TY - JOUR
T1 - Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma
AU - Hayashi, Masanori
AU - Baker, Alissa
AU - Goldstein, Seth Daniel
AU - Albert, Catherine M.
AU - Jackson, Kyle W.
AU - McCarty, Gregory
AU - Kahlert, Ulf D.
AU - Loeb, David M.
N1 - Funding Information:
The authors thank Charles Eberhart, Christine Pratilas, and Sara Sukumar for helpful discussions and suggestions. This work was supported by National Institutes of Health grant (1R01CA138212-01) (DML) and the Liddy Shriver Sarcoma Initiative (DML) as well as the Core Grant supporting the Sidney Kimmel Comprehensive Cancer Center, 2P30 CA006973. Work was also supportedby Giant Food Children's Cancer Research Fund and the National Pediatric Cancer Foundation. M.H. was supported by a Pablove Foundation Pediatric Cancer Research grant and by the SARC Sarcoma SPORE Career Development Award (5U54CA168512-02). UDK is supported by the Strategic Research Fund of the Heinrich-Heine University.
PY - 2017
Y1 - 2017
N2 - The most pressing unmet clinical need for patients with Ewing sarcoma (ES) is the prevention and treatment of metastasis. The Wnt signaling pathway regulates a number of cellular functions associated with metastasis, including proliferation, motility, and stem cell self-renewal. Functional interaction between Wnt ligands and their receptors requires palmitoylation by Porcupine (Porcn), making this an ideal therapeutic target. We studied the effect of WNT974, a potent, selective Porcn inhibitor, on ES metastasis. In vitro, WNT974 does not affect ES proliferation or sarcosphere formation, but suppresses multiple transcriptional regulators of metastasis and inhibits cell migration. In vivo, in an orthotopic implantation/amputation model of spontaneous distant metastasis, single agent WNT974 treatment leads to a significant delay in formation of lung metastasis and a substantial improvement in post-amputation survival without a major effect on primary tumor growth. The drug produces no survival benefit in a tail vein injection model, supporting the hypothesis that WNT974 inhibits early steps in the metastatic cascade, such as migration and invasion. Our findings strongly implicate Wnt signaling in the early steps of ES metastasis and demonstrate that WNT974 has the potential to significantly improve the survival of ES patients through the specific inhibition of metastasis.
AB - The most pressing unmet clinical need for patients with Ewing sarcoma (ES) is the prevention and treatment of metastasis. The Wnt signaling pathway regulates a number of cellular functions associated with metastasis, including proliferation, motility, and stem cell self-renewal. Functional interaction between Wnt ligands and their receptors requires palmitoylation by Porcupine (Porcn), making this an ideal therapeutic target. We studied the effect of WNT974, a potent, selective Porcn inhibitor, on ES metastasis. In vitro, WNT974 does not affect ES proliferation or sarcosphere formation, but suppresses multiple transcriptional regulators of metastasis and inhibits cell migration. In vivo, in an orthotopic implantation/amputation model of spontaneous distant metastasis, single agent WNT974 treatment leads to a significant delay in formation of lung metastasis and a substantial improvement in post-amputation survival without a major effect on primary tumor growth. The drug produces no survival benefit in a tail vein injection model, supporting the hypothesis that WNT974 inhibits early steps in the metastatic cascade, such as migration and invasion. Our findings strongly implicate Wnt signaling in the early steps of ES metastasis and demonstrate that WNT974 has the potential to significantly improve the survival of ES patients through the specific inhibition of metastasis.
KW - Ewing sarcoma
KW - Metastasis
KW - Patient-derived xenograft
KW - Preclinical model
KW - Wnt signaling
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U2 - 10.18632/oncotarget.19432
DO - 10.18632/oncotarget.19432
M3 - Article
C2 - 29108227
AN - SCOPUS:85030465392
VL - 8
SP - 78265
EP - 78276
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 45
ER -