Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Landmark clinical studies of new drugs developed to target specific forms of cancer were reported in 2001. Herceptin, a monoclonal antibody against the Her2/neu receptor tyrosine kinase, prolonged the survival of women with Her-2/neu positive metastatic breast cancer, when combined with chemotherapy. STI-571, a small molecule inhibitor of the Bcr-Abl, c-kit and platelet derived growth factor receptor tyrosine kinases, produced dramatic clinical responses in patients with Bcr-Abl positive chronic myeloid leukemia and c-kit positive gastrointestinal stromal tumors. These examples have galvanized the cancer research community to extend kinase-inhibitor therapy to other cancers.
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PMID:Rational therapeutic intervention in cancer: kinases as drug targets. 1179 May 64

Signal transduction refers to communication processes used by regulatory molecules to mediate the essential cell processes of growth, differentiation, and survival. Signal transduction elements interact through complex biochemically related networks. Aberrations in signal transduction elements can lead to increased proliferative potential, sustained angiogenesis, tissue invasion and metastasis, and apoptosis inhibition. Most human neoplasms have aberrant signal transduction elements. Several compounds that target aberrant signal transduction elements, such as those in the ErbB family of tyrosine kinase receptors and mammalian target of rapamycin, are in development. To date, commercially available signal-transduction-targeting compounds include trastuzumab, a monoclonal antibody against the ErbB-2 receptor for the treatment of metastatic breast cancer overexpressing the ErbB-2 (HER-2) receptor, and gefitinib, an inhibitor of the ErbB-1 receptor tyrosine kinase that recently received regulatory approval for the treatment of patients with non-small cell lung cancer. In contrast to traditional cytotoxic treatments, although signal transduction inhibitors are capable of inducing tumor regression, particularly in malignancies that are principally driven by specific target aberrations, preclinical and early clinical investigations suggest that their predominant beneficial effects are growth inhibitory in nature; therefore, new clinical trial designs and evaluation end points may be required to ultimately assess their value. Prospective profiling of patients and tumors to determine treatment response is also essential to the success of these clinical trials. However, responsiveness to these novel therapies is dependent on a multitude of factors that ultimately determine the robustness and quality of the downstream response.
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PMID:Signal events: Cell signal transduction and its inhibition in cancer. 1467 Dec 24

In cancer cells, the ErbB2 receptor tyrosine kinase can be activated in two ways: by overexpression or by ligand-mediated stimulation of another ErbB receptor. The ErbB2-targeting antibody trastuzumab (Herceptin) is used for treatment of metastatic breast cancer patients whose tumors overexpress ErbB2. A new structural study in this issue of Cancer Cell reveals how targeting ErbB2 with another antibody, pertuzumab (Omnitarg), prevents ligand-induced dimerization of ErbB2 with the other ErbB receptors. Pertuzumab's novel mode of action might offer additional therapeutic opportunities for treatment of tumors expressing ligand-activated ErbB2.
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PMID:A new therapeutic antibody masks ErbB2 to its partners. 1509 39

Recently, clinical studies of new drugs development to target specific forms of cancer were reported. Herceptin, a monoclonal antibody against the Her2/neu receptor tyrosine kinase, prolonged the survival of women with Her2/neu positive metastatic breast cancer. STI571, a small molecule inhibitor of the BCR/ABL, c-Kit and platelet derived growth factor receptor tyrosine kinase, produced pronounced clinical responses in patients with BCR/ABL positive chronic myeloid leukemia and c-Kit positive gastrointestial stromal tumors. In order to consider the use of the inhibitor of tyrosine kinases activity as anticancer drug, their mechanisms of the oncogenic activation and their impact on tumor transformation should be studied. The treatment with tyrosine kinase inhibitors such as STI571 or herceptin was a spectacular clinical success which stimulated research on the structure and function of both kinases and their inhibitors.
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PMID:[Tyrosine kinases. New target of anticancer therapy]. 1638 Nov 69

Metastatic breast cancer is still defined as an incurable disease, with the lungs being the most common metastatic sites in breast cancer patients. Epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase family, is known to be involved in survival, migration, angiogenesis and metastasis of cancer. The spontaneous pulmonary metastasis mouse model was applied to evaluate the effects of the EGFR tyrosine kinase inhibitor, erlotinib, on the prevention of pulmonary metastasis in curatively resected breast carcinoma. The expression of EGF and EGFR was significantly strong in pulmonary metastatic nodules compared to those in primary breast carcinoma tissue. A treatment of erlotinib (oral gavage, 50 mg/kg/day, every day for 6 weeks) given to mastectomized mice inhibited the incidence of pulmonary metastasis. The number of metastatic pulmonary nodules was significantly reduced in the erlotinib-treated group compared with the control. Therefore, erlotinib may play a role in preventing pulmonary metastasis, which shows the strong expression of EGF and EGFR after curative resection of primary breast cancer.
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PMID:Erlotinib prevents pulmonary metastasis in curatively resected breast carcinoma using a mouse model. 1678 33

Cell migration plays a central role in processes such as development, wound healing and cancer metastasis. Here we describe a novel interaction between DDR1, a receptor tyrosine kinase activated by collagen, and the phosphoprotein DARPP-32 in mammary epithelial cells. DARPP-32 expression was readily detected in non-transformed mammary cell lines, but was strongly reduced or even absent in breast tumor cell lines, such as MCF7. Transfection of MCF7 cells with DARPP-32 resulted in severely impaired cell migration, while DARPP-32 transfection into the DDR1-deficient breast cancer cell line MDA-MB-231 did not alter migration. Co-expression of both DDR1 and DARPP-32 in MDA-MB-231 cells inhibited migration, thereby supporting a critical role of the DDR1/DARPP-32 complex in motility. Mutational substitution of the phosphorylation sites Thr-34 or Thr-75 on DARPP-32 revealed that phosphorylation of Thr-34 is necessary for the ability of DARPP-32 to impair breast tumor cell migration. Thus, DARPP-32 signaling downstream of DDR1 is a potential new target for effective anti-metastatic breast cancer therapy.
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PMID:Phosphorylation of DARPP-32 regulates breast cancer cell migration downstream of the receptor tyrosine kinase DDR1. 1702 69

Lapatinib is an oral receptor tyrosine kinase inhibitor, targeting both the ErbB-1 and ErbB-2 receptors. Pre-clinical in vitro and in vivo models indicate that lapatinib is active as monotherapy, synergistically in combination with trastuzumab, and in trastuzumab-resistant cell lines. Early clinical trials also provide evidence in patients that lapatinib is active against breast cancer. This paper reviews results of phase II and III clinical trials of lapatinib in metastatic breast cancer, evidence for its potential in patients with brain metastases, and current clinical trials as adjuvant treatment in early-stage disease. Our improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes is allowing us to bring patient-specific novel therapies such as lapatinib to the clinic.
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PMID:Lapatinib: current status and future directions in breast cancer. 1711 Jun 23

The ERBB2 proto-oncogene, commonly referred to as the human epidermal growth factor receptor-2 (HER2) gene, encodes a 185 kd receptor tyrosine kinase. Overexpression of the protein leads to constitutive activity of the HER2 receptor and breast tumor development through enhanced cell proliferation, survival, motility and adhesion. Overabundance of the HER2 receptor, typically caused by amplification of the HER2 gene, is present in approximately 10-30% of invasive breast cancers, and is associated with an aggressive disease course and decreased disease-free and overall survival in node-positive patients. Tratuzumab, a humanized murine monoclonal antibody, offers a targeted treatment modality for tumors that over express the HER2 protein. Tratuzumab, shown to be effective and initially approved for treatment of metastatic breast cancer, has recently been shown to be very effective in the adjuvant setting. Thus, to offer prognostic information and to direct appropriate treatment it is important to provide accurate laboratory assessment of the status of HER2. This article provides an overview of the methods currently used to assess HER2.
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PMID:HER2 testing: a review of detection methodologies and their clinical performance. 1718 84

Lapatinib is an oral receptor tyrosine kinase inhibitor, inhibiting both the ErbB-1 and ErbB-2 receptors. Lapatinib has been shown to have activity in ErbB-2-overexpressing breast cancer in several phase II and III clinical trials. Specifically, lapatinib is effective in patients with metastatic breast cancer, with inflammatory breast cancer, and possibly, with brain metastases. An ongoing clinical trial and another anticipated clinical trial will investigate lapatinib as adjuvant treatment in early-stage disease. Lapatinib has specific toxicities, the most common being diarrhea and rash. Cardiac toxicity is rarely seen with lapatinib. This paper reviews lapatinib-associated toxicities and provides practical management recommendations based on available data.
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PMID:Lapatinib-associated toxicity and practical management recommendations. 1767 7

Neo-angiogenesis appears to be a critical feature of tumor growth, migration, and metastasis. Therefore, inhibition of angiogenesis is an appealing strategy for treatment of cancer. Since angiogenesis is the result of several mechanistic processes, controlled by numerable pro- and anti-angiogenic factors and their receptors, multiple possibilities to prevent or reverse tumor-induced neo-vascularization have been proposed. Of these, currently, the most promising approach has been the use of bevacizumab, a humanized monoclonal antibody directed against the most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF). Bevacizumab has been shown to be active in several malignancies, in particular colo-rectal cancer. Although early studies of bevacizumab in far-advanced metastatic breast cancer were disappointing, the results of a recently reported clinical trial by the Eastern Oncology Group comparing first line paclitaxel with or without bevacizumab has demonstrated statistically significant improvements in response rates and time progression. Ongoing studies are now investigating the benefits of bevacizumab with other chemotherapeutic and biologic agents in early metastatic disease as well as in the adjuvant setting. Other anti-angiogenic agents remain in early clinical trials. Small molecular inhibitors of VEGF receptor tyrosine kinase activity, such as sunitinib, appear promising. Nearly 40 years after it was first proposed, inhibition of angiogenesis appears to be gaining a role in medical oncology.
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PMID:Angiogenesis as targeted breast cancer therapy. 1770 41


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