TY - JOUR
T1 - An orally available small-molecule inhibitor of c-Met, PF-2341066, reduces tumor burden and metastasis in a preclinical model of ovarian cancer metastasis
AU - Zillhardt, Marion
AU - Christensen, James G.
AU - Lengyel, Ernst
N1 - Funding Information:
Abbreviations: ALK, anaplastic lymphoma kinase; ECM, extracellular matrix; HGF, hepatocyte growth factor; MMP, matrix metalloproteinase Address all correspondence to: Ernst Lengyel, University of Chicago, Department of Obstetrics and Gynecology, Section of Gynecologic Oncology, MC 2050, 5841 South Maryland Ave, Chicago, IL 60637. E-mail: elengyel@uchicago.edu 1Ernst Lengyel holds a Clinical Scientist Award in Translational Research from the Burroughs Wellcome Fund and is supported by grants from the Ovarian Cancer Research Fund (Liz Tilberis Scholars Program) and the National Cancer Institute (RO1 CA111882). Received 4 June 2009; Revised 28 September 2009; Accepted 30 September 2009 Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1522-8002/10/$25.00 DOI 10.1593/neo.09948
PY - 2010/1
Y1 - 2010/1
N2 - Deregulated expression of the hepatocyte growth factor (HGF) receptor, c-Met, in cancer contributes to tumor progression and metastasis. The objective of this study was to determine whether blocking c-Met with an orally available c-Met inhibitor, PF-2341066, reduces tumor burden and increases survival in a xenograft model of ovarian cancer metastasis. Treatment of mice injected interperitoneally with SKOV3ip1 cells showed reduced overall tumor burden. Tumor weight and the number of metastases were reduced by 55% (P < .0005) and 62% (P < .0001), respectively. Treatment also increased median survival from 45 to 62 days (P = .0003). In vitro, PF-2341066 reduced HGF-stimulated phosphorylation of c-Met in the tyrosine kinase domain as well as phosphorylation of the downstream signaling effectors, Akt and Erk. It was apparent that inhibition of the pathways was functionally important because HGF-induced branching morphogenesis was also inhibited. In addition, proliferation and adhesion to various extracellular matrices were inhibited by treatment with PF-2341066, and the activity of matrix metalloproteinases was decreased in tumor tissue from treated mice compared with those receiving vehicle. Overall, these data indicate that PF-2341066 effectively reduces tumor burden in an in vivo model of ovarian cancer metastasis and may be a good therapeutic candidate in the treatment of patients with ovarian cancer.
AB - Deregulated expression of the hepatocyte growth factor (HGF) receptor, c-Met, in cancer contributes to tumor progression and metastasis. The objective of this study was to determine whether blocking c-Met with an orally available c-Met inhibitor, PF-2341066, reduces tumor burden and increases survival in a xenograft model of ovarian cancer metastasis. Treatment of mice injected interperitoneally with SKOV3ip1 cells showed reduced overall tumor burden. Tumor weight and the number of metastases were reduced by 55% (P < .0005) and 62% (P < .0001), respectively. Treatment also increased median survival from 45 to 62 days (P = .0003). In vitro, PF-2341066 reduced HGF-stimulated phosphorylation of c-Met in the tyrosine kinase domain as well as phosphorylation of the downstream signaling effectors, Akt and Erk. It was apparent that inhibition of the pathways was functionally important because HGF-induced branching morphogenesis was also inhibited. In addition, proliferation and adhesion to various extracellular matrices were inhibited by treatment with PF-2341066, and the activity of matrix metalloproteinases was decreased in tumor tissue from treated mice compared with those receiving vehicle. Overall, these data indicate that PF-2341066 effectively reduces tumor burden in an in vivo model of ovarian cancer metastasis and may be a good therapeutic candidate in the treatment of patients with ovarian cancer.
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U2 - 10.1593/neo.09948
DO - 10.1593/neo.09948
M3 - Article
C2 - 20072648
AN - SCOPUS:73949092289
SN - 1522-8002
VL - 12
SP - 1
EP - 10
JO - Neoplasia
JF - Neoplasia
IS - 1
ER -