Gene knockdown by EpCAM aptamer-siRNA chimeras suppresses epithelial breast cancers and their tumor-initiating cells

Adi Gilboa-Geffen, Peter Hamar, Minh T.N. Le, Lee Adam Wheeler, Radiana Trifonova, Fabio Petrocca, Anders Wittrup, Judy Lieberman

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39 Citations (Scopus)

Abstract

Effective therapeutic strategies for in vivo siRNA delivery to knockdown genes in cells outside the liver are needed to harness RNA interference for treating cancer. EpCAM is a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells (TIC, also known as cancer stem cells). Here, we show that aptamer-siRNA chimeras (AsiC, an EpCAM aptamer linked to an siRNA sense strand and annealed to the siRNA antisense strand) are selectively taken up and knock down gene expression in EpCAM+ cancer cells in vitro and in human cancer biopsy tissues. PLK1 EpCAM-AsiCs inhibit colony and mammosphere formation (in vitro TIC assays) and tumor initiation by EpCAM+ luminal and basal-A triple-negative breast cancer (TNBC) cell lines, but not EpCAM+ mesenchymal basal-B TNBCs, in nude mice. Subcutaneously administered EpCAM-AsiCs concentrate in EpCAM+ Her2+ and TNBC tumors and suppress their growth. Thus, EpCAM-AsiCs provide an attractive approach for treating epithelial cancer.

Original languageEnglish
Pages (from-to)2279-2291
Number of pages13
JournalMolecular Cancer Therapeutics
Volume14
Issue number10
DOIs
Publication statusPublished - Oct 1 2015

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Gilboa-Geffen, A., Hamar, P., Le, M. T. N., Wheeler, L. A., Trifonova, R., Petrocca, F., Wittrup, A., & Lieberman, J. (2015). Gene knockdown by EpCAM aptamer-siRNA chimeras suppresses epithelial breast cancers and their tumor-initiating cells. Molecular Cancer Therapeutics, 14(10), 2279-2291. https://doi.org/10.1158/1535-7163.MCT-15-0201-T