antibodies, and further attempts to personalize targeted treatments by using appropriate biomarkers as well as to develop novel scaffolds with properties that are superior to those of the antibodies now in clinical use.
Methods Mol Biol 2009
PMID:Therapeutic antibodies: current state and future trends--is a paradigm change coming soon? 1925 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>