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: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 receptor for epidermal growth factor (EGFR) is overexpressed in many cancers. One important signaling pathway regulated by EGFR is the phosphatidylinositol 3'-kinase (PI3K)-phosphoinositide-dependent kinase 1-Akt pathway. Activation of Akt leads to the stimulation of antiapoptotic pathways, promoting cell survival. Akt also regulates the mammalian target of rapamycin (mTOR)-S6K-S6 pathway to control cell growth in response to growth factors and nutrients. Recent reports have shown that the sensitivity of non-small-cell lung cancer cell lines to EGFR inhibitors such as erlotinib (Tarceva, OSI Pharmaceuticals) is dependent on inhibition of the phosphatidylinositol 3'-kinase-phosphoinositide-dependent kinase 1-Akt-mTOR pathway. There can be multiple inputs to this pathway as activity can be regulated by other receptors or upstream mutations. Therefore, inhibiting EGFR alone may not be sufficient for substantial inhibition of all tumor cells, highlighting the need for multipoint intervention. Herein, we sought to determine if rapamycin, an inhibitor of mTOR, could enhance erlotinib sensitivity for cell lines derived from a variety of tissue types (non-small-cell lung, pancreatic, colon, and breast). Erlotinib could inhibit extracellular signal-regulated kinase, Akt, and S6 only in cell lines that were the most sensitive. Rapamycin could fully inhibit S6 in all cell lines, but this was accompanied by activation of Akt phosphorylation. However, combination with erlotinib could down-modulate rapamycin-stimulated Akt activity. Therefore, in select cell lines, inhibition of both S6 and Akt was achieved only with the combination of erlotinib and rapamycin. This produced a synergistic effect on cell growth inhibition, observations that extended in vivo using xenograft models. These results suggest that combining rapamycin with erlotinib might be clinically useful to enhance response to erlotinib.
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PMID:Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. 1712 14

Erlotinib, a potent inhibitor of the tyrosine-kinase (TK) activity of human epidermal growth factor receptor (HER1/EGFR), produces significant survival and quality of life benefits in patients with previously treated advanced-stage non-small-cell lung cancer. Although the survival benefit from erlotinib was observed in varied subgroups of patients, the radiographic responses were more common in certain patient subgroups, such as women, never-smokers, patients with adenocarcinoma histology, patients of Asian ethnicity, and patients with presence of HER1/EGFR TK domain mutations. Herein, we describe a white male former smoker with advancedstage squamous cell non-small-cell lung cancer, who responded to first-line erlotinib. A molecular analysis of the tumor did not reveal HER1/EGFR TK mutations. This case study, along with subgroup analyses of the BR.21 phase III study, suggests that patients should not be selected for erlotinib treatment based only on characteristics, such as smoking status, tumor histology, HER1/EGFR TK mutation status, sex, or ethnicity.
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PMID:Response to erlotinib in first-line treatment of non-small-cell lung cancer in a white male smoker with squamous-cell histology. 1723 98

The initial diagnosis of lung carcinoma is frequently made by fine-needle aspiration biopsy. Novel therapeutic strategies of this disease include tyrosine kinase inhibitors (TKI), such as gefitinib (Iressa) or erlotinib (Tarceva), which target the kinase domain of epidermal growth factor receptor (EGFR). Somatic mutations of this region have been shown to predict a therapeutic response of lung carcinomas to TKI. EGFR mutations have been described in adenocarcinomas of the lung, especially the bronchioloalveolar subtype, which has both cytopathologic and histopathologic definitions. This study investigates whether tumors with EGFR mutations display a characteristic phenotype on fine-needle aspiration biopsy. We identified 37 fine-needle aspiration biopsy of lung masses on which molecular analysis for EGFR mutations was available. Molecular analysis was performed on DNA isolated from formalin-fixed, paraffin-embedded, or frozen tissue from the corresponding core biopsies/cell blocks or resection specimens followed by PCR with primers for the tyrosine kinase region exons 18-24 and nucleotide sequence analysis by gel electrophoresis. Two observers who were blinded to the mutational data assessed several cytomorphological parameters. A semiquantitative analysis included predominant tissue pattern (flat or overlapping), nuclear features (nucleoli, intranuclear inclusions, grooves), cytoplasmic qualities, and extracellular material. All cases were adenocarcinomas primary in the lung. Thirteen cases showed EGFR mutations in exons 18, 19, 20, or 21 of the tyrosine kinase domain. The 24 cases negative for the relevant mutation served as the control group. Tumors with EGFR mutations were statistically more likely to demonstrate a predominantly flat, monolayer architecture (P=0.04) with nuclear inclusions (P=0.014) and the absence of macronucleoli (P=0.001). The predominance of flat monolayers in conjunction with the absence of extracellular mucin and macronucleoli indicated the presence of EGFR mutations with a positive predictive value of 69% and a negative predictive value of 92%. All four cases with extracellular mucin were negative for the examined mutations. Some of the traditional cytomorphological features of bronchioloalveolar carcinoma, i.e., flat monolayers, intranuclear inclusions, and the absence of macronucleoli, statistically correlated with the presence of mutations within the tyrosine kinase region of EGFR. Cytomorphological features could serve as an adjunctive predictive marker of response to TKIs and possibly to other new therapies in development.
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PMID:Cytomorphological correlates of epidermal growth factor receptor mutations in lung carcinoma. 1742 21

We created an Epidermal Growth Factor Receptor (EGFR) Mutation Database (http://www.cityofhope.org/cmdl/egfr_db) that curates a convenient compilation of somatic EGFR mutations in non-small-cell lung cancer (NSCLC) and associated epidemiological and methodological data, including response to the tyrosine kinase inhibitors Gefitinib and Erlotinib. Herein, we analyze 809 mutations collected from 26 publications. Four super hotspots account for 70% of reported mutations while two-thirds of 131 unique mutations have been reported only once and account for only 11% of reported mutations. Consistent with strong biological selection for gain of function, the reported mutations are virtually all missense substitutions or in-frame microdeletions, microinsertions, or microindels (colocalized insertion and deletion with a net gain or loss of 1-50 nucleotides). Microdeletions and microindels are common in a region of exon 19. Microindels, which account for 8% of mutations, have smaller inserted sequences (95% are 1 to 5 bp) and are elevated 16-fold relative to mouse somatic microindels and to human germline microindels. Microdeletions/microindels are significantly more frequent in responders to Gefitinib or Erlotinib (P = 0.003). In addition, EGFR mutations in smokers do not carry signatures of mutagens in cigarette smoke. Otherwise, the mutation pattern does not differ significantly with respect to gender, age, or tumor histology. The EGFR Mutation Database is a central resource of EGFR sequence variant data for clinicians, geneticists, and other researchers. Authors are encouraged to submit new publications with EGFR sequence variants to be included in the database or to provide direct submissions via The WayStation submission and publication process (http://www.centralmutations.org).
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PMID:Database of somatic mutations in EGFR with analyses revealing indel hotspots but no smoking-associated signature. 1742 53

Abnormal expression and signaling of ErbB receptors has been implicated in multiple epithelial malignancies, including pancreatic cancer. Erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been recently approved for pancreatic cancer treatment, but there are no reliable predictors of patient response. Expression of additional ErbB receptors seems to influence tumor response to EGFR-targeted therapy. We analyzed the influence of ErbB3 expression on pancreatic cancer cell response to erlotinib treatment. Proliferation assays of five human pancreatic cancer cell lines were performed following treatment with erlotinib. Expression and phosphorylation profiles of ErbB receptors and downstream adaptor protein (Akt, ERK1/2, STAT3, mTOR) were evaluated following stimulation with EGF or neuregulin-beta. The formation of EGFR homodimers and EGFR-ErbB3 heterodimers, necessary to enable ErbB3 downstream signaling, was demonstrated by chemical cross-linking assays. The effects of RNA inhibition of ErbB3 on sensitivity to erlotinib treatment were evaluated in AsPC-1 pancreatic cancer cells. Erlotinib inhibited Akt phosphorylation and proliferation of all the ErbB3-expressing cell lines but did not affect mTOR activation. Cross-linking studies confirmed the presence of EGFR-ErbB3 heterodimers in pancreatic cancer cells. Only the ErbB3-deficient MIA PaCa-2 cells displayed persistent Akt activation and ongoing proliferation in spite of erlotinib treatment. siRNA-mediated inhibition of ErbB3 expression in AsPC-1 cells resulted in acquired resistance to erlotinib treatment. Pancreatic cancer cells which lack ErbB3 do not display activation of the ErbB3-PI3K-Akt cascade induced by EGFR/ErbB3 heterodimers and become less critically dependent on EGFR signaling and therefore resistant to erlotinib. Pancreatic cancer expression of ErbB3 may be useful for EGFR-targeted therapy patient selection.
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PMID:ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib. 1745 47

The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase (TK) receptor that is frequently expressed in many epithelial tumors. The signaling pathways of EGFR is involved in cancer cell proliferation, apoptosis, angiogenesis, invasions and metastasis. The EGFR was the first receptor to be proposed for cancer therapy and two EGFR-targeted pharmacological approaches have been successfully developed: monoclonal antibodies and small-molecule inhibitor of the EGFR TK enzymatic activity. Erlotinib is a quinazoline derivative that selectively and reversibly inhibits the TK activity of EGFR. Erlotinib, on the basis of the results of a large randomized phase III clinical trial (BR21) in which show a survival benefit versus placebo-treated patients, received regular approval for the treatment of advanced non-small-cell lung cancer (NSCLC) patients after failure a platinum-containing chemotherapy. Erlotinib was recently approved in combination with gemcitabine chemotherapy for the treatment of advanced pancreatic cancer, and continues to be investigated in a number of tumor types. Furthermore, it has been investigated the role of factors that would predict the efficacy of erlotinib treatment, including anatomoclinical, pathologic and molecular features. This review will focus on the clinical results available with erlotinib in the treatment of NSCLC, pancreatic, head and neck and other tumor types.
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PMID:Erlotinib in cancer treatment. 1759 29

Erlotinib is an inhibitor of the tyrosine-kinase domain of the epidermal growth factor receptor-1 (EGFR). This drug is used to treat some solid cancers, particularly advanced non-small-cell lung carcinoma. Similar to other EGFR inhibitors, erlotinib is responsible for a series of skin adverse reactions, particularly acneiform lesions. We described the incidental effect of erlotinib on actinic keratoses which became markedly inflamed and showed partial regression. Inflammation appeared to spontaneously decrease while on erlotinib treatment. This reaction in the skin neoplasm is perhaps a visible and accessible model for predicting the effect in the deep-seated neoplasm targeted by the drug.
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PMID:Erlotinib-responsive actinic keratoses. 1767 4

Pancreatic cancer represents the fourth leading cause of cancer-related mortality in the United States. The vast majority of patients are diagnosed at advanced stages of the disease, at which time gemcitabine-based chemotherapy is typically offered as the standard of care. However, as investigators have arrived at a greater understanding of pancreatic tumor biology, newer therapeutic agents that "target" specific pathways or molecules governing the growth, spread, and maintenance of tumor cells have gained considerable interest. Erlotinib, an orally bioavailable small molecule inhibitor of the epidermal growth factor receptor, is the first of these targeted compounds to be approved for use in combination with gemcitabine for patients with advanced pancreatic cancer. Other targeted agents, including monoclonal antibodies and small molecule inhibitors aimed at a variety of targets, also have been extensively evaluated, with limited success to date. A newer strategy worth pursuing involves tailoring an individual patient's therapy according to the molecular characteristics of both host and tumor, as has shown promise in other solid tumor types.
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PMID:Future strategies for targeted therapies and tailored patient management in pancreatic cancer. 1767 64

New cancer-specific therapies are based on specific molecular alterations of malignant tumors which are targeted by small inhibitory molecules or specific antibodies. During the development of these agents potential molecular targets are characterized for their expression and importance for pathogenesis and clinical course of the disease. Frequently the assumption is made that the degree of expression of the target protein or the molecular alteration of the target gene allows a prediction if a certain patient will profit from the therapy against this specific protein or not. The first example was that breast cancer patients with overexpression and/or amplification of Her-2 respond to a Her-2-specific antibody (Herceptin) therapy. The expression or activation of the Epidermal Growth Factor Receptor (EGFR, Her-1) are altered in many epithelial tumours and clinical studies indicate that they have important roles in tumor aetiology and progression. Several EGFR-specific monoclonal antibodies and specific tyrosine kinase inhibitors were developed in the last years. Cetuximab is approved for the treatment of metastatic colorectal cancer and advanced squamous cell carcinoma of the head and neck and is investigated in numerous trials for other tumors. The expression of EGFR in the tumor was a prerequisite for the therapy in the first trials, giving the pathologist a central role in treatment decision. However, recent data clearly demonstrate that the degree of EGFR expression does not correlate with therapy response. Therefore a therapy should be not denied to a individual patient solely because of lack of EGFR expression in the tumor. Tyrosine kinase inhibitors (e. g. Gefitinib, Erlotinib) are effective in the treatment of non small cell lung cancer and also investigated in ongoing trials in many cancer types. The correlation of therapy response with both specific molecular alterations (EGFR tyrosine kinase domain mutations) and clinicopathological features (Asian ethnicity, women, non-smokers, bronchioloalveolar differentation) is a good example of the potential role of predictive molecular pathology in the future.
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PMID:[Role of predictive pathology in oncology--example of new therapies targeting EGFR]. 1786 89


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