Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma

Masanori Hayashi, Alissa Baker, Seth D. Goldstein, Catherine M. Albert, Kyle W. Jackson, Gregory McCarty, Ulf D. Kahlert, David M. Loeb

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)78265-78276
Number of pages12
JournalOncotarget
Volume8
Issue number45
DOIs
StatePublished - 2017

Keywords

  • Ewing sarcoma
  • Metastasis
  • Patient-derived xenograft
  • Preclinical model
  • Wnt signaling

ASJC Scopus subject areas

  • Oncology

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    Hayashi, M., Baker, A., Goldstein, S. D., Albert, C. M., Jackson, K. W., McCarty, G., Kahlert, U. D., & Loeb, D. M. (2017). Inhibition of porcupine prolongs metastasis free survival in a mouse xenograft model of Ewing sarcoma. Oncotarget, 8(45), 78265-78276. https://doi.org/10.18632/oncotarget.19432