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:C0027627 (metastases)
103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dual inhibition of ErbB-1 (EGFR) and ErbB-2 (HER-2) tyrosine kinases has been found to exert greater biologic effects in the inhibition of signaling pathways promoting cancer cell proliferation and survival than inhibition of either receptor alone. The novel dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) has been shown to inhibit tumor cell growth in vitro and in xenograft models for a variety of human tumors. Preliminary findings in a phase I study of lapatinib in patients with solid tumors indicate doses up to 1,800 mg per day are well tolerated. No grade 4 toxicities were observed and only two of 43 patients had grade 3 toxicity (diarrhea). Clinical activity of lapatinib was observed in these patients; nine patients with a variety of tumors remained on study for > or =4 months, one with a complete response (head and neck cancer). In a phase IB study in pretreated metastatic cancer patients with disease that could be biopsied, grade 1 or 2 diarrhea and rash were the most common adverse events. Three patients with breast cancer refractory to trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) had partial responses and 12 patients with a variety of tumors had stable disease. Assessment of biologic correlates in these patients indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response. Lapatinib currently is being evaluated in phase II and phase III trials in patients with metastatic breast cancer.
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PMID:Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. 1516 42

Both the availability of multiple treatment modalities and novel therapeutic targets make the correct prognostic stratification and the identification of truly predictive factors an issue of major debate in gastric cancer. Along with "classic" prognostic factors such as those related to the diffusion of the tumour at diagnosis (i.e., depth of gastric wall infiltration, locoregional lymph nodes or distant metastases) or those concerning the pathologic characteristics of the tumour, other, innovative, factors should be considered if a better definition of the characteristics of the tumour is to be given. These biological factors are often derived from the genetic process, which is thought to represent a crucial step to gastric cancer (DNA copy number changes, microsatellite instability, thymidilate synthase, E-cadherin, beta-catenin, mucin antigen, p53, c-erb B-2, COX-2, matrix metalloproteinases, VEGFR and EGFR). Some of those putative prognostic indicators can also be considered predictive of response to therapy as they are a molecular target either to chemotherapeutics (i.e., thymidilate synthase that is targeted by 5FU) or to a new class of antineoplastic molecules (i.e., c-erb B-2 targeted by trastuzumab, COX-2 by NSAIDs, matrix metalloproteinases, EGFR and VEGFR by specific inhibitors).
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PMID:Molecular biology of sporadic gastric cancer: prognostic indicators and novel therapeutic approaches. 1524 77

We utilized the high-throughput tissue microarray method to characterize immunohistochemical expression patterns with correlations to prognosis in rectal cancer. Immunostaining for the markers Ki-67, Bcl-2, p53, EGFR, E-cadherin, beta-catenin, MLH1 and MSH2 was performed in 269 rectal cancers. Expression profiles were correlated to metastasis-free survival. Immunostaining revealed frequent upregulation and/or aberrant staining patterns for several of the markers, but Ki-67, p53, Bcl-2 and EGFR did not show any correlation to prognosis. However, reduced membranous staining for beta-catenin (p = 0.04), lack of cytoplasmic staining for beta-catenin (p = 0.04), reduced membranous staining for E-cadherin (p = 0.02) and lack of cytoplasmic staining for E-cadherin (p = 0.02) correlated with metastatic disease. Multivariate analysis including the factors Dukes' stage and tumor differentiation grade demonstrated increased risk of metastatic disease in tumors with lack of cytoplasmic staining for beta-catenin (HR = 3.1, p = 0.02), reduced membranous staining for beta-catenin (HR = 1.7, p = 0.06) and reduced membranous staining for E-cadherin (HR = 2.1, p = 0.06). Loss of MMR protein expression was confirmed to be a rare event in rectal cancer with loss of MLH1 staining in 3% and MSH2 in 1% of the tumors. The lack of prognostic information contributed by most of these markers suggests that single markers for prognosis may be of limited value in rectal cancer. However, altered expression of beta-catenin and E-cadherin correlated with metastatic disease, and these markers may have prognostic importance in rectal cancer.
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PMID:Immunohistochemical patterns in rectal cancer: application of tissue microarray with prognostic correlations. 1530 Aug 4

Androgen withdrawal is the only effective therapy for patients with advanced prostate cancer, but progression to androgen independence ultimately occurs in almost all patients. Novel therapeutic strategies targeting molecular mechanisms that mediate resistance to hormonal and chemotherapeutic treatment are highly warranted. Here, we aimed to evaluate the expression of potential therapeutic targets in advanced prostate cancer. A tissue microarray (TMA) containing samples from 535 tissue blocks was constructed, including benign prostatic hyperplasia as controls (n = 65), prostatic intraepithelial neoplasia (PIN; n = 78), clinically localized prostate cancers (n = 181), as well as hormone-refractory local recurrences (n = 120) and distant metastases (n = 91). The expression of 13 different proteins was analyzed using immunohistochemistry (Bcl-2, p53, ILK, Syndecan-1, MUC-1, EGFR, HER2/neu, HSP-90, Ep-CAM, MMP-2, CD-10, CD-117 and Ki67). Significant overexpression in hormone-refractory prostate cancer and metastatic tissue compared to localized prostate cancer was found for Ki67 (64% vs. 9%), Bcl-2 (11% vs. 1%), p53 (35% vs. 4%), Syndecan-1 (38% vs. 3%), EGFR (16% vs. 1%) and HER2/neu (16% vs. 0%). Overexpression of CD-117 was restricted to 1 single metastasis. All other markers did not show relevant differences in expression between subgroups. Taken together, p53, Bcl-2, Syndecan-1, EGFR and HER2/neu are preferentially expressed in hormone-refractory and metastatic prostate cancer. Selected inhibition of these targets might offer a strategy to treat advanced tumors and prevent further progression. Treatment decisions should not be based on findings in primary tumors but rather on tissues from recurrent or metastatic lesions.
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PMID:Expression patterns of potential therapeutic targets in prostate cancer. 1547 3

Prognosis and survival of patients with hepatocellular carcinoma (HCC) is still very poor, and no therapies are currently available to inhibit tumour growth and metastases. Recently, we reported that the expression of an extracellular matrix component (ECM), namely Laminin-5 (Ln-5), is directly related to poor prognosis in HCC patients. The aim of our study is to investigate the preclinical effect of gefitinib in an in vitro HCC model. We found that the IC(50) of gefitinib in HCC cells ranged from 0.7 to 10.0 muM, whereas Ln-5 inhibited the activity of gefitinib in a dose-dependent manner. Complete inhibition of phosphorylated (p)-EGFR (epidermal growth factor receptor) was obtained within 6 h exposure to gefitinib and complete restoration of the receptor status was obtained after 24 h. A downstream effect yields a decrease in p-Akt and p-Erk 1/2. The addition of exogenous Ln-5 has no effect on p-EGFR, whereas it restores p-Erk 1/2 and p-Akt. Consistently, Ln-5 induces recovery of HCC cells from Gefitinib-induced apoptosis. In conclusion, gefitinib inhibits HCC cell growth and we report for the first time that Ln-5, but not other ECM molecules, reduces the ability of gefitinib to inhibit cell growth via Akt. As patients with HCC have different Ln-5 expression levels, these results may help to better understand which patients might benefit from gefitinib treatment.
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PMID:Laminin-5 offsets the efficacy of gefitinib ('Iressa') in hepatocellular carcinoma cells. 1554 72

Salivary gland cancers are a rare malignancy accounting for less than 1% of all cancers and 3-6% of cancers of the head and neck region. The classification of salivary gland tumors is traditionally based on morphology and the different subtypes exhibit various clinical behaviors. The low grade and biologically indolent cell types include the adenoid cystic, acinic cell and adenocarcinoma while the salivary duct, squamous and mucoepidermoid are more active and high grade. The initial management of salivary gland malignancies is to assess resectability and possible adjuvant radiation therapy. Those with locoregional recurrence or metastatic disease are treated with systemic therapy. Numerous studies with small sample sizes have assessed the activity of different cytotoxic agents. Both single agent and combination chemotherapy have been used for the treatment of this disease. For these agents, the response rates are generally modest with objective response rates ranging from 15-50%. Duration of response is typically cited in the range of 6-9 months. Clinicopathological data have demonstrated correlations between poor clinical outcomes and the expression of molecular markers such as mutated p53 protein and vascular endothelial growth factor (VEGF) in salivary gland cancers. Recent studies have also evaluated the epidermal growth factor receptor family including erbB1/EGFR and erbB2/HER2 as potential therapeutic targets. While the prognostic significance of EGFR overexpression has not been well defined, overexpression of the HER2 oncoprotein has been associated with biological aggressiveness and poor prognosis in most series. Given the suboptimal response rates, duration of response, and toxicity of conventional chemotherapy, a better understanding of the biology of salivary gland malignancies will lead to improved prognostication and treatment. With the emergence of molecular targeted therapy, these tumors become an optimal candidate for trials of investigational drugs and established drugs for new indications.
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PMID:An update on the systemic therapy of malignant salivary gland cancers: role of chemotherapy and molecular targeted agents. 1557 19

We investigated the variability in infectivity of cells in primary brain tumor samples from different patients using an HSV-1 amplicon vector. We studied the infectivity of HSV-1 amplicon vectors in tumor samples derived from neurosurgical resections of 20 patients. Cells were infected with a definite amount of HSV-1 amplicon vector HSV-GFP. Transduction efficiency in primary tumor cell cultures was compared to an established human glioma line. Moreover, duration of transgene expression was monitored in different tumor cell types. All primary cell cultures were infectable with HSV-GFP with variable transduction efficiencies ranging between 3.0 and 42.4% from reference human Gli36 Delta EGFR glioma cells. Transduction efficiency was significantly greater in anaplastic gliomas and meningiomas (26.7+/-17.4%) compared to more malignant tumor types (glioblastomas, metastases; 11.2+/-8.5%; P=0.05). To further investigate the possible underlying mechanism of this variability, nectin-1/HevC expression was analyzed and was found to contribute, at least in part, to this variability in infectability. The tumor cells expressed the exogenous gene for 7 to 61 days with significant shorter expression in glioblastomas (18+/-13 d) compared to anaplastic gliomas (42+/-24 d; P<0.05). Interindividual variability of infectivity by HSV-1 virions might explain, at least in part, why some patients enrolled in gene therapy for glioblastoma in the past exhibited a sustained response to HSV-1-based gene- and virus therapy. Infectivity of primary tumor samples from respective patients should be tested to enable the development of efficient and safe herpes vector-based gene and virus therapy for clinical application.
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PMID:Variability in infectivity of primary cell cultures of human brain tumors with HSV-1 amplicon vectors. 1567 97

Advances in molecular biology have identified tumor markers that not only predict prognosis and therapeutic response but may also function as potential therapeutic targets. Activated growth factor receptors induce breast cancer cells to proliferate, invade, and metastasize in experimental models. Overexpression of growth factor receptors has been associated with a poor clinical outcome in breast cancer patients. Biological therapy with monoclonal antibody directed against growth factor receptor pathways became important targeted therapy in breast cancer and is being pursued on various fronts. The anti-HER2 antibody trastuzumab is approved in the metastatic setting and is now trying to find the place in the adjuvant setting. Phase II and III studies with antibodies directed against VEGF and EGFR are also ongoing.
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PMID:Monoclonal antibody-based targeted therapy in breast cancer. 1577 17

Squamous cell carcinoma of the head and neck (SCCHN) tends to run an aggressive course and the prognosis has remained virtually unchanged in recent decades. The development of novel therapeutic strategies to improve patient outcome centres on the biology of the disease, namely the pivotal c-erbB family of growth factor receptors. c-erbB1 (or epidermal growth factor receptor, EGFR), is key to the pathogenesis of SCCHN and plays a central role in a complex network of downstream integrated signalling pathways. EGFR overexpression, detected in up to 90% of SCCHN, correlates with an increased risk of locoregional tumour relapse following primary therapy and relative resistance to treatment. The biological sequelae of erbB receptor activation are not simply cell proliferation, but also inhibition of apoptosis, enhanced migration, invasion, angiogenesis and metastasis: the 'hallmarks of cancer' [1]. As EGFR overexpression is associated with a poor clinical outcome in SCCHN, this receptor is attractive as a therapeutic target and the successful development of targeted therapies represents a paradigm shift in the medical approach to head and neck cancer. However, the extensive cross talk between signalling pathways, the multiple molecular aberrations and genetic plasticity in SCCHN all contribute to inherent and acquired resistance to both conventional and novel therapies. Understanding the cancer cell biology, in particular the significance of co-expression of c-erbB (and other) receptors, and the cell survival stimuli from (for example) activation of the phosphoinositide 3-kinase (PI3-kinase) cascade is fundamental to overcome current limitations in biologically targeted therapies.
Cancer Metastasis Rev 2005 Jan
PMID:Biological significance of c-erbB family oncogenes in head and neck cancer. 1578 72

The expressions of all four receptors in the epidermal growth factor receptor family, EGFR. HER2, HER3, and HER4 were evaluated by immunohistochemistry in 19 cases of metastatic squamous cell carcinoma of the oral cavity and base of tongue. EGFR had a similar and high expression in both primary tumours and the corresponding metastases, while the expression in normal epithelium was lower in most cases. HER2 was not expressed to the same extent as EGFR. However, when HER2 was well expressed, it was in most cases expressed to the same extent and intensity in the primary tumours, metastases, and normal epithelium. The expression of HER3 and HER4 varied and was mainly cytoplasmic in all cases studied. No overexpression of HER3 and HER4 in tumours was seen as compared to normal epithelium. In order to further investigate the distribution of HER3, two HER3 expressing cell lines originating from tongue cancer were analysed in vitro, using radiolabelled anti-HER3 antibodies directed to the extracellular domains of the receptor. The results indicated that HER3 was not present in measurable amounts in the cellular membrane. There is a need for improved diagnostics and therapy for the studied type of tumours, e.g. using radiolabelled antibodies or ligands, and EGFR seemed suitable as target since the expression was high, membrane associated and similar in the primary tumours and the corresponding metastases.
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PMID:Expression of EGFR, HER2, HER3, and HER4 in metastatic squamous cell carcinomas of the oral cavity and base of tongue. 1580 7


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