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At least 865 records · Page 48Linked to original sources
PubMed2005

Pathology of the future: molecular profiling for targeted therapy.

Recent evidence suggests that each patient's cancer has a unique subset of molecular pathogenetic derangements. These derangements may both genetic and proteomic alterations. Genomic and proteomic research tools enable genome-wide assessment of gene expression as well as kinase driven cell signaling events. These tools are illuminating the molecular derangements of individual tumors, even if these tumors have similar morphological characteristics. A combination of laser capture microdissection with multiplexed phosphoproteomic analysis using reverse phase protein microarray technology is being used to identify protein molecular signatures of individual tumors. The in vivo state of multiple kinase driven signal pathways may be evaluated by reverse phase protein microarray with a panel of specific antibodies developed based upon our knowledge of biological processes. Molecular profiling of individual patient's tumors is currently being evaluated in clinical trials at the National Institutes of Health, National Cancer Institute for monitoring Epidermal Growth Factor (EGF) cell signaling events for patients with breast and ovarian cancer.

Forecasting↗
PubMedDate not supplied

Trastuzumab: targeted therapy for the management of HER-2/neu-overexpressing metastatic breast cancer.

Breast cancers are a biologically heterogeneous group of mammary tumors with distinct natural histories and varied responses to established therapies. They have long been divided into those that are hormone sensitive [as defined by expression of the estrogen receptor alpha (ERalpha) and/or the progesterone receptor (PR)] and those that are not. Notably, only those breast cancers that express ERalpha and/or PR typically respond to hormonal therapy with tamoxifen, aromatase inhibitors, or the newer agent fulvestrant. More recently, the transmembrane tyrosine kinase receptor HER-2/neu was identified as an oncogene overexpressed by about 30% of breast cancers. These HER-2/neu-overexpressing breast cancers define a subset of breast tumors that are characteristically more aggressive, and women who develop them have a shorter survival. Trastuzumab (Herceptin), a humanized monoclonal antibody specific for HER-2/neu, has revolutionized the management of metastatic HER-2/neu-overexpressing breast cancers. As a single agent, it produces response rates similar to those of many single-agent chemotherapeutic agents active in metastatic breast cancer and has limited toxicity. Combining trastuzumab with chemotherapy can result in synergistic antitumor activity. The clear efficacy of trastuzumab against HER-2/neu-overexpressing metastatic breast cancer has led to a keen interest in testing its role in the management of early breast cancer, and multiple large clinical trials are currently in progress. This review summarizes the available clinical data on the use of trastuzumab in HER-neu-overexpressing breast cancer and briefly highlights emerging opportunities for innovative, trastuzumab-based breast cancer therapies.

Animals↗
PubMedDate not supplied

[Idiopathic hypereosinophilic syndrome: toward a new molecular-targeted therapy and a new cytomorphological and molecular definition].

Idiopathic hypereosinophilic syndrome is characterised by chronic hypereosinophilia leading to tissue damage, and after exclusion of reactive eosinophilia. Until recently no specific or efficient therapeutic was available. In 2003, a recurrent interstitial deletion 4q12 leading to the fusion of the FIP1L1 and PDGFRA genes was detected in hypereosinophilic syndromes. The resulting protein has constitutive tyrosine kinase activity which explains clinical and cytological remission of hypereosinophilic syndrome after treatment by a specific tyrosine kinase inhibitor, imatinib mesylate or Glivec, usually used in chronic myeloid leukaemia. Here we report a patient with hypereosinophilic syndrome associated to peculiar morphology of neutrophilic series and the 4q12 deletion. He presented clinical and haematological remission since the introduction of imatinib mesylate therapy.

Adult↗
PubMed2005

[Molecular targeted therapy--non-small-cell lung cancer and gefitinib].

Gefitinib (Iressa, ZD 1839) is an orally bioavailable small molecule that selectively inhibits epidermal growth factor receptor(EGFR) tyrosine kinase activity. Gefitinib causes a dramatic response in approximately 10% to 20% of patients with non-small-cell lung cancer (NSCLC) who receive prior chemotherapy. Studies of gefitinib in combination chemotherapy in first-line therapy of advanced NSCLC have, however, failed to show improvement of survival. Gefitinib also failed to prolong survival in a placebo controlled clinical trial for patients with pretreated advanced NSCLC. In addition, gefitinib did not improve survival as maintenance therapy after chemoradiation in patients with Stage III NSCLC. A possible explanation for the lack of a survival benefit seen in these studies might be failure to select of patients suitable for gefitinib treatment. Empirically, and also in phase II trials, a good clinical response has been observed most frequently in women, nonsmokers, patients with adenocarcinomas, and East Asian patients. Recently, mutations and amplifications of the EGFR gene identified in a subset of NSCLC have been reported to be useful for prediction of enhanced sensitivity to gefitinib. It is also known that some recurrent tumors have a secondary mutation in the EGFR kinase domain, T 790 M, conferring drug resistance. In Japan, a significant number of patients often develop fatal interstitial lung disease after the introduction of gefitinib, although it is, in general, well tolerated. In the future, we must demonstrated benefits of gefitinib treatment in prospective clinical trials by recruiting patients selected on the basis of biological characteristics. It is also important to further elucidate various issues that include other determinants of gefitinib sensitivity, other mechanisms of resistance to gefitinib or mechanisms or predictive factors of interstitial lung disease by close collaboration among clinicians and basic researchers.

Antineoplastic Agents↗