Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER-2/neu oncogene is localized to chromosome 17q and shares significant homology with the epidermal growth factor receptor. As a result of its potential role in the selection of therapy, HER-2/neu testing has reached near-standard-of-practice status in breast cancer. There is considerable interest in HER-2/neu as a prognostic factor and target of therapy in tumors of the gastrointestinal tract. In this review of HER-2/neu expression in esophageal squamous cell carcinoma and adenocarcinomas of the esophagus, stomach, and colon, a wide range of expression of HER-2/neu from 0 to 83% likely reflects both differences in methods and reagents, as well as study bias associated with patient selection (i.e., early versus advanced disease). For esophageal squamous cell carcinoma, little information exists as to the prognostic significance of HER-2/neu expression. In adenocarcinoma associated with Barrett's esophagus there is contradictory data. However, most of the information available indicates that this marker has significant prognostic value. In gastric adenocarcinoma, the wide expression range may truly reflect patient selection because HER-2/neu positivity appears linked to advanced rather than early disease with limited invasion. The majority of studies favor a significant prognostic value of HER-2/neu status for this tumor. Finally, in colorectal cancer HER-2/neu overexpression also appears to be a significant adverse outcome indicator as judged by the current published literature. In conclusion, given that either HER-2/neu protein overexpression or gene amplification is associated with approximately one-fourth of all gastrointestinal tract malignancies, strategies designed to employ the marker in therapy selection appear warranted. During the next several years it will not be surprising to see these tumors treated with antiHER-2/neu modalities such as Herceptin, likely in combination with other agents initially for patients with advanced disease, and possibly for individuals with high-risk lesions in an adjuvant setting.
 ...
PMID:The HER-2/neu oncogene in tumors of the gastrointestinal tract. 1145 21

The ErbB/HER protein-tyrosine kinases, which include the epidermal growth factor receptor, consist of a growth-factor-binding ectodomain, a single transmembrane segment, an intracellular protein-tyrosine kinase catalytic domain, and a tyrosine-containing cytoplasmic tail. The genes for the four members of this family, ErbB1-ErbB4, are found on different human chromosomes. Null mutations of any of the ErbB family members result in embryonic lethality. ErbB1 and ErbB2 are overexpressed in a wide variety of tumors including breast, colorectal, ovarian, and non-small cell lung cancers. The structures of the ectodomains of the ErbB receptors in their active and inactive conformation have shed light on the mechanism of receptor activation. The extracellular component of the ErbB proteins consists of domains I-IV. The activating growth factor, which binds to domains I and III, selects and stabilizes a conformation that allows a dimerization arm to extend from domain II to interact with an ErbB dimer partner. As a result of dimerization, protein kinase activation, trans-autophosphorylation, and initiation of signaling occur. The conversion of the inactive to active receptor involves a major rotation of the ectodomain. The ErbB receptors are targets for anticancer drugs. Two strategies for blocking the action of these proteins include antibodies directed against the ectodomain and drugs that inhibit protein-tyrosine kinase activity. A reversible ATP competitive inhibitor of ErbB1 (ZD1839, or Iressa) and an ErbB1 ectodomain directed antibody (IMC-C225, or Erbitux) have been approved for the treatment of non-small cell lung cancer and colorectal cancer, respectively. An ErbB2/HER2 ectodomain directed antibody (trastuzumab, or Herceptin) has also been approved for the treatment of breast cancer. Current research promises to produce additional agents based upon these approaches.
 ...
PMID:The ErbB/HER receptor protein-tyrosine kinases and cancer. 1515 34

Monoclonal antibodies (mAbs) against growth factors or their receptors have been revealed to be effective therapeutic agents for solid tumors. Trastuzumab (humanized anti-HER2 mAb) is the first mAb approved for the treatment of a solid tumor, metastatic breast cancer. Large-scale phase III clinical trials are now ongoing to further evaluate the additive effects on chemotherapy and the efficacy as a maintenance monotherapy. Another anti-HER2 mAb CH401 that we developed also seems to have good potential. This chimeric mAb completely suppressed the growth of established human tumor xenografts in SCID mice after a single injection. Furthermore, CH401 characteristically showed much stronger induction of apoptosis in HER2-overexpressing gastric cancer cells compared to trastuzumab. Additional targets now being intensively evaluated are epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF). Both cetuximab (chimeric anti-EGFR mAb) and bevacizumab (humanized anti-VEGF mAb) have recently been shown to be of clinical value for metastatic colorectal cancer. Anti-idiotype mAbs are unique as active immunotherapeutic agents, and survival benefits have been observed in clinical trials for solid tumors.
 ...
PMID:Monoclonal antibodies as effective therapeutic agents for solid tumors. 1529 22

The regulatory agency approvals in the United States and Europe of imatinib mesylate (Gleevec) for patients with bcr/abl-positive chronic myelogenous leukemia, cetuximab (Erbitux) for patients with epidermal growth factor receptor overexpressing metastatic colorectal cancer, the antiangiogenesis agent bevacizumab (Avastin), and the proteasome inhibitor bortezomib (Velcade)--and the considerable public interest in new anticancer drugs that take advantage of specific genetic defects that render the malignant cells more likely to respond to specific treatment--are driving a new era of integrated diagnostics and therapeutics. The recent discovery of a drug response predicting activating mutation in the epidermal growth factor receptor gene for patients with non-small cell lung cancer treated with gefitinib (Iressa) has intensified this interest. In this review, the history of targeted anticancer therapies is highlighted, with focus on the development of molecular diagnostics for hematologic malignancies and the emergence of trastuzumab (Herceptin), an antibody-based targeted therapy for HER-2/neu overexpressing metastatic breast cancer: The potential of pharmacogenomic strategies and the use of high-density genomic microarrays to classify and select therapy for cancer are briefly considered. This review also considers the widely held view that, in the next 5 to 10 years, the clinical application of molecular diagnostics will further revolutionize the drug discovery and development process; customize the selection, dosing, route of administration of existing and new therapeutic agents; and truly personalize medical care for cancer patients.
 ...
PMID:Targeted therapies for cancer 2004. 1548 59

We have prepared the map of regional distribution of cervical cancer in Hungary. Serial HPV genotyping of sexual partners provided evidence for the sexually transmitted infections. Molecular epidemiology studies revealed activating c-kit mutation in bilateral testicular cancers. A cost-effective molecular staging method was introduced to the management of breast cancer patients. Genomic profiling identified the gene signature of Herceptin and taxane sensitivity of breast cancer. In colon cancer patients we have determined the mutational spectrum of hMLH1 and hMSH2 genes in Hungary. The prognostic power of SHMT and MTHFR polymorphism was determined in colorectal cancer patients. In head and neck cancer the gene signature of cisplatin sensitivity and the EGFR polymorphism was determined. We have introduced a cost-effective in vitro assay to determine the drug resistance of pediatric leukemias. The prognostic power of N-myc genotyping was determined in neuroblastoma patients. A phase I trial for gene therapy of brain cancer was started by using a GM-CSF adenoviral vector system. Using global genomic approaches the gene signature of malignant melanoma and its metastatic disease was determined. We have found that Ca-channel blockers and EGFR tyrosine kinase inhibitors are effective in preclinical human melanoma models in breaking the apoptosis resistance of this tumor.
 ...
PMID:[Activity of the National Oncology R&D Consortium in 2004]. 1590 26

AREG (Amphiregulin), BTC (beta-cellulin), EGF, EPGN (Epigen), EREG (Epiregulin), HBEGF, NRG1, NRG2, NRG3, NRG4 and TGFA (TGFalpha) constitute EGF family ligands for ERBB family receptors. Cetuximab (Erbitux), Pertuzumab (Omnitarg) and Trastuzumab (Herceptin) are anti-cancer drugs targeted to EGF family ligands, while Gefitinib (Iressa), Erlotinib (Tarceva) and Lapatinib (GW572016) are anti-cancer drugs targeted to ERBB family receptors. AREG and TGFA are biomarkers for Gefitinib non-responders. The TCF/LEF binding sites within the promoter region of human EGF family members were searched for by using bioinformatics and human intelligence (Humint). Because three TCF/LEF-binding sites were identified within the 5'-promoter region of human AREG gene, comparative genomics analyses on AREG orthologs were further performed. The EPGN-EREG-AREG-BTC cluster at human chromosome 4q13.3 was linked to the PPBP-CXCL segmental duplicons. AREG was the paralog of HBEGF at human chromosome 5q31.2. Chimpanzee AREG gene, consisting of six exons, was located within NW_105918.1 genome sequence. Chimpanzee AREG was a type I transmembrane protein showing 98.0% and 71.4% total amino-acid identity with human AREG and mouse Areg, respectively. Three TCF/LEF-binding sites within human AREG promoter were conserved in chimpanzee AREG promoter, but not in rodent Areg promoters. Primate AREG promoters were significantly divergent from rodent Areg promoters. AREG mRNA was expressed in a variety of human tumors, such as colorectal cancer, liver cancer, gastric cancer, breast cancer, prostate cancer, esophageal cancer and myeloma. Because human AREG was characterized as potent target gene of WNT/beta-catenin signaling pathway, WNT signaling activation could lead to Gefitinib resistance through AREG upregulation. AREG is a target of systems medicine in the field of oncology.
 ...
PMID:Canonical WNT signaling pathway and human AREG. 1668 31

Thorough understanding of the complex interactions between components of immunological response has led to the arousal of the concept of immune-mediated anti-cancer therapy. Although, the use of monoclonal antibodies (MAbs) in hematological malignancies met with success, therapy of solid tumors has been impeded by many obstacles. Some MAbs have increased the efficacy of treatment of certain tumors with acceptable adverse events. Trastuzumab, cetuximab and bevacizumab have become FDA approved for the treatment of breast and colorectal cancer, respectively. The dosing strategies, timing and schedule of antibody administration, duration of treatment are yet to be determined under specific circumstances. Combinations with other biologic agents, such as small-molecule inhibitors of the same pathway would be really useful. Multimodality approaches are based on synergistic effects observed with the combination of antibodies with chemotherapeutic drugs and/or radiotherapy. Immune-mediated effects may be further exploited with the use of bivalent (bispecific) molecules, while radioimmunotherapy via radiolabelling of the antibody is feasible. Modified recombinant antibodies could be applied for toxin delivery to tumor cells, while molecules fused with drug-activating enzymes can mediate prodrug therapy. Increased penetrability into tumors can also be achieved with novel antibody fragments. In the future, better selection of patient subpopulations with tumors overexpressing disease-related clinical biomarkers could result in an increase in both efficacy and specificity of antibody-based treatment.
 ...
PMID:Monoclonal antibodies in the management of solid tumors. 1701 51

The measurement of tumor markers is currently one of the most rapidly growing areas in laboratory medicine. Lack of sensitivity and specificity preclude the use of most existing markers for the early detection of malignancy. For patients with diagnosed malignancy, however, markers are potentially useful in determining prognosis, predicting therapeutic response, maintaining surveillance following curative surgery and monitoring therapy in advanced disease. Clinically useful markers include CEA in the surveillance of patients with diagnosed colorectal cancer, AFP and HCG in the management of patients with non-seminomatous germ cell tumors, HCG in the management of patients with trophoblastic disease, CA 125 for monitoring therapy in patients with ovarian cancer, estrogen receptors for predicting response to hormone therapy in breast cancer and HER-2 for the identification of women with breast cancer likely to respond to trastuzumab (Herceptin). Although widely used, the impact of PSA screening in reducing mortality from prostate cancer remains to be shown.
 ...
PMID:Role of tumor markers in patients with solid cancers: A critical review. 1744 88

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.
 ...
PMID:[Role of predictive pathology in oncology--example of new therapies targeting EGFR]. 1786 89

Monoclonal antibodies have emerged as a class of novel oncology therapeutics. The selectivity and specificity, the unique pharmacokinetics, and the ability to engage and activate the immune system differentiate these biologics from traditional small molecule anticancer drugs. In this review, we focus on 4 antibodies approved for clinical use in treating solid tumors, trastuzumab (Herceptin) for breast cancer, bevacizumab (Avastin) for colorectal cancer and non-small cell lung cancer, cetuximab (Erbitux) for colorectal cancer and head and neck cancer, and panitumumab (Vectibix) for colorectal cancer. The anticancer effects of these antibodies derive from blockade of growth factor/receptor interaction and/or down-regulation of oncogenic proteins (eg, growth factor receptors) on the tumor cell surface, and for some of these antibodies from the ability to elicit effector mechanisms of the immune system, such as antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity. The mechanism behind each antibody, the registration trials for their approved indications, and emerging indications are the focus of this article. We also review clinical considerations including commonly observed and antibody-related side effects, and dosing schedules. In addition, perspectives on challenges and opportunities of oncology antibody clinical development, antibody engineering, and the use of pharmacogenomics are presented.
 ...
PMID:Antibody-based therapy for solid tumors. 1853 57


1 2 3 Next >>