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The phosphatidylinositol-3-kinase (PI3K)/mTOR pathway has been a major focus of attention for cancer researchers in the past decade. A preliminary and incomplete understanding of the molecular biology of this complex network has importantly conditioned not only the development of the first generation of mTOR inhibitors, but also the biomarker studies(More)
PURPOSE Fibroblast growth factor receptor 1 (FGFR1) and FGFR2 amplifications are observed in approximately 10% of breast cancers and are related to poor outcomes. We evaluated whether dovitinib (TKI258), an inhibitor of FGFR1, FGFR2, and FGFR3, presented antitumor activity in FGFR-amplified breast cancers. EXPERIMENTAL DESIGN Preclinical activity of(More)
Selective inhibition of the mitogen activated protein kinase (MAPK) pathway with either BRAF or MEK inhibition has emerged as the key component for the treatment of BRAF-mutant metastatic melanoma. New evidence from several phase III trials suggests that the combination of BRAF and MEK inhibitors improves tumor response rate and progression-free survival(More)
Metastatic breast cancer (MBC) remains an incurable disease, with the goals of care aimed at maximizing the patient's duration and quality of life. Treatment options for MBC have become more efficacious and numerous. In addition to endocrine and chemotherapy agents, a number of targeted agents, including trastuzumab and bevacizumab, have further enhanced(More)
The fibroblast growth factor receptor (FGFR) cascade plays crucial roles in tumor cell proliferation, angiogenesis, migration and survival. Accumulating evidence suggests that in some tumor types, FGFRs are bona fide oncogenes to which cancer cells are addicted. Because FGFR inhibition can reduce proliferation and induce cell death in a variety of in vitro(More)
Clinical experience increasingly suggests that molecular prescreening and biomarker enrichment strategies in phase I trials with targeted therapies will improve the outcomes of patients with cancer. In keeping with the exigencies of a personalized oncology program, tumors from patients with advanced chemorefractory colorectal cancer were analyzed for(More)
INTRODUCTION Current methods to determine HER2 (human epidermal growth factor receptor 2) status are affected by reproducibility issues and do not reliably predict benefit from anti-HER2 therapy. Quantitative measurement of HER2 may more accurately identify breast cancer (BC) patients who will respond to anti-HER2 treatments. METHODS Using selected(More)
PURPOSE MAPK and PI3K/AKT/mTOR pathways play important roles in many tumors. In this study, safety, antitumor activity, and pharmacokinetics of buparlisib (pan class PI3K inhibitor) and trametinib (MEK inhibitor) were evaluated. EXPERIMENTAL DESIGN This open-label, dose-finding, phase Ib study comprised dose escalation, followed by expansion part in(More)
Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase α (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit(More)
Patients with primary HER2-positive breast cancer benefit from HER2-targeted therapies. Nevertheless, a significant proportion of these patients die of disease progression due to mechanisms of drug resistance. MicroRNAs (miRNAs) are emerging as critical core regulators of drug resistance that act by modulating the epithelial-to-mesenchymal transition (EMT)(More)