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)

The expression of EGFR, HER2 and HER3 receptors were analyzed in immunohistochemical preparations from primary esophageal tumours and corresponding lymph node metastases. The goal was to evaluate whether any of these receptors are suitable as targets for radionuclide based imaging and therapy. The receptor expressions were evaluated in parallel samples, primary tumour and metastasis, from each patient (n=51). The majority of the cases were esophageal squamous cell carcinomas, ESCC (n=40). The HercepTest scoring was used for the analysis of both HER2 and EGFR expression (0, 1+, 2+ or 3+). HER3 was only evaluated as negative, weak or strong staining. EGFR overexpression (2+/3+) was found in 67.5% (27/40) of both the ESCC primary tumours and the corresponding lymph node metastases. There were only a few changes in these EGFR-scores: two cases from 2+/3+ to 0/1+ when the primary tumours were compared to the corresponding metastases and 2 changes the other way around. HER2 overexpression (2+/3+) was found in only 3 of the primary ESCC tumours and 2 of the lymph node metastases. EGFR and HER2 stainings were found mainly in the cell membranes. The HER3 staining (weak or strong) was mainly cytoplasmic and granular and was observed in about half (20/39) of the cases, for both the ESCC primary tumours and the corresponding lymph node metastases. It was concluded that ESCC lymph node metastases generally have a strong expression of EGFR in their cell membranes and to the same extent as in the primary tumours. The stability in EGFR expression is encouraging for efforts to develop radionuclide based EGFR imaging agents. It is also possible that EGFR targeting agents (e.g. Iressa, Tarceva, Erbitux or radiolabelled antibodies) can be applied for therapy of ESCC.
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PMID:EGFR, HER2 and HER3 expression in esophageal primary tumours and corresponding metastases. 1767 74

Grb7 is a member of the Grb7 family of proteins, which also includes Grb10 and Grb14. All three proteins have been found to be overexpressed in certain cancers and cancer cell lines. In particular, Grb7 (along with the receptor tyrosine kinase erbB2) is overexpressed in 20-30% of breast cancers. In general, growth factor receptor bound (Grb) proteins bind to activated membrane-bound receptor tyrosine kinases (RTKs; e.g., the epidermal growth factor receptor, EGFR) through their Src homology 2 (SH2) domains. In particular, Grb7 binds to erbB2 (a.k.a. EGFR2) and may be involved in cell signaling pathways that promote the formation of metastases and inflammatory responses. In previous studies, we reported the solution structure and the backbone relaxation behavior of the Grb7-SH2/erbB2 peptide complex. In this study, isothermal titration calorimetry studies have been completed by measuring the thermodynamic binding parameters of several phosphorylated and non-phosphorylated peptides representative of natural Grb7 receptor ligands as well as ligands developed through combinatorial peptide screening methods. The entirety of these calorimetric studies is interpreted in an effort to describe the specific ligand binding characteristics of the Grb7 protein.
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PMID:Calorimetric investigation of phosphorylated and non-phosphorylated peptide ligand binding to the human Grb7-SH2 domain. 1770 31

In the majority of cases, death from bladder cancer results from metastatic disease. Understanding the closely linked mechanisms of invasion, metastasis and angiogenesis in bladder cancer has allowed us to develop new therapeutic strategies that harbor the promise of decisive improvements in patient survival. The essential link between cell based experiments and the translation of novel agents into human patients with bladder cancer is the animal model. With emphasis on the orthotopic xenograft model, this review outlines some key mechanisms relevant to angiogenesis and the development of metastasis in bladder cancer. We highlight especially pathways related to MMP-9, IL-8, VEGF and EGFR. Most commonly, expression patterns of these markers in patients have correlated to disease progression and patient survival, which has led to laboratory investigations of these markers and eventually novel targeted therapies that are translated back into the clinic by means of clinical trials. Although imperfect in their translatability into clinical efficacy, animal models remain a critical tool in bladder cancer research.
Cancer Metastasis Rev 2007 Dec
PMID:Bladder cancer angiogenesis and metastasis--translation from murine model to clinical trial. 1772 80

Replication-selective oncolytic viruses (virotherapeutics) are being developed as novel cancer therapies with unique mechanisms of action, but limitations in i.v. delivery to tumors and systemic efficacy have highlighted the need for improved agents for this therapeutic class to realize its potential. Here we describe the rational, stepwise design and evaluation of a systemically effective virotherapeutic (JX-963). We first identified a highly potent poxvirus strain that also trafficked efficiently to human tumors after i.v. administration. This strain was then engineered to target cancer cells with activation of the transcription factor E2F and the EGFR pathway by deletion of the thymidine kinase and vaccinia growth factor genes. For induction of tumor-specific cytotoxic T lymphocytes, we further engineered the virus to express human GM-CSF. JX-963 was more potent than the previously used virotherapeutic Onyx-015 adenovirus and as potent as wild-type vaccinia in all cancer cell lines tested. Significant cancer selectivity of JX-963 was demonstrated in vitro in human tumor cell lines, in vivo in tumor-bearing rabbits, and in primary human surgical samples ex vivo. Intravenous administration led to systemic efficacy against both primary carcinomas and widespread organ-based metastases in immunocompetent mice and rabbits. JX-963 therefore holds promise as a rationally designed, targeted virotherapeutic for the systemic treatment of cancer in humans and warrants clinical testing.
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PMID:Rational strain selection and engineering creates a broad-spectrum, systemically effective oncolytic poxvirus, JX-963. 1796 76

The increasing number of patients with hepatocellular carcinoma (HCC) and the highly unfavourable prognosis of the disease are two important reasons why more effort needs to be devoted to investigating other therapies able to block or reduce tumor progression and cancer metastasis. The underlying cirrhosis on which HCC develops limits the use of common chemotherapies, mainly because of their toxicity. Recently, great attention has been paid to a family of molecules that inhibits the tyrosine kinase (TK) receptors, because of their relevant role in activating intracellular pathways responsible for several biological activities of the HCC cells. In particular, proliferation, invasion, survival, apoptosis, are regulated by Erk1/2 and Akt pathways, that can be considered for this reason as potential therapeutic targets. Therefore, the idea is to fight HCC by blocking the molecular mechanisms exploited by the cancer to develop and to metastasize. The epithelial growth factor and the vascular endothelial growth factor receptors (EGFR and VEGFR, respectively) have been identified as the major targets for these new therapies. In this review the biological role of both growth factors in HCC will be discussed, together with the use of anti-EGFR and anti-VEGFR. The preliminary results obtained in vitro or in "in vivo" experimental models have been very promising, whereas the few studies conducted in patients have been not comparably satisfactory. This could be because of the limited number of patients and of their advanced stage of HCC, nevertheless the possibilities of using this family of drugs should be further explored, together with aspects contributing to a better understanding of the molecular mechanisms driving HCC progression.
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PMID:Tyrosine kinase inhibitors: a potential approach to the treatment of hepatocellular carcinoma. 1804 82

Background A 52-year-old woman whose last known pregnancy was 12 years before presentation was diagnosed with mixed trophoblastic tumor that included placental-site trophoblastic tumor, epithelioid trophoblastic tumor, and focal choriocarcinoma. There was no clear evidence of metastatic disease on initial evaluation. Investigations Histopathology, laboratory tests, immunohistochemistry, chest X-ray, CT scan of the chest, abdomen, and pelvis, fine-needle aspiration biopsy, PET-CT scan.Diagnosis Metastatic chemoresistant placental-site trophoblastic tumor positive for EGFR, VEGF receptor, and platelet-derived growth factor receptor. Management Abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic radiation, etoposide, methotrexate, actinomycin D/cyclophosphamide and vincristine chemotherapy, left thoracotomy with wedge resection, taxol, etoposide, cisplatin therapy, right thoracotomy with wedge resection.
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PMID:Placental-site trophoblastic tumors: a case of resistant pulmonary metastasis. 1822 27

EGFR represents a promising therapeutic target in urothelial cancer (UC). Our study aimed to investigate the clinicopathological significance of EGFR in upper urinary tract UC. EGFR was immunohistochemically assessed (EGFR pharmDX kit(TM)) in 268 consecutive tumours using a tissue microarray technique and correlated with other histopathological parameters as well as patient outcome. EGFR immunoreactivity was observed in 140/253 (55%) evaluable UCs and was associated with high tumour stage (47% pTa/pT1 vs 66% pT2-pT4; p=0.003) and high tumour grade (45% low grade vs 67% high grade; p<0.001). In addition, EGFR expression was associated with metaplastic squamous and/or glandular differentiation (p<0.001). EGFR staining intensity was 1+ in 49%, 2+ in 31%, and 3+ in 20% of cases. EGFR 3+ staining intensity was associated with the occurrence of metastatic disease by univariate analysis (p=0.016). Multivariate analysis, however, proved only pT stage >1 (p<0.001) and high tumour grade (p<0.001) to be independent predictors of patient outcome. In conclusion, EGFR was significantly associated with advanced disease and metaplastic squamous and/or glandular differentiation. Since UCs with metaplastic morphology have been shown to be more resistant to conventional radiotherapy or chemotherapy, the strikingly strong EGFR expression in these tumours may offer a new perspective for affected patients.
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PMID:EGFR expression in urothelial carcinoma of the upper urinary tract is associated with disease progression and metaplastic morphology. 1825 77

Lung cancer is the most common cancer and a highly lethal disease, with improvements in survival rates being dependent on advances in early detection and improved systemic therapies applied to surgery and/or irradiation in early-stage disease. Non-small cell lung cancer (NSCLC) represents around 80% of all lung cancers, and unfortunately at diagnosis most patients have advanced unresectable disease with a very poor prognosis. Indeed, 30%-40% of patients treated with first-line therapy will subsequently be candidates for second-line treatment. Current U.S. Food and Drug Administration-approved second-line treatments are docetaxel (a taxane), pemetrexed (a folate antimetabolite), and erlotinib (an epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor [TKI]). Gefitinib, another EGFR TKI, currently has only limited use in North America and is not available in Europe. These and other new molecular-target-specific agents may have the potential to maximize therapeutic benefit while minimizing toxicity to normal cells. Overexpression of EGFR is reported to occur in 40%-80% of NSCLC cases, and EGFR mutations are associated with a significantly higher response rate and longer duration of response following treatment with EGFR TKIs. Another option is antiangiogenesis: the growth and persistence of solid tumors and their metastases are angiogenesis dependent, and so antiangiogenic therapies have been developed, such as the use of TKIs that block the vascular endothelial growth factor receptor. In fact, many commonly used chemotherapeutic drugs have antiangiogenic activity. Ongoing studies are focusing on patient selection and targeted therapies, and there are many new agents undergoing clinical trials.
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PMID:Systemic treatment for advanced (stage IIIb/IV) non-small cell lung cancer: more treatment options; more things to consider. Introduction. 1826 68

In advanced pancreatic cancer, single-agent gemcitabine became the standard therapy approximately 10 years ago. Subsequently, combinations of gemcitabine with fluorouracil, cisplatin, irinotecan, oxaliplatin, or pemetrexed produced no clear survival benefit. Among the newer approaches, targeting human epidermal growth factor receptor (HER-1/EGFR) shows promise. The U.S. Food and Drug Administration recently approved erlotinib (a HER-1/EGFR tyrosine kinase inhibitor) combined with gemcitabine for the first-line treatment of advanced pancreatic cancer. This combination showed a statistically significant survival benefit over gemcitabine alone in locally advanced or metastatic disease (the median overall survival time was 6.24 months versus 5.91 months; hazard ratio, 0.82; p = .038); however, the clinical significance of this survival difference has been questioned. Additionally, a large phase III trial where the addition of cetuximab (an anti-HER-1/EGFR monoclonal antibody [mAb]) to gemcitabine failed to result in a longer overall survival time than with gemcitabine alone has been reported. Targeting vascular endothelial growth factor (VEGF) with bevacizumab (a recombinant, humanized IgG1 mAb that binds to VEGF) in combination with gemcitabine was investigated in a phase II trial, with promising outcomes that were unfortunately not supported by a subsequent phase III study. While the future treatment of pancreatic cancer may be influenced by the potential of certain biomarkers to predict better response to molecular-targeted therapies, allowing individualization of patient therapy, there are currently no clear candidates, and this remains an interesting area for further investigation.
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PMID:New therapeutic directions for advanced pancreatic cancer: targeting the epidermal growth factor and vascular endothelial growth factor pathways. 1837 39

At the Centre Oscar Lambret, the anticancer centre of the North of France, sentinel lymph node (SLN) procedures are routinely performed for localized (T0-T1, N0, M0) breast carcinoma without any previous treatment, in order to prevent the deleterious effects of axillary lymph node dissection. The present study was undertaken to assess if the expression in the tumor of a panel of 19 genes would allow to predict histological SLN involvement. We looked at cytokeratin 19 (CK19), mucin-1 (MUC1), mammaglobin (MGB1), cyclin D1 (CCND1), the four members of the HER/ErbB growth factor receptor family (EGFR, HER2-4), insulin-like growth factor-1 receptor (IGF-1R), estradiol receptors (ERalpha, ERbeta), progesterone receptor (PR), vascular endothelial growth factors (VEGF, VEGF-C), urokinase-like plasminogen activator (uPA), matrix metalloproteinases 2 and 9 (MMP2, MMP9), ets-related transcription factor ERM, and E-cadherin (CDH1). Their expression was quantified by real-time RT-PCR in 134 breast cancer samples and the relationships with SLN metastases were analyzed. A slight increase (35-40%) in CK19 and HER3 expression was observed in the tumors of patients with SLN metastases compared to those of patients without metastases, even if neither CK19 expression nor HER3 expression allowed to distinguish patients with micrometastases from patients with macrometastases. We conclude that the tumoral expression of biological parameters involved in cell proliferation or playing a critical role in the metastatic process, including tumor invasion and angiogenesis, is not strongly associated with SLN metastases.
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PMID:Real-time reverse-transcription PCR to quantify a panel of 19 genes in breast cancer: relationships with sentinel lymph node invasion. 1840 45


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