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)

Angiogenesis is a strongly regulated process, which is dependent upon a complex interplay between inhibitory and stimulatory angiogenic factors. It is essential for tumor growth and metastasis: increased angiogenesis is correlated with poor prognosis in cancer patients. Many novel compounds that potently inhibit formation of neoplastic blood vessels have been recently developed. Major categories of angiogenesis antagonists include protease inhibitors, direct inhibitors of endothelial cell proliferation and migration, angiogenic growth factor suppressors, inhibitors of endothelial-specific integrin/survival signalling, copper chelators, and inhibitors with other specific mechanisms. There is increasing interest in developing angio-suppressive agents for colorectal cancer treatment. Some 20 direct and indirect antiangiogenesis drugs are currently being evaluated in clinical trials in colorectal cancer (CRC). Promising results have been reported. These include an increase in overall survival and reduction in the risk of death (Bevacizumab), reversal of cellular resistance (Cetuximab) and activity as second-line therapy in patients who have exhausted other available treatment options (Cetuximab, ABX-EGF, PTK-787, Gefitinib, Erlotinib). This review will outline the mechanisms of action of the principal antiangiogenic drugs, summarize the available data on the use of these new drugs in colorectal cancer, discuss their impact in clinical practice and offer a glimpse into how antiangiogenetic therapy will be integrated into the future care of patients with gastrointestinal cancers.
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PMID:Colorectal cancer and antiangiogenic therapy: what can be expected in clinical practice? 1589 May 25

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.
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PMID:Molecularly targeted therapy for gastrointestinal cancer. 1589 18

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.
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PMID:Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. 1589 64

Interferon-alpha (IFNalpha) treatment is associated with up-regulation of epidermal growth factor receptor (HER1/EGFR) expression and marked growth inhibition while maintaining the sensitivity of the target colon cancer cells to epidermal growth factor (Gut 2004;53:123). We aimed to determine the effect of combining IFNalpha and Erlotinib (an HER1/EGFR inhibitor) on colon cancer cell line growth. Crystal-violet staining and flow cytometry were used to assess cell proliferation and expression of HER1/EGFR. IFNalpha pre-treatment followed by a combination of IFNalpha plus Erlotinib significantly enhanced the sensitivity of 7/9 of colon cancer cell lines by 7-43%. This approach may have clinical implications for improving treatment based on targeting of HER1/EGFR.
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PMID:Interferon-alpha promotes the anti-proliferative effect of Erlotinib (OSI-774) on human colon cancer cell lines. 1592 58

The majority of patients with ovarian cancer, especially those who present with stages IIIC and IV, will relapse soon after completion of platinum-based induction treatment. It is imperative to find ways to improve and/or enhance the efficacy of induction and to prolong the duration of the first remission. The epidermal growth factor receptor (EGFR) family has been exploited, and currently, three agents that directly target this group of receptors are in use in the treatment of colorectal, non-small-cell lung and breast cancers. EGFR and HER2/neu are overexpressed in a significant percentage of epithelial ovarian cancers. Thus, it would be reasonable to explore directly targeted therapy in ovarian cancer. Numerous investigational trials involving a variety of EGFR inhibitors in ovarian cancer are ongoing. Our institution has an active phase II clinical study that seeks to define the role of erlotinib (Tarceva) in potentiating first-line chemotherapy, and to determine whether the drug offers a significant contribution as maintenance therapy. It is hoped that data from these and other studies will help investigators to understand more clearly the biology of ovarian cancer and to delineate the role of EGFR inhibitors in the management of ovarian cancer.
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PMID:Epidermal growth factor receptor inhibitors for the treatment of epithelial ovarian cancer. 1593 21

Erlotinib (Tarceva, OSI-774; Pfizer, Inc.) is an orally-active, targeted inhibitor of the epidermal growth factor receptor (EGFR/HER1), which is part of a key regulatory pathway in cancer. Patients with advanced, incurable non-small cell lung cancer (NSCLC) may derive a clinical benefit from first- and second-line chemotherapy, but third-line treatment with available cytotoxic agents is not effective. Remarkably, EGFR/HER1 antagonists have demonstrated activity as second- and even third-line treatment for this disease. Erlotinib is the first of this novel class of drug to demonstrate a statistically significant and clinically relevant difference in overall survival, progression free survival and time to disease related symptoms (cough, pain, shortness of breath) compared with treatment with best supportive care in patients who have failed standard first- or second-line chemotherapy. This paper reviews the pharmacology, preclinical and clinical data to support the use of erlotinib in NSCLC.
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PMID:Erlotinib in non-small cell lung cancer: a review. 1595 27

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 HER1/EGFR tyrosine kinase inhibitor. Pertuzumab (Omnitarg), a novel HER2-specific, recombinant, humanized monoclonal antibody, prevents heterodimerization of HER2 with other HERs. Both mechanisms disrupt signaling pathways, resulting in tumor growth inhibition. We evaluated whether inhibition of both mechanisms is superior to monotherapy in tumor cell lines expressing different HER levels. Human non-small cell lung cancer (NSCLC) cells (Calu-3: HER1/EGFR 0+, HER2 3+; QG56: HER1/EGFR 2-3+, HER2 0+) and breast cancer cells (KPL-4: HER1/EGFR 2-3+, HER2 3+) were implanted into BALB/c nu/nu mice and severe combined immunodeficient beige mice, respectively. Tumor-bearing mice (n = 12 or 15 per group) were treated with vehicle (Captisol or buffer), erlotinib (orally, 50 mg/kg/d), pertuzumab (i.p. 6 mg/kg/wk with a 2-fold loading dose), or erlotinib and pertuzumab for 20 (QG56), 27 (KPL-4), or 49 (Calu-3) days. Drug monotherapy had antitumor activity in all models. Tumor volume treatment-to-control ratios (TCR) with erlotinib were 0.36 (Calu-3), 0.79 (QG56), and 0.51 (KPL-4). Pertuzumab TCR values were 0.42, 0.51, and 0.64 in Calu-3, QG56, and KPL-4 models, respectively. Combination treatment resulted in additive (QG56: TCR 0.39; KPL-4: TCR 0.38) or greater than additive (Calu-3: TCR 0.12) antitumor activity. Serum tumor markers for NSCLC (Cyfra 21.1) and breast cancer (soluble HER2) were markedly inhibited by combination treatment (80-97% in Calu-3 and QG56; 92% in KPL-4), correlating with decreased tumor volume. Overall, erlotinib and pertuzumab are active against various human xenograft models, independently of HER1/EGFR or HER2 expression. A combination of these HER-targeted agents resulted in additive or greater than additive antitumor activity.
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PMID:Combination treatment with erlotinib and pertuzumab against human tumor xenografts is superior to monotherapy. 1603 49

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with limited therapeutic options, a high recurrence rate and mortality. Standard therapy is maximal surgical resection and radiotherapy (RT). Recent data suggest combining temozolomide with RT is better than RT alone. Adjuvant chemotherapy has a modest impact on survival. For relapsed patients there is no standard therapy, but options include chemotherapeutic agents or new agents in development. One approach to improve outcome is using targeted agents that interfere with cell-surface receptors or intracellular signaling pathways. Between 40% and 50% of GBM tumors show HER1/EGFR dysregulation, and almost half co-express the constitutively active mutant receptor subtype EGFRvIII, which may contribute to the aggressive and refractory course of GBM. Numerous studies show a relationship between aberrant HER1/EGFR biology and tumorigenicity in GBM cells. Two available HER1/EGFR tyrosine kinase inhibitors (TKIs) are gefitinib (Iressa) and erlotinib (Tarceva); both show antitumor and radiosensitization effects in vitro and in animal models of GBM. Clinical trials in patients with GBM and other gliomas are ongoing. Preliminary and published results from trials of gefitinib in recurrent GBM show no increased time to progression or overall survival (OS) compared with historical controls. Studies with erlotinib show greater antitumor activity in patients with GBM than with gefitinib, although the impact of both agents on OS remains unclear. GBM treatment with HER1/EGFR TKIs alone or combined with other targeted therapies and conventional modalities deserve further investigation and refinement, as does our understanding of their mechanisms of action and the role of genetics.
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PMID:HER1/EGFR tyrosine kinase inhibitors for the treatment of glioblastoma multiforme. 1607 12

Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti-oestrogen therapy, and to tamoxifen in particular, have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors, notably the epidermal growth factor receptor (EGFR) and HER2. Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor (ER) signalling. Inhibition of receptor tyrosine kinase activity involved in the EGFR signalling cascade forms the basis for the use of EGFR specific tyrosine kinase inhibitors exemplified by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva). Such agents have proved promising in pre-clinical studies and are currently in clinical trials in breast cancer, where gefitinib has been studied more extensively to date. Here, we present an overview of the current development of gefitinib in clinical breast cancer. This includes results from our clinical breast cancer trial 1839IL/0057 that demonstrate the efficacy of gefitinib within ER-positive, tamoxifen-resistant patients with locally advanced/metastatic disease, where parallel decreases in EGFR signal transduction and the Ki67 (MIB1) proliferation marker can be detected as predicted from model system studies. We also consider trials examining combination treatment with gefitinib and anti-hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay/prevent onset of anti-hormone resistance.
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PMID:Overview of tyrosine kinase inhibitors in clinical breast cancer. 1611 90

The aim of this single-arm, phase II study was to estimate the tumor response rate and safety profile of erlotinib HCl (erlotinib, Tarceva, OSI-774) monotherapy in patients with refractory, recurrent, HER1/EGFR-positive epithelial ovarian tumors, who had failed prior taxane and/or platinum-based chemotherapy. Thirty-four patients received 150 mg erlotinib orally once daily for up to 48 weeks or until disease progression or dose-limiting toxicity. Two patients had partial responses, lasting 8+ and 17 weeks, giving an objective response rate of 6% (95% confidence interval [CI], 0.7-19.7%). Fifteen patients (44%) had stable disease, and 17 patients (50%) had progressive disease. Median overall survival was 8 months (95% CI, 5.7-12.7 months), with a 1-year survival rate of 35.3% (95% CI, 19.8-53.5%). Patients with rash survived significantly longer than those without (P= 0.009), correlating with rash grade. Erlotinib was generally well tolerated. The most frequent erlotinib-related adverse events were rash (68%) and diarrhea (38%). Erlotinib had marginal activity but was generally well tolerated. The safety profile appears more favorable than typically experienced with standard chemotherapeutic agents, which is encouraging in these heavily pretreated patients. Combination of erlotinib with chemotherapy or other targeted agents should be considered.
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PMID:Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. 1617 25


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