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

---

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

We have found using differential display of mRNA that the growth factor heregulin beta 1 (HRG), a combinatorial ligand for human epidermal growth factor receptors (HERs), induced expression of G3BP, the Ras GTPase-activating protein SH3 domain-binding protein, in breast cancer cells. G3BP is a downstream effector protein of Ras signaling with ATP-dependent RNase and helicase activities, which may link Ras signaling with RNA turnover and cell cycle progression. In human breast cancer cells, HRG induced G3BP mRNA and protein expression. Up-regulation of G3BP was found in MCF7 breast cancer cells overexpressing HER2. G3BP was also overexpressed in human breast tumors in parallel with HER2 overexpression and in an estrogen-independent manner, suggesting a role for G3BP in cancer progression. In addition, HRG stimulation of breast cancer cells promoted phosphorylation of G3BP and increased the association of G3BP with GTPase-activating protein, both of which are essential for G3BP activity. G3BP ATPase activity was also significantly increased by HRG treatment. Furthermore, HRG treatment resulted in G3BP translocation to the nucleus and colocalization with acetylated histone H3, a hallmark of active transcription sites. G3BP induction, phosphorylation, ATPase activity, and relocalization after HRG treatment could all be blocked by pretreatment with the anti-receptor HER2 monoclonal antibody Herceptin (trastuzumab), which may suggest additional applications for this therapeutic antibody. These findings demonstrate for the first time the receptor-dependent regulation of G3BP, a downstream effector of Ras signaling, by HRG, a growth factor with diverse functions in breast cancer cells.
...
PMID:Heregulin induces expression, ATPase activity, and nuclear localization of G3BP, a Ras signaling component, in human breast tumors. 1188 85

Despite intensive treatment efforts, the prognosis for lung cancer is very poor; less than 15% of patients survive 5 years. Trastuzumab, a monoclonal antibody targeting the HER2/neu protein receptor, is effective in the treatment of metastatic breast cancer and may be useful in the treatment of non-small cell lung cancer (NSCLC). Using the HercepTest (Dako; Carpenteria, CA), 25% of NSCLC show 2+ or greater HER2/neu expression, but only 6% to 8% of NSCLC tumors have 3+ overexpression. Positive HER2/neu expression is most often seen in adenocarcinomas compared with squamous cell carcinomas or large cell carcinomas, and is rarely seen in small cell lung cancer. As determined by fluorescence in situ hybridization analysis, the high degree of HER2/neu gene expression and gene amplification seen in breast cancer is lower in NSCLC. Polysomy is the cause of increased HER2/neu expression in most NSCLC. Prospective clinical studies with trastuzumab in lung cancer are ongoing. Future studies in NSCLC need to include immunohistochemistry and fluorescence in situ hybridization analysis to determine the method of choice for evaluating clinically relevant HER2/neu-positive tumors.
...
PMID:HER2/neu expression in malignant lung tumors. 1189 14

Despite improvements in care of patients with breast cancer, up to half develop refractory or resistant disease. There is therefore a need for new, modified anticancer therapies with greater effectiveness, tolerability to patients, and tumour specificity. Trastuzumab (Herceptin) is the first clinically available oncogene-targeted therapeutic agent for treatment of solid tumours. Clinical trials in patients positive for HER2 (human epidermal-growth-factor receptor 2) show that trastuzumab is effective and well tolerated; as a single-agent second-line or third-line treatment, the drug produced durable tumour responses. First-line trastuzumab in combination with chemotherapy, particularly paclitaxel, significantly improved time to disease progression, duration of response, and time to treatment failure. Combination therapy resulted in a 25% improvement in overall survival compared with chemotherapy alone. Patients with HER2 gene amplification, high overexpression of HER2 (3+ on immunohisto-chemistry), or both features, obtained the greatest clinical benefit. Trastuzumab is the first monoclonal antibody with efficacy in breast cancer and the first gene-product-targeted therapy to produce a significant survival advantage in this disease. Trastuzumab is likely to find its ultimate role in the adjuvant setting. Its development provides a model for the integration of other gene-targeted therapies into breast-cancer management to improve survival and quality of life.
...
PMID:Trastuzumab: hopes and realities. 1190 99

The human epidermal growth factor receptor-2(HER2) is overexpressed/amplified in a number of cancers. HER2 is implicated in disease initiation and progression and associated with poor prognosis. Trastuzumab(Herceptin) is a recombinant DNA-derived humanized anti-HER2 monoclonal antibody that selectively binds with high affinity to extra-cellular domain. In vitro assay, trastuzumab has been shown to inhibit the proliferation of human tumor cells that overexpressed HER2 and to be a mediator of antibody-dependent cellular toxicity. Clinical trials have demonstrated that it is effective as both single and combination with chemotherapeutic agent in recurrent and metastatic breast cancer patients who's tumor tissue are overexpressed HER2. The incidence of severe adverse events were low but the occurrence of cardiac toxicity was unexpectedly high if trastuzumab was combined with anthracycline containing chemotherapy. The further studies are underway to assess the role of trastuzumab in combination chemotherapy, adjuvant chemotherapy and other type of tumors.
...
PMID:[Rationale for Herceptin in the clinical use]. 1190 59

The HER2/neu protein is thought to be a unique and useful target for antibody therapy of cancers overexpressing the HER2/neu gene. The recombinant humanized anti-HER2 monoclonal antibody, trastuzumab(Herceptin) has recently been available for clinical use in Japan. In this paper, the details of this novel biologic agent are reviewed in conjunction with the results of the clinical trials for breast cancer.
...
PMID:[Breast cancer]. 1190 74

Herceptin has provided the first proof that tyrosine kinase modulation, through monoclonal antibodies can translate into improved clinical outcomes in cancer therapy. The development of Herceptin was encouraged by the biologic significance of HER2 overexpression. Although the number of patients affected by the targeted molecular abnormality(30% of breast cancer patients) is small and the response rate observed in patients after treated with single agent Herceptin is rather low, the ability to document overexpression of the target in breast biopsies, and a growing interest in biologic therapy facilitated the rapid accrual of patients to clinical trials. The challenges of applying research techniques of molecular biology to routine clinical testing have been demonstrated by the experiences with the HER2/neu oncogene. Immunohistochemistry and fluorescence in situ hybridization yielded discrepant results regarding the frequency and degree of HER2 alterations even within the same sample. In order to make the complexity of interpretation of the discrepancy simple, it is wise to build an algorithm to help clinicians follow the ideal sequence of laboratory testings. The experience gained in the testing of Herceptin has provided important lessons for the future testing of molecularly targeted compounds.
...
PMID:[Genetic testing for effective Herceptin therapy]. 1190 80

Overexpression of the p185/HER2 protein is seen in 20%-25% of primary breast cancers and is associated with poor prognosis. Recent phase II and III clinical trials demonstrate that trastuzumab is active against breast tumors, both as a single agent and in combination with chemotherapy. In patients with HER2-overexpressing metastatic breast cancer, use of trastuzumab in combination with chemotherapy is associated with a 20% reduction in relative risk of death and an increase in median survival from 20.3 to 25.1 months compared to chemotherapy alone. Side effects include fever and chills and an unexpected increase in doxorubicin/trastuzumab-associated cardiomyopathy. Clinical development is now focused on trastuzumab in combination with chemotherapy regimens that do not contain an anthracycline. Trastuzumab in combination with docetaxel is synergistic in vitro. Data from ongoing clinical trials are consistent with this finding. Preliminary data from 3 phase II studies suggest a 44%-63% response rate when the combination is used first or second line in HER2-overexpressing metastatic breast cancer. The combination of docetaxel with trastuzumab is well tolerated and has not been associated with significant cardiotoxicity. Given in vitro evidence that platinum salts act synergistically with trastuzumab and docetaxel, and phase II data suggesting clinical efficacy and good tolerability, the combination of platinum salt plus trastuzumab and docetaxel is now being assessed in adjuvant trials
...
PMID:Combining the anti-HER2 antibody trastuzumab with taxanes in breast cancer: results and trial considerations. 1197 Jul 40

Breast cancers with high expression of HER2 are associated frequently with aggressive, poor prognosis disease and resistance to chemotherapy-induced apoptosis. Geldanamycin and its less toxic analogue, 17- (allylamino)-17-demethoxygeldanamycin (17-AAG) are ansamycin antibiotics that bind to a highly conserved pocket in the hsp 90 chaperone protein and inhibit its function. Hsp 90 is required for the refolding of proteins during environmental stress and the conformational maturation of certain signaling proteins. Among the most sensitive targets of 17-AAG are the HER kinases. Therefore, tumors that are dependent on these kinases may be especially sensitive to 17-AAG either alone or in combination with chemotherapy. In this study we demonstrate that cells that overexpress HER2 are 10-100-fold more sensitive to 17-AAG than cancer cells expressing low levels of HER2. We found that HER2 is degraded in several cell lines, but only cell lines with high levels of HER2 are sensitive to the drug. The effects of 17-AAG on growth and apoptosis are because of inhibition of signaling through HER2-HER3, phosphatidylinositol 3'- kinase. The absence of HER3 and the introduction of constitutively active p110alpha rendered cells with high HER2 expression more resistant to 17-AAG. These findings suggest that 17-AAG may be useful for the treatment of breast cancer cells with high levels of HER2. However, the overexpression of HER2 alone may not be predictive of response, because the coexpression of HER3 and the activation of phosphatidylinositol 3'-kinase may play a crucial role in the response of these cells to 17-AAG and other drugs directed against HER2. These observations have important clinical implications because they may help to identify patients that are most likely to benefit from 17-AAG and may explain resistance to Herceptin as seen in many patients.
...
PMID:Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway. 1203 25

Trastuzumab (Herceptin) provides clinical benefits for patients diagnosed with advanced breast cancers that have overexpressed the HER2 protein or have amplified the HER2 gene. The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-31 is designed to test the advantage of adding Herceptin to the adjuvant chemotherapeutic regimen of doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) in the treatment of stage II breast cancer with HER2 overexpression or gene amplification. Eligibility is based on HER2 assay results submitted by the accruing institutions. We conducted a central review of the first 104 cases entered in this trial on the basis of immunohistochemistry (IHC) results. We found that 18% of the community-based assays, which were used to establish the eligibility of patients to participate in the B-31 study, could not be confirmed by HercepTest IHC or fluorescence in situ hybridization (FISH) by a central testing facility. This report provides a snapshot of the quality of HER2 assays performed in laboratories nationwide.
...
PMID:Real-world performance of HER2 testing--National Surgical Adjuvant Breast and Bowel Project experience. 1269 58

Overexpression of the HER2/neu oncogene and receptor protein has been reported in 20%-30% of patients with breast cancer and is associated with a poor prognosis. HER2/neu expression in breast cancer patients assessed by fluorescence in situ hybridization or immunohistochemistry is a predictor for response to trastuzumab, a humanized monoclonal antibody against the HER2/neu cell-surface protein. Data regarding HER2/neu expression in lung cancer are more limited, and there is little information regarding HER2/neu expression and response to trastuzumab alone or in combination with chemotherapeutic agents. Gemcitabine is an active agent against non-small-cell lung cancer (NSCLC) and has demonstrated activity in breast cancer as well. In vitro modified tetrazolium salt growth assays were performed to determine whether the combination of trastuzumab/gemcitabine produced synergistic or additive effects on breast and lung cancer cell lines. The effects of trastuzumab alone, gemcitabine alone, and the trastuzumab/gemcitabine combination was evaluated on 4 NSCLC cell lines, 1 small-cell lung cancer (SCLC) cell line, and 2 breast cancer cell lines. HER2/neu surface protein expression was assessed by fluorescence flow cytometry and immunohistochemistry. Fluorescence in situ hybridization analysis was used to study gene expression. Trastuzumab treatment alone resulted in growth inhibition in all cell lines expressing HER2/neu and the inhibitive effect correlated with the level of cell surface HER2/neu protein expression. Treatment with gemcitabine alone resulted in growth inhibition in both breast and NSCLC cell lines. A synergistic growth inhibition effect was seen with the trastuzumab/ gemcitabine combination as indicated by combination index values < 1. The degree of synergy observed did not directly correlate with the level of surface protein expression, as synergy was seen even in cancer cell lines expressing low levels of HER2/neu. No treatment effect was seen in the SCLC cell line, which did not express HER2/neu. These preclinical studies indicate a need to study the clinical synergistic effects of the gemcitabine/trastuzumab combination in breast cancer and NSCLC patients whose tumors overexpress HER2/ neu.
...
PMID:Preclinical studies of gemcitabine and trastuzumab in breast and lung cancer cell lines. 1205 39


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

---