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      Role of erlotinib in the management of pancreatic cancer

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          Abstract

          Pancreatic cancer is a largely chemo-resistant disease with a poor prognosis. Despite the adoption of gemcitabine monotherapy as a standard of care, outcomes remain poor. Until recently randomized phase III studies have not demonstrated superiority of various cytotoxic combinations or a number of the newer biologic targeted drugs. The situation has changed with capecitabine and erlotinib, either of which in combination with gemcitabine produces a small increase in survival. Erlotinib is a small molecule tyrosine kinase inhibitor against epidermal growth factor receptor which has an important role in the molecular pathogenesis of pancreatic cancer. In both pre-clinical and early clinical evaluation it has shown anti-tumor activity against pancreatic cancer in combination with gemcitabine. A randomized phase III study in locally advanced and metastatic pancreatic cancer has shown a survival advantage for the combination of gemcitabine plus erlotinib over gemcitabine alone. The rationale for the clinical development of erlotinib in combination with gemcitabine in pancreatic cancer culminating in this randomized trial, together with pharmacologic, toxicity and patient selection considerations form the focus of this review.

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          Most cited references 75

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          Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.

          Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non-small-cell lung cancer (NSCLC). The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described. Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses. EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P < .001). Among erlotinib-treated patients, EGFR mutations were associated with improved response rate (P < .05) and there was a trend toward an erlotinib benefit on TTP (P = .092), but not improved survival (P = .96). KRAS mutations (21% of tumors) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy-treated patients. EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib, and may predict greater likelihood of response. Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Further studies are needed to confirm the findings of this retrospective subset analysis.
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            NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1.

            Accumulating evidence implicates the transcription factor NF-kappaB as a positive mediator of cell growth, but the molecular mechanism(s) involved in this process remains largely unknown. Here we use both a skeletal muscle differentiation model and normal diploid fibroblasts to gain insight into how NF-kappaB regulates cell growth and differentiation. Results obtained with the C2C12 myoblast cell line demonstrate that NF-kappaB functions as an inhibitor of myogenic differentiation. Myoblasts generated to lack NF-kappaB activity displayed defects in cellular proliferation and cell cycle exit upon differentiation. An analysis of cell cycle markers revealed that NF-kappaB activates cyclin D1 expression, and the results showed that this regulatory pathway is one mechanism by which NF-kappaB inhibits myogenesis. NF-kappaB regulation of cyclin D1 occurs at the transcriptional level and is mediated by direct binding of NF-kappaB to multiple sites in the cyclin D1 promoter. Using diploid fibroblasts, we demonstrate that NF-kappaB is required to induce cyclin D1 expression and pRb hyperphosphorylation and promote G(1)-to-S progression. Consistent with results obtained with the C2C12 differentiation model, we show that NF-kappaB also promotes cell growth in embryonic fibroblasts, correlating with its regulation of cyclin D1. These data therefore identify cyclin D1 as an important transcriptional target of NF-kappaB and reveal a mechanism to explain how NF-kappaB is involved in the early phases of the cell cycle to regulate cell growth and differentiation.
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              Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer.

              The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in many epithelial tumors. Receptor activation leads to recruitment and phosphorylation of several downstream intracellular substrates, leading to mitogenic signaling and other tumor-promoting cellular activities. In human tumors, receptor overexpression correlates with a more aggressive clinical course. Taken together, these observations indicate that the EGFR is a promising target for cancer therapy. Monoclonal antibodies directed at the ligand-binding extracellular domain and low-molecular weight inhibitors of the receptor's tyrosine kinase are currently in advanced stages of clinical development. These agents prevent ligand-induced receptor activation and downstream signaling, which results in cell cycle arrest, promotion of apoptosis, and inhibition of angiogenesis. They also enhance the antitumor effects of chemotherapy and radiation therapy. In patients, anti-EGFR agents can be given safely at doses that fully inhibit receptor signaling, and single-agent activity has been observed against a variety of tumor types, including colon carcinoma, non-small-cell lung cancer, head and neck cancer, ovarian carcinoma, and renal cell carcinoma. Although antitumor activity is significant, responses have been seen in only a minority of the patients treated. In some clinical trials, anti-EGFR agents enhanced the effects of conventional chemotherapy and radiation therapy. Ongoing research efforts are directed at the selection of patients with EGFR-dependent tumors, identification of the differences among the various classes of agents, and new clinical development strategies.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                December 2006
                December 2006
                : 2
                : 4
                : 435-445
                Affiliations
                [1 ]Royal Marsden Hospital Sutton, Surrey, UK
                [2 ]School of Cancer Studies, University of Liverpool, Royal Liverpool University Hospital Liverpool, UK
                [3 ]Gastrointestinal and Lymphoma Units, Royal Marsden Hospital Sutton, Surrey, UK
                Author notes
                Correspondence: John Neoptolemos Division of Surgery and Oncology, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, UK Tel +44 151 706 4175 Fax +44 151 706 5798 Email j.p.neoptolemos@ 123456liv.ac.uk
                Article
                1936363
                18360654
                © 2006 Dove Medical Press Limited. All rights reserved
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