Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Based on limited but compelling immunohistochemical data demonstrating individual overexpression of the tyrosine kinase growth factor receptors, c-erbB-2 and c-met, in significant percentages of human cholangiocarcinoma (ChC), we investigated if combined overexpression of both c-neu, the rat homologue of c-erbB-2, and c-met, the receptor for hepatocyte growth factor/scatter factor (HGF/SF), might represent a characteristic, early event associated with furan-induced cholangiocarcinogenesis in rat liver. Specifically, through the use of immunohistochemistry, in situ hybridization (ISH), and Western and Northern blotting, we found that both c-neu and c-met are prominently overexpressed in intestinal metaplastic lesions in early putative precancerous cholangiofibrotic tissue formed in the livers of rats after 6 weeks of furan treatment when compared with normal and hyperplastic intrahepatic biliary epithelia. We further demonstrated that c-neu and c-met are concordantly overexpressed in neoplastic glandular epithelia in later-developed primary "intestinal-type" of ChC formed in the livers of furan-treated rats, as well as in subsequently derived transplantable mucin-producing tumors. Overexpression of c-neu and c-met correlated with increased proliferating cell nuclear antigen (PCNA)-labeling indices, which were determined to be three to four times higher in intestinal metaplastic glands in precancerous cholangiofibrotic tissue and in neoplastic glands in the primary "intestinal type" of ChC than in hyperplastic bile ductular structures within either cholangiofibrotic or bile duct-ligated (BDL) livers. The c-neu and c-met receptor proteins overexpressed in different in vivo passages of a transplantable ChC each contained immunoreactive phosphotyrosines, indicating an activated state. However, we did not detect evidence of either gene amplification of c-neu or c-met or of a common transmembrane-activating mutation in c-neu expressed in transplantable ChC. Our findings indicate that altered expression of c-neu and c-met occurs relatively early in the process of furan-induced cholangiocarcinogenesis in rat liver and may play a potentially important role in its pathogenesis. They further indicate a common alteration in tyrosine kinase growth factor receptor expression linking early putative precancerous intestinal metaplastic lesions in liver to later-developed mucin-producing biliary cancer.
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PMID:Overexpression of C-NEU and C-MET during rat liver cholangiocarcinogenesis: A link between biliary intestinal metaplasia and mucin-producing cholangiocarcinoma. 1021 29

Biliary tract cancer, carcinoma of the extrahepatic bile ducts, carcinoma of the gall bladder, ampullary carcinoma and intrahepatic cholangiocarcinoma are often identified at an advanced stage and have poor prognoses. Although effective chemotherapy regimens are needed, their development remains unsatisfactory. From the results of a phase III clinical trial (ABC-02 trial), gemcitabine plus cisplatin is the standard first-line chemotherapeutic regimen for advanced biliary tract cancer. A phase III trial of gemcitabine plus cisplatin vs. gemcitabine plus S-1 therapy (FUGA-BT) demonstrated the non-inferiority of gemcitabine plus S-1 to gemcitabine plus cisplatin. A phase III trial of gemcitabine plus cisplatin vs. gemcitabine plus cisplatin plus S-1 (MITSUBA) was conducted, and the report on the results of the final analysis is being awaited. A standard second-line chemotherapeutic regimen has not yet been established. Fluoropyrimidines are frequently used in clinical practice. Despite many clinical trials being conducted with molecular targeted agents including erlotinib, cetuximab, panitumumab, bevacizumab, sorafenib, cediranib, trametinib and vandetanib, no agent has shown to be effective for advanced biliary tract cancer. Next-generation sequencing shows great promise by allowing rapid mutational analysis of multiple genes in human cancers, and attractive driver genetic alterations have been reported in biliary tract cancer. FGFR2 fusion gene, mutations of IDH1/2, BRAF, BRCA1/2, ATM, PIK3CA and overexpression of c-MET and HER2/neu are reported relatively frequently and are interesting targets. Therefore, future development in precision medicine utilizing next-generation sequencing is expected. Although the efficacy of immune checkpoint inhibitors, such as anti-PD-1, anti-PD-L1 and anti-CTLA4 antibodies, remains unknown at present, basic data and results of ongoing clinical trials are anticipated.
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PMID:New developments in systemic therapy for advanced biliary tract cancer. 2989 94

Gallbladder cancer is an aggressive cancer that continues to be an important health care issue in certain regions of the world such as Southeast Asia and Latin America. Most patients are diagnosed at an advanced, unresectable stage and systemic therapy is their only option. Gallbladder cancer patients have traditionally been included in clinical trials for biliary tract cancer. Thus, systemic chemotherapy options for this cancer are similar to those for cholangiocarcinoma, including gemcitabine and cisplatin in the first line and FOLFOX in the second-line setting. Ongoing phase III clinical trials may change the systemic therapy paradigm for this cancer. Molecular profiling has indicated important genetic differences between gallbladder cancer and cholangio-carcinoma, which affects choice of targeted therapy. Her2/neu amplification, PIK3CA mutations and DNA repair genetic aberrations are relatively frequent and represent actionable targets for this cancer.
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PMID:Systemic therapy for gallbladder cancer. 3148 90