Priority Research Papers:
Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma
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Masanori Hayashi1, Alissa Baker1, Seth D. Goldstein1, Catherine M. Albert1,3, Kyle W. Jackson1, Gregory McCarty1, Ulf D. Kahlert1,2 and David M. Loeb1
1 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
2 Neurosurgical Clinic, University Medical Center Düsseldorf, Düsseldorf, Germany
3 Seattle Children’s Hospital, University of Washington, Seattle, WA, USA
David M. Loeb, email:
Keywords: metastasis, patient-derived xenograft, preclinical model, Wnt signaling, Ewing sarcoma
Received: May 12, 2017 Accepted: June 26, 2017 Published: July 21, 2017
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.
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