abstract: (in mice) MEK1/2 Inhibitor Selumetinib (AZD6244) Inhibits Growth of Ovarian Clear Cell Carcinoma in a PEA-15–Dependent Manner in a Mouse Xenograft Model

Blogger's Note: in research (mice)

Abstract

Clear cell carcinoma (CCC) of the ovary tends to show resistance to standard chemotherapy, which results in poor survival for patients with CCC. Developing a novel therapeutic strategy is imperative to improve patient prognosis. Epidermal growth factor receptor (EGFR) is frequently expressed in epithelial ovarian cancer. One of the major downstream targets of the EGFR signaling cascade is extracellular signal–related kinase (ERK). PEA-15, a 15-kDa phosphoprotein, can sequester ERK in the cytoplasm. MEK1/2 plays a central role in integrating mitogenic signals into the ERK pathway. We tested the hypothesis that inhibition of the EGFR–ERK pathway suppresses tumorigenicity in CCC, and we investigated the role of PEA-15 in ERK-targeted therapy in CCC. We screened a panel of 4 CCC cell lines (RMG-I, SMOV-2, OVTOKO, and KOC-7c) and observed that the EGFR tyrosine kinase inhibitor erlotinib inhibited cell proliferation of EGFR-overexpressing CCC cell lines through partial dependence on the MEK/ERK pathway. Furthermore, erlotinib-sensitive cell lines were also sensitive to the MEK inhibitor selumetinib (AZD6244), which is under clinical development. Knockdown of PEA-15 expression resulted in reversal of selumetinib-sensitive cells to resistant cells, implying that PEA-15 contributes to selumetinib sensitivity. Both selumetinib and erlotinib significantly suppressed tumor growth (P < 0.0001) in a CCC xenograft model.  
However, selumetinib was better tolerated; erlotinib-treated mice exhibited significant toxic effects (marked weight loss and severe skin peeling) at high doses. Our findings indicate that the MEK–ERK pathway is a potential target for EGFR-overexpressing CCC and indicate that selumetinib and erlotinib are worth exploring as therapeutic agents for CCC. Mol Cancer Ther; 11(2); 360–9. ©2011 AACR

Expert Review - slides: Renal Cell Carcinoma Biology and the Rationale for VEGF (sorafenib, sunitinib, erlotinib, avastin, interleukins, etc)

Note: if you are unable to access this slide presentation it is because you need to register on the site (free); it may be of interest to those with clear cell ovarian cancer; the largest % of renal cancers are of the clear cell subtype (a known ~75%) ------------------------------------------------------------------------------------------------------- MODULE 1: Renal Cell Carcinoma Biology and Rationale for VEGF Expert review with Lee Lokey, MD, and Brian I. Rini, MD, focusing on renal cell carcinoma
Discussant:	Brian I. Rini, MD—Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio, United States
Interviewed by:	Lee Lokey, MD—prIME Oncology, Atlanta, Georgia, United States

Letter to the Editor: Unexpected gastrointestinal toxicity from Docetaxel/Carboplatin/Erlotinib followed by maintenance Erlotinib treatment for newly diagnosed stage III/IV ovarian cancer, primary peritoneal, or fallopian tube cancer

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Erlotinib added to carboplatin and paclitaxel as first-line treatment of ovarian cancer: A phase II study based on surgical reassessment

BACKGROUND: The purpose of this study was to determine whether adding the anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to carboplatin/paclitaxel improved pathologic complete response (pCR) at reassessment surgery in epithelial ovarian, fallopian tube, or primary peritoneal cancers (OFPC).
CONCLUSIONS: Among unselected patients, erlotinib plus carboplatin-paclitaxel did not improve pCR rates compared with historical experience with carboplatin-paclitaxel alone in patients with stage III-IV OFPC.