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)

Monoclonal antibody-directed therapy has been used as an effective treatment for some cancers that overexpress HER2/neu and vascular endothelial growth factor (VEGF). Overexpression of the HER2/neu oncogene and VEGF has been reported to occur in adenocarcinomas of the colon. Assessing whether HER2/neu and VEGF overexpression could serve as prognostic indicators for stage II colon cancer may provide insight into optimal treatment following surgery. Demographic and tumor characteristics from 109 patients diagnosed with stage II colon cancer between 1991 and 1996 were assessed for HER2/neu and VEGF expression using immunohistochemical staining techniques. Of the 109 cases, 107 (98%) were histologically classified as adenocarcinomas, 105 (96%) were grades 2/3, and 105 (96%) were stage T3. Only 12 cases (11%) exhibited HER2/neu overexpression and 72 cases (66%) exhibited VEGF expression. There was no significant difference in overall survival or in time to recurrence between the groups with and without HER2/neu overexpression. There was a trend toward decreased overall survival with VEGF expression (P = 0.07), but no difference in time to recurrence (P = 0.63). There were 18 patients who received adjuvant chemotherapy, but removal of these patients from the analysis did not change the results. There was no association between HER2/neu and VEGF expression and patient demographics or tumor characteristics, with the exception of VEGF expression and mucinous histology (P < 0.01). Our results do not support an association between HER2/neu or VEGF expression and overall survival or time to recurrence in stage II colon cancer. With further investigation, a significant correlation may be found between VEGF expression and prognosis, and thus direct therapy with a monoclonal antibody.
Clin Colorectal Cancer 2004 Nov
PMID:Expression of vascular endothelial growth factor and HER2/neu in stage II colon cancer and correlation with survival. 1555 9

Inhibition of the epidermal growth factor receptor (EGFR) represents one of the most important avenues for research and development in the field of cancer therapy. The EGFR is a member of the ErbB receptor tyrosine kinase (TK) family, which also includes ErbB-2 (HER2/neu), ErbB-3 (HER3), and ErbB-4 (HER4). Current EGFR therapies available for use include monoclonal antibodies, such as cetuximab, and small-molecule EGFR TK inhibition by agents such as erlotinib. Side effects of these agents include dermatologic manifestations without the bone marrow suppressive properties of chemotherapy. Understanding of rash and how it relates to EGFR inhibitor toxicity and, perhaps more importantly, EGFR inhibitor response must be more clearly defined with clinical trials. The optimum management of rash in patients receiving anti-EGFR therapy remains somewhat controversial; this is secondary to imprecise classification of rash as well as the lack of clinical trials to determine the most appropriate treatment algorithm for these patients. We propose a treatment strategy to help aggressively treat dermatologic side effects allowing patients to continue receiving therapy without dose interruption or drug discontinuation.
Clin Colorectal Cancer 2005 Nov
PMID:Management of rash and other toxicities in patients treated with epidermal growth factor receptor-targeted agents. 1633 49

Gastrointestinal stromal tumor (GIST) has become a well-recognized pathologic entity defined by expression of the KIT protein and often associated with gain of function mutations of the c-KIT oncogene. Imatinib, a specific inhibitor of the aberrant KIT protein, is an approved, well-tolerated oral drug for the management of metastatic or inoperable GIST. Traditional radical surgery resection for locally advanced, recurrent, or metastatic GIST is associated with a poor outcome. The rationale for combining imatinib with surgery for GIST, either as an adjuvant agent in the situation of primary resection for patients at high risk or in the neoadjuvant setting for patients with locally advanced, recurrent, or metastatic disease, is compelling in the continuous effort to improve disease-free and overall survival. Several clinical trials are addressing these issues as well as timing of surgery, assessment of drug response, and the addition of surgical resection in the situation of focal progressive disease on imatinib. The results of these studies will be meaningful in future standard therapy consideration.
Clin Colorectal Cancer 2006 Nov
PMID:Combining imatinib with surgery in gastrointestinal stromal tumors: rationale and ongoing trials. 1710 Oct 65

Gastrointestinal stromal tumors (GISTs) are clinically diagnosed by positive immunohistochemical staining of KIT, a type III receptor tyrosine kinase. Most GISTs contain gain-of-function, ie, oncogenic mutations in c-KIT or in platelet-derived growth factor receptor-alpha (PDGFR-alpha), which appears to be the major initiating event that drives the pathogenesis for GIST. Furthermore, mutations in either of these genes appear to be required for tumor growth and progression. This scenario can be thought of as "oncogenic addiction" and is one of the major reasons why some GISTs respond significantly to therapies that target these mutant receptors. In addition to mutations in c-KIT or PDGFR-alpha, genomic alterations contribute to disease progression. Moreover, GISTs that harbor different c-KIT or PDGFR-alpha mutations have different molecular signatures at the level of gene expression, which further contributes to the complexity of GIST biology and variable responses to treatment. This article will discuss the molecular basis of pathogenesis and genetic and genomic alterations that contribute to GIST tumorigenesis and disease progression as well as the heterogeneity of this disease.
Clin Colorectal Cancer 2006 Nov
PMID:The molecular pathogenesis of gastrointestinal stromal tumors. 1710 Oct 67

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal cancer of teh gastrointestinal tract. They are characterized by the expression of KIT. Therapeutically, metastatic GISTs are effectively treated by imatinib, a tyrosine kinase inhibitor (TKI) with activity against KIT and platelet-derived growth factor receptor. Gastrointestinal stromal tumors refractory to standard therapy with imatinib are a clinical challenge. This has lead to the clinical testing of a variety of agents used alone or in combination with other TKIs. Sunitinib, a multitargeted TKI, is the first drug available fort eh treatment of these patients. Additional trials are ongoing, evaluating the efficacy of the novel KIT TKIs AMG 706 and AMN 107 (nilotinib). RAD001, PKC412, and bavacizumab are being tested in conjunction with imatinib. Lastly, the heat-shock protein-90 inhibitor IPI-540 is also in phase I evaluation in imatinib-refractory patients with GIST. The future management of GIST is likely to be altered by the availability of more agents and by better biologic understanding of the patient populations each agent best treats.
Clin Colorectal Cancer 2006 Nov
PMID:Beyond imatinib: second generation c-KIT inhibitors for the management of gastrointestinal stromal tumors. 1741 50

The human epidermal growth factor receptor (HER1/EGFR/ErbB1) signaling is aberrant and overexpressed in many solid malignancies making it an appealing target for biologic agents. Among the classes of drugs targeting EGFR are monoclonal antibodies and EGFR tyrosine kinase inhibitors, which have been shown effective and generally well tolerated in different clinical settings. The majority of patients treated with EGFR inhibitors (EGFRIs) develop specific dose-dependent skin toxicity. This side effect may lead to physical and psychosocial discomfort which can result in dose reduction or treatment interruption. The relationship between rash and clinical outcome has stimulated interest in this particular toxicity as a possible surrogate marker of efficacy in patients treated with targeted agents against EGFR. This review aims to summarize and update the current knowledge of the clinical presentation, predictive and prognostic value, and the management of EGFRI-related skin toxicity.
Clin Colorectal Cancer 2008 Jan
PMID:Epidermal growth factor receptor inhibitor-related skin toxicity: mechanisms, treatment, and its potential role as a predictive marker. 1827 75

The identification of prognostic determinants of colorectal cancer (CRC), including prediction of occult metastasis, is of urgent consideration, based on the tremendous differences in outcome and survival between patients who present with metastasis or develop metastasis versus those patients with organ-confined or nonrecurrent disease. Currently, a great deal of attention has been focused on using gene expression profiles of tumor specimens as a launch point for prognostic biomarker discovery. In our study, we chose to focus on functional protein-based pathway biomarkers as a new information archive because it is these proteins that form the functional signaling networks that control cell growth, motility, apoptosis, survival, and differentiation. We used reverse-phase protein microarray analysis of laser capture microdissected CRC tumor specimens to profile broad cell signaling pathways from patients who presented with liver metastasis versus patients who remained recurrence free after follow-up. Our results indicate that members of the EGFR and COX2 signaling pathways appear differentially activated in the primary tumors of patients with synchronous metastatic disease. If validated in larger study sets, this pathway defect might be useful as a prognostic clinical tool as well as a guide to potential therapeutic intervention strategies that target occult disease and/or preventative measure.
Clin Colorectal Cancer 2009 Mar
PMID:Multiplexed Cell Signaling Analysis of Metastatic and Nonmetastatic Colorectal Cancer Reveals COX2-EGFR Signaling Activation as a Potential Prognostic Pathway Biomarker. 1942 5

Colorectal cancer is a significant healthcare problem in the United States, with meaningful improvement in survival over the past few years. Much of that improvement is attributable to the availability of molecularly targeted therapies, such as inhibitors of the vascular endothelial growth factor (bevacizumab) and epidermal growth factor receptor (cetuximab and panitumumab), in addition to active cytotoxic agents. KRAS mutations have long been described to play an adverse prognostic role in colorectal cancer. KRAS is downstream from EGFR, and oncogenic mutations will yield a constitutively active protein that will override EGFR control of downstream signaling. Such mutations in KRAS would therefore confer resistance to anti-EGFR antibodies. The cumulative results of several trials incorporating more than a thousand patients in studies of cetuximab and panitumumab confirm that the presence of KRAS mutation in tumors is highly predictive of resistance to anti-EGFR therapy. These findings are likely to change the landscape of metastatic CRC treatment by providing an improved patient-tailored approach.
Clin Colorectal Cancer 2009 Jul
PMID:KRAS testing in metastatic colorectal cancer: implications on the use of biologic agents. 1963 27

The identification of prognostic determinants of colorectal cancer (CRC), including prediction of occult metastasis, is of urgent consideration, based on the tremendous differences in outcome and survival between patients who present with metastasis or develop metastasis versus those patients with organ-confined or nonrecurrent disease. Currently, a great deal of attention has been focused on using gene expression profiles of tumor specimens as a launch point for prognostic biomarker discovery. In our study, we chose to focus on functional protein-based pathway biomarkers as a new information archive because it is these proteins that form the functional signaling networks that control cell growth, motility, apoptosis, survival, and differentiation. We used reverse-phase protein microarray analysis of laser capture microdissected CRC tumor specimens to profile broad cell signaling pathways from patients who presented with liver metastasis versus patients who remained recurrence free after follow-up. Our results indicate that members of the EGFR and COX2 signaling pathways appear differentially activated in the primary tumors of patients with synchronous metastatic disease. If validated in larger study sets, this pathway defect might be useful as a prognostic clinical tool as well as a guide to potential therapeutic intervention strategies that target occult disease and/or preventative measure.
Clin Colorectal Cancer 2009 Apr
PMID:Multiplexed cell signaling analysis of metastatic and nonmetastatic colorectal cancer reveals COX2-EGFR signaling activation as a potential prognostic pathway biomarker. 1973 73

Neuroendocrine tumors comprise a heterogeneous group of neoplasms derived from peptide- and amine-producing cells of the neuroendocrine system. Gastroenteropancreatic NET are differentiated into tumors and carcinomas based on their malignant potential and subdivided into those arising from the pancreas (islet cell tumors or pancreatic NET) and the more classical gut "carcinoids". Moderate to well differentiated NET have historically been considered rare tumors but recent epidemiological statistics suggest that their frequency has increased substantially over the past three decades. While the incidence of NET is increasing, data from both the US and UK demonstrate no improvement in outcomes over a similar time period. Due to the generally indolent biology of NET, most patients present with advanced disease before symptoms become apparent. In patients with localized NET, the 5-year survival rates after resection range from 60 to 90%, while regional lymph node involvement decreases the 5-year survival rates after surgery to 50-75%. Patients with distant metastases have a 5 year survival rate of approximately 25-40%. Conventional cytotoxic chemotherapy is of unclear benefit in patients with these generally slow growing tumors. Multiple agents have been tested in Phase 2 and Phase 3 trials. In general, the lack of major objective responses with significant toxicities has limited routine use of traditional chemotherapy agents and has emphasized the need to develop new agents in these diseases. This review will focus on emerging molecularly-targeted treatments with an emphasis on their underlying biologic and preclinical rationale.
Clin Colorectal Cancer 2011 Dec
PMID:Emerging therapies for advanced gastroenteropancreatic neuroendocrine tumors. 2181 38


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