Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Epidermal Growth Factor Receptor (EGFR) family, including EGFR, HER2, HER3, and HER4, is implicated in the development and progression of cancer, and is expressed in many human epithelial malignancies, including Non-Small Cell Lung Cancer (NSCLC). Several molecules were synthesized to inhibit the extracellular domain of EGFR, such as cetuximab (Erbitux), the extracellular domain of HER2, such as trastuzumab (Herceptin) or the EGFR tyrosine kinase domain, such as gefitinib (Iressa) and erlotinib (Tarceva). Gefitinib and erlotinib are orally active, selective EGFR tyrosine-kinase inhibitors (EGFR-TKI) that produce objective response rates in about 10% of advanced NSCLC. More recently, erlotinib produced a significant improvement in survival when compared to placebo in pretreated NSCLCs. Among clinical characteristics, although female gender, and adenocarcinoma histology, showed to be significantly associated to TKI sensitivity, never smoking history is probably the most relevant factor. Presence of specific EGFR gene mutations or EGFR gene amplification confer a particularly sensitive phenotype, and patients with activation of the anti-apoptotic protein Akt are more sensitive, when Akt activation is sustained by a EGFR dependent mechanism. Cetuximab is a human-murine chimeric anti-EGFR IgG monoclonal antibody that has demonstrated both in vitro and in vivo antitumor activity in tumor cell lines expressing EGFR. It has shown impressive activity when combined with radiation by increasing the antitumor effect of radiation therapy. Cetuximab has a synergistic effect with cisplatin and may play a role in reversing resistance to chemotherapy. Cetuximab demonstrated to be active in pretreated NSCLCs, and its activity as first-line therapy in combination with chemotherapy is currently under evaluation. Efforts should be made for the identification of biological mechanism underlying cetuximab sensitivity and emerging data suggest that the drugs is more active in patients with EGFR gene amplification. In NSCLC, trastuzumab produced disappointing results when combined with chemotherapy, but probably patients were not properly selected. Recent findings in gefitinib treated patients support HER2 analysis by fluorescence in situ hybridization as a complementary test for selection of patient candidate for EGFR targeted therapies. Combination of EGFR targeting agents with other biological drugs is under investigation.
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PMID:Epidermal growth factor receptor (EGFR) targeted therapies in non-small cell lung cancer (NSCLC). 1839 76

Concurrent chemoradiotherapy (CCRT) is one of the standard treatments for advanced head and neck cancer (HNC). Intensive combination chemotherapy has been re-considered for neo-adjuvant chemotherapy in functional preservation protocol. Molecular targeting drugs (MTG) have proved effective for HNC not only in basic study but in many clinical phase II trials. Cetuximab, an anti-EGFR monoclonal antibody, is a key drug for regimens including MTG. Phase III trials with CDDP/carboplatin+5-FU vs CDDP/carboplatin+5-FU+cetuximab proved the combination with cetuximab was statistically effective for survival of patients with recurrent/metastatic HNC. Combination with cetuximab prolonged survival from 7.4 months to 10.1 months in this report. A good response rate and survival rate are reported in phase II study for chemoradiotherapy with CDDP and cetuximab. The three-year overall survival and local control rate were 76% and 71%, respectively. The combination with MTG will be important in CCRT for advanced HNC. It may well be considered the standard treatment for recurrent/metastatic HNC patients in future.
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PMID:[Combination therapy with molecular targeting drugs for head and neck cancer]. 1848 10

We carried out a multicentric retrospective study on cetuximab + chemotherapy in pre-treated refractory patients outside clinical protocols, by registering the main clinical and pathological parameters. We evaluated 144 pre-treated patients. Cetuximab was administered usually in combination with irinotecan (93.8%). A 45% disease control rate (complete plus partial responses plus stable disease) was obtained in 55 patients and was related to absence of weight loss (p<0.0001) and high grade (> or =2) skin toxicity (p<0.0001). Median time to progression (TTP) was 4 months (95%CI 2.7-5.3) and median overall survival (OS) was 11.8 months (95%CI 8.5-15.1). Performance status << or =1, no weight loss and high grade (>or =22) skin toxicity were related both to a longer TTP (p=0.035, p=0.035, p=0.0017) and OS (p<0.0001, p<0.0001, p=0.006). According to multivariate analysis, the absence of weight loss was related to longer TTP (HR 0.331, p=0.004) and OS (HR 0.176, p<0.0001), and EGFR over-expression (3+) to longer TTP (HR 0.402, p=0.020).
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PMID:The role of cetuximab in pre-treated refractory patients with metastatic colorectal cancer: outcome study in clinical practice. 1860 95

Here we report for the first time that proteins can function as unique reducing agents to produce gold nanoparticles from gold salts. We demonstrate that three different proteins, namely, bovine serum albumin (BSA), Rituximab (RIT--an anti-CD20 antibody) and Cetuximab (C225--anti-EGFR antibody), reduce gold salts to gold nanoparticles (GNP). Interestingly, among all the three proteins tested, only BSA can reduce gold salts to gold nanotriangles (GNT). BSA-induced formation of GNT can be controlled by carefully selecting the reaction condition. Heating or using excess of ascorbic acid (AA) as additional reducing agent shifts the reaction towards the formation of GNP with flower-like morphology, whereas slowing down the reaction either by cooling or by adding small amount of AA directs the synthesis towards GNT formation. GNT is formed only at pH 3; higher pHs (pH 7 and pH 10) did not produce any nanoparticles, suggesting the involvement of specific protein conformation in GNT formation. The nanomaterials formed by this method were characterized using UV-visible (UV-vis) spectroscopy and transmission electron microscopy (TEM). This is an important finding that will have uses in various nanotechnological applications, particularly in the green synthesis of novel nanomaterials based on protein structure.
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PMID:Protein-mediated autoreduction of gold salts to gold nanoparticles. 1868 31

The introduction of concepts proposing multiple cellular subgroups in the normal female breast leads to the hypothesis that distinct cellular phenotypes in the female breast give rise to different subtypes of breast carcinomas e.g. expressing ER, HER2 and EGFR differentially. Therefore, origin of breast carcinoma types may be based on the formation of a cancer prone field in which the committed progenitor cells pass mutations to their progenies, glandular as well as myoepithelial cells. The existence of such field within the human breast was inferred from the results on primary breast cancer obtained by PCR-based microsatellite analysis of allelic imbalance (AI) of the EGF receptor gene. Here, normal breast tissue shows egfr AI adjacent to breast cancer tissue also harboring egfr gene AI. The therapeutic implications of such a model are fundamental, as tumors may display different phenotypes which arise from transformation of different progenitor cells as well as from transformation of more differentiated progenies within a cancer prone field. Thereby they may show up with different clinical courses of the disease, higher rates of metastases and responses to therapy. In this review, we discuss this mechanism focusing on the EGF receptor as an example for regulators of progenitor cell growth in many tissues. Phylloides tumors serve as a putative model for embryonic differentiation stage ruled by EGFR signaling and give insights into the tumor-host-interaction. The inhibition of the EGF receptor by specific monoclonal antibodies (e.g. Erbitux) will give an answer in as far EGFR-signaling is decisive for the development of an invasive breast cancer. For this purpose new models have been inaugurated which vary in the EGF receptor gene dosage and protein expression. Moreover, we discuss the EGF receptor as a target for the treatment of pre-malignant lesions with a high risk for malignant growth, e.g. DCIS, which certainly will be detected more frequently by mammography screening programs soon.
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PMID:Allelic imbalances of the egfr gene as key events in breast cancer progression--the concept of committed progenitor cells. 1869 Aug 49

EGFR overexpression in salivary gland carcinomas provides the rational for the investigation of anti-EGFR treatments in recurrent and/or metastatic salivary gland cancers (RMSGCs). The activity of cetuximab in terms of clinical benefit rate (CBR) defined as the occurrence of objective response (CR or PR) or stable disease (SD) for >or=6months was investigated. From April to December 2005, 30 patients [23 adenoid cystic carcinoma (ACC) and 7 non-ACC] were treated with cetuximab at 400mg/m(2)/week followed by 250mg/m(2)/week until progression, major toxicity or voluntary discontinuation. EGFR expression and gene status were retrospectively analyzed by immunocytochemistry and fluorescence in situ hybridization, respectively. A median of 14 courses of cetuximab (range 5-54) were infused. Skin toxicity was the main adverse event. Cetuximab provides a CBR in 50% (95% CL, 31 to 69%) of cases. None tumor sample showed EGFR gene amplification and an increased EGFR copy number was observed in 12% of samples, all ACC. Skin rash >or=G2, EGFR overexpression and EGFR copy number were not statistically correlated to CB. In RMSGCs further evaluations of EGFR targeting agents are advisable and should take place by appropriate tumor biological selection, differentiating ACC from non-ACC.
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PMID:Cetuximab in recurrent and/or metastatic salivary gland carcinomas: A phase II study. 1880 10

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.
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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

Pharmacogenetics and pharmacogenomics are keys to the success of personalized medicine, prescribing drugs based on a patient's individual genetic and biological profile. In this review, we will focus on the application of pharmacogenetics and pharmacogenomics in developing monoclonal antibody (MAb) therapeutics in oncology. The significance of pharmacogenomics in MAb therapeutics is highlighted by the association between polymorphisms in Fc receptors and clinical response to anti-CD20 MAb rituximab (Rituxan) or anti-ganglioside GD2 MAb 3F8, as well as the potential link between polymorphisms in HER2 and cardiac toxicity in patients treated with the anti-HER2 MAb trastuzumab (Herceptin). The dependence on gene copy number or expression levels ofHER2 and epidermal growth factor receptor (EGFR) for therapeutic efficacy of trastuzumab and cetuximab (Erbitux), respectively, supports the importance of selecting suitable patient populations based on their pharmacogenetic profile. In addition, a better understanding of target mutation status and biological consequences will benefit MAb development and may guide clinical development and use of these innovative therapeutics. The application of pharmacogenetics and pharmacogenomics in developing MAb therapeutics will be largely dependent on the discovery of novel surrogate biomarkers and identification of disease- and therapeutics-relevant polymorphisms. Challenges and opportunities in biomarker discovery and validation, and in implementing clinical pharmacogenetics and pharmacogenomics in oncology MAb development and clinical practice will also be discussed.
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PMID:Pharmacogenetics and pharmacogenomics in oncology therapeutic antibody development. 1895 38

Three prominent hallmarks of triple-negative/basal-like breast carcinomas, a subtype of breast cancer gene phenotype associated with poor relapse-free and overall survival, are overexpression of the epidermal growth factor receptor (EGFR), hyperactivation of the MEK/ERK transduction pathway and high sensitivity to DNA-damaging agents. The cytotoxic interaction between EGFR inhibitors (monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors such as gefitinib) and DNA cross-linking agents (e.g. platinum derivatives) might represent a promising combination for the treatment of triple-negative/basal-like breast tumors that are dependent upon EGFR/MEK/ERK signaling. We evaluated the growth and molecular interactions of the anti-EGFR antibody cetuximab (erbitux) and the DNA cross-linking agent cisplatin (cis-diammedichloroplatinum; CDDP) in the gefitinib-resistant MDA-MB-468 breast cancer cell line, an in vitro model system that shows many of the recurrent basal-like molecular abnormalities including ER-PR-HER2-negative status, TP53 deficiency, EGFR overexpression, PTEN loss and constitutive activation of the MEK/ERK pathway. Unlike other basal-like breast cancer models, MDA-MB-468 cells do not carry mutations of the key DNA repair gene BRCA1. Concurrent treatment with sub-optimal doses of cetuximab significantly enhanced CDDP-induced apoptotic cell death. However, an isobologram-based mathematical assessment of the nature of the interaction revealed a loss of synergism when employing a high-dose of cetuximab. Since BRCA1 depletion has been found to decrease DNA damage repair and cell survival in MDA-MB-468 cells when treated with DNA-damaging drugs, we employed ELISA-based quantitative analyses to measure BRCA1 protein levels in CDDP+/- cetuximab-treated cells. Cetuximab as single agent was as efficient as CDDP at increasing BRCA1 protein expression. Interestingly, cetuximab co-exposure significantly antagonized the ability of CDDP to up-regulate BRCA1 expression. Low-scale phosphor-proteomic approaches [i.e. phospho-receptor tyrosine kinase (RTK) and phospho-mitogen-activated protein kinases (MAPKs) Array Proteome Profiler capable of simultaneously identifying the relative levels of phosphorylation of 42 different RTKs and 23 different MAPKs and other serine/threonine kinases, respectively] revealed the ability of Cetuximab, as single agent, to paradoxically induce hyper-phosphorylation of EGFR while concomitantly deactivating p42/44 (ERK1/ERK2) MAPK. Unexpectedly, ELISA-based quantitative analyses of EGFR protein content demonstrated that simultaneous exposure to cetuximab and optimal doses of CDDP completely depleted EGFR protein in MDA-MB-468 cells. Although these findings preclinically support, at least in part, ongoing clinical trials for 'triple-negative/basal-like' metastatic breast cancer patients who are receiving either cetuximab alone versus cetuximab plus carboplatin (http://www.clinicaltrials.gov/ct/show/NCT00232505), the unexpected ability of CDDP to promote a complete depletion of the cetuximab target EGFR further suggests that treatment schedules, cetuximab/CDDP doses and BRCA1 status should be carefully considered when combining anti-EGFR antibodies and platinum derivatives in triple-negative/basal-like breast carcinomas.
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PMID:Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin in gefitinib-resistant MDA-MB-468 cells: new prospects in the treatment of triple-negative/basal-like breast cancer. 1902 Jul 49

ErbBs signalling is always associated with the development of the majority of solid cancers via both the MAPK pathway leading to cell cycle progression and the PI3K pathway causing cell survival. As a consequence, many ErbB antagonists have been developed and patented for cancer treatment purposes. These antagonists belong to two drug classes: monoclonal antibodies (mAbs) and small molecules competing with ATP and inhibiting the tyrosine kinase domain (TKIs). Three patented mAbs are currently approved in clinical cancer treatment: Trastuzumab (Herceptin) directed against HER2 and used to treat breast cancer, Cetuximab and Panitumumab which are anti-EGFR antibodies approved for colorectal cancer treatment. Unfortunately, these mAbs are facing cancer resistance mediated by paracrine activation of other ErbB members or compensatory ErbB signalling factors. In parallel, three TKIs have been approved to treat cancer: Gefitinib (Iressa), Erlotinib (Tarceva) inhibiting specifically EGFR and approved to treat non small cell lung cancer and Lapatinib (Tykerb) which has the dual specificity EGFR/HER2 and recently approved to treat metastatic breast cancer. These TKIs are also facing resistance mutations within the TK domain which increase its affinity to ATP. Resistance problems are leading to the adoption of a new strategy based on the combination of different therapies and this is likely to be the most promising future of cancer treatments.
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PMID:ErbB antagonists patenting: "playing chess with cancer". 1907 65


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