Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human cancer is caused by multiple factors, such as genetic predisposition, chronic persistent inflammation, environmental factors, life style, and aging. Dysregulated proliferation, dysregulated adhesion, resistance to apoptosis, resistance to senescence, and resistance to anti-cancer drugs are features of cancer cells. Accumulation of multiple epigenetic changes and genetic alterations of cancer-associated genes during multi-stage carcinogenesis results in more malignant phenotypes. Post-genome science is characterized by omics data related to genome, transcriptome, proteome, metabolome, interactome, and epigenome as well as by high-throughput technology, such as whole-genome tiling oligonucleotide array, array CGH with 32,433 overlapping BAC clones, transcriptome microarray, mass spectrometry, tissue-based expression array, and cell-based transfection array. Benchtop oncology supplies Desktop oncology with large amounts of omics data produced by high-throughput technology. Desktop oncology establishes knowledge on cancer-related biomarkers, such as predisposition markers, diagnostic markers, prognostic markers, and therapeutic markers, by using bioinformatics and human intelligence of experts for data mining and text mining. Bedside oncology applies the knowledge established by Desktop oncology to determine therapeutics for cancer patients. Antibody drugs (Trastuzumab/Herceptin, Cetuximab/Erbitux, Bevacizumab/Avastin, et cetera), small molecule inhibitors for tyrosine kinases (Gefitinib/Iressa, Erlotinib/Tarceva, Imatinib/Gleevec, et cetera), conventional cytotoxic drugs, and anti-hormonal drugs are used for cancer chemotherapy. Biomarker monitoring contributes to therapeutic optional choice and drug dosage determination for cancer patients. Knowledge on biomarkers is feedforwarded from desktop to bedside in the translational research, and then biomarker monitoring is feedbacked from bedside to desktop in the reverse translational research. Desktop oncology is indispensable for cancer research in the post-genome era. Combination of genetic screening for cancer predisposition in the general population and precise selection of therapeutic options during cancer management could contribute to the realization of personalized prevention and to dramatically improve the prognosis of cancer patients in the future.
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PMID:Bioinformatics for cancer management in the post-genome era. 1655 Nov 36

Small molecule tyrosine kinase inhibitors (TKIs) are developed to block intracellular signaling pathways in tumor cells, leading to deregulation of key cell functions such as proliferation and differentiation. Over 25 years ago, tyrosine kinases were found to function as oncogenes in animal carcinogenesis; however, only recently TKIs were introduced as anti cancer drugs in human cancer treatment. Tyrosine kinase inhibitors have numerous good qualities. First, in many tumor types they tend to stabilize tumor progression and may create a chronic disease state which is no longer immediately life threatening. Second, side effects are minimal when compared to conventional chemotherapeutic agents. Third, synergistic effects are seen in vitro when TKIs are combined with radiotherapy and/or conventional chemotherapeutic agents. In this article, we will give an update of the tyrosine kinase inhibitors that are currently registered for use or in an advanced stage of development, and we will discuss the future role of TKIs in the treatment of solid tumors. The following TKIs are reviewed: Imatinib (Gleevec/Glivec), Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva), Lapatinib (GW-572016, Tykerb), Canertinib (CI-1033), Sunitinib (SU 11248, Sutent), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava).
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PMID:Small molecule tyrosine kinase inhibitors in the treatment of solid tumors: an update of recent developments. 1710 52

The epidermal growth factor receptor (EGFR) plays an important role in non-small cell lung cancer growth. Small molecules can specifically target the tyrosine kinase activity of the EGFR's intracellular domain and thus inhibit downstream pathways influencing cell proliferation and survival. Gefitinib and erlotinib have been developed as single-agents for the treatment of patients who have relapsed following one or more courses of chemotherapy. Erlotinib has exhibited significant overall survival benefit in a second- or third-line setting compared to placebo for unselected patients. A beneficial effect on survival has been observed in almost all subgroups of patients and the response rate was higher in women, non-smokers, Asian patients and patients with adenocarcinoma. Somatic mutations in the tyrosine kinase domain of EGFR have been shown to be strong predictive markers for drug response to gefitinib or erlotinib and led to a new insight into adenocarcinoma carcinogenesis. High EGFR gene copy number seems to be predictive of EGFR tyrosine kinase inhibitors-related effect on survival observed in second- or third-line treatment. Future use of EFGR tyrosine kinase inhibitors should be based on improved clinical and molecular selection of patients who are likely to derive the greatest benefit from these drugs, especially in first-line setting.
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PMID:[Tyrosine kinase inhibitors in the management of non-small cell lung cancer]. 1823 13

Arsenic is an established lung carcinogen, however, the carcinogenic mechanisms are currently under investigation. Phosphorylation of the epidermal growth factor receptor (EGFR) has been reported with arsenic exposure in bladder cells. EGFR is a tyrosine kinase transmembrane receptor that regulates important processes in carcinogenesis, including cell survival, cell cycle progression, tumor invasion, and angiogenesis. We investigated the mechanisms of EGFR pathway activation by levels of arsenic relevant to human exposure scenarios both in vitro using cultured lung epithelial cells, and in lung tumors samples from New England Lung Cancer Study participants. Toenail arsenic levels were used as an internal biomarker of arsenic exposure. Our in vitro data suggest that arsenic increases levels of the EGFR ligand, heparin binding-EGF, and activate EGFR phosphorylation in the lung. Downstream of EGFR, arsenic exposure increased pERK and cyclin D1 levels. These effects were inhibited by treatment of cultured cells with the EGFR tyrosine kinase inhibitor, Tarceva (erlotinib). In a consecutive series of human lung tumor specimens, pEGFR protein levels were higher in subjects with elevated toenail arsenic levels compared to those with low exposure (odds ratio adjusted for other factors, OR 4.1 (95% confidence interval 1.1-15.6) (p = 0.04). These data suggest that arsenic exposure may stimulate EGFR pathway activation in the lung. Moreover, the tumors that arise in arsenic-exposed individuals also exhibit signs of EGFR pathway dysregulation. Further work is needed to assess the clinical utility of targeting the EGFR pathway in subgroups of lung cancer patients who have been exposed to elevated levels of arsenic.
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PMID:Arsenic activates EGFR pathway signaling in the lung. 1936 41

Epidermal growth factor receptor (EGFR) is a transmembrane receptor with a cytoplasmic tyrosine kinase (TK) domain present on many solid tumors including non-small cell lung cancer (NSCLC). Once stimulated by ligand, the downstream pathway is activated leading to cell growth, survival, and carcinogenesis. There are several methods of EGFR inhibition including monoclonal antibodies directed against the external region and small molecule inhibitors of TK domain. Erlotinib and gefitinib are orally available small molecule EGFR TK inhibitors, with proven efficacy in NSCLC. The most common side effects are skin toxicity and diarrhea. Erlotinib has been shown to improve survival compared to placebo in second or third-line therapy for NSCLC. However, erlotinib in combination with chemotherapy failed to show a survival advantage in two first-line studies which could be due to the timing of chemotherapy administration. In general, patients with adenocarcinoma histology, female gender, Asian ethnicity, and never smokers have a better response when treated with erlotinib. This could be related to the presence of EGFR mutations, lack of KRAS mutations, or overexpression of EGFR as measured by fluorescent in-situ hybridization (FISH) analysis. Future studies should concentrate on further development of predictors of clinical benefit with erlotinib, overcoming resistance to erlotinib that develops in initial responders, as well as more effective sequencing of erlotinib with chemotherapy and combinations of the drug with other "targeted" therapeutic agents.
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PMID:Review of erlotinib in the treatment of advanced non-small cell lung cancer. 1970 4

Pancreatic cancer has proven to be chemo-resistant, with gemcitabine being the only cytotoxic agent approved for advanced pancreatic cancer since 1996. Tyrosine kinase inhibitors represent a newer generation of chemotherapeutic agents targeting specific tumor pathways associated with carcinogenesis including cell cycle control, signal transduction, apoptosis and angiogenesis. These agents present a more selective way of treating pancreatic cancer. Erlotinib is the prototype of the tyrosine kinase inhibitors with proven efficacy in advanced pancreatic cancer and has been recently approved in that setting. Multiple other tyrosine kinase inhibitors targeting the VEGFR, PDGFR, and Src kinases are in various phases of clinical trials testing. The preliminary results of these trials have been disappointing. Current challenges in pancreatic cancer clinical trials testing include improving patient selection, identifying effective combinations, improving the predictive value of current preclinical models and better study designs. This review summarizes the present clinical development of tyrosine kinase inhibitors in pancreatic cancer and strategies for future drug development.
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PMID:Small molecule tyrosine kinase inhibitors in pancreatic cancer. 1970 51

The Human Papillomavirus type-16 (HPV-16) E6 and E7 oncogenes are selectively retained and expressed in cervical carcinomas, and expression of E6 and E7 is sufficient to immortalize human cervical epithelial cells. Expression of the epidermal growth factor receptor (EGFR) is often increased in cervical dysplasia and carcinoma, and HPV oncoproteins stimulate cell growth via the EGFR pathway. We found that erlotinib, a specific inhibitor of EGFR tyrosine kinase activity, prevented immortalization of cultured human cervical epithelial cells by the complete HPV-16 genome or the E6/E7 oncogenes. Erlotinib stimulated apoptosis in cells that expressed HPV-16 E6/E7 proteins and induced senescence in a subpopulation of cells that did not undergo apoptosis. Since immortalization by HPV E6/E7 is an important early event in cervical carcinogenesis, the EGFR is a potential target for chemoprevention or therapy in women who have a high risk for cervical cancer.
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PMID:Inhibition of the epidermal growth factor receptor by erlotinib prevents immortalization of human cervical cells by Human Papillomavirus type 16. 2198 20

Epidermal growth factor receptor (EGFR) is a known target in cancer therapy and targeting the receptor has proven to be extremely successful in treating cancers that are dependent on EGFR signaling. To that effect, targeted therapies to EGFR such as Cetuximab, Panitumumab-monoclonal antibodies and Gefitinib, Erlotinib-tyrosine kinase inhibitors have had success in therapeutic scenarios. However, the development of resistance to these drugs makes it necessary to combine anti- EGFR therapies with other inhibitors, so that resistance can be overcome by the targeting of alternate signaling pathways. On the other hand, components of the inflammatory pathway, within and around a tumor, provide a conducive environment for tumor growth by supplying numerous cytokines and chemokines that foster carcinogenesis. Interleukin 6 (IL-6) is one such cytokine that is found to be associated with inflammation-driven cancers and which also plays a crucial role in acquired resistance to anti-EGFR drugs. The EGFR and IL-6 signaling pathways crosstalk in multiple ways, through various mediators and downstream signaling pathways driving resistance and hence co-targeting them has potential for future cancer treatments. Here we provide an overview on the crosstalk between the EGFR and IL-6 pathways, and discuss how co-targeting these two pathways could be a promising combination therapy of the future.
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PMID:Cross-talk between EGFR and IL-6 drives oncogenic signaling and offers therapeutic opportunities in cancer. 2968 May

Cholangiocarcinoma (CCA) is a fatal disease with increasing morbidity and poor prognosis due to poor response to conventional chemotherapy or radiotherapy. Neurotensin (NTS) has long been recognized as an important factor in the central nervous system and as an endocrine agent in the peripheral circulation via NTS receptor (NTSR) mediated actions. In recent years, NTS has been implicated in the carcinogenesis of numerous cancers; however, its role in cholangiocarcinoma remains obscure. Here, we observed the expression of NTS in cholangiocarcinoma vs. non-cancerous tissues and found that up-regulation of NTS facilitated cholangiocarcinoma cell metastasis and down-regulation of NTS inhibited their migration ability. Mechanistically, NTS drove cholangiocarcinoma cell metastasis via the EGFR/AKT pathway. Both the PI3-K inhibitor LY294002 or EGFR inhibitor Erlotinib stopped the discrepant metastatic capacity between NTS-depleted cholangiocarcinoma cells and control cells, further confirming that EGFR/AKT was required in NTS-promoted cholangiocarcinoma cell metastasis. More importantly, overexpression of NTS predicted poor prognosis of CCA patients. In summary, NTS could promote cholangiocarcinoma cells metastasis by amplifying EGFR/AKT signaling and may therefore be useful to predict patient prognosis.
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PMID:Neurotensin promotes cholangiocarcinoma metastasis via the EGFR/AKT pathway. 3035 40