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

doi:10.1158/1535-7163.MCT-15-0201-T

Gene Knockdown by EpCAM Aptamer-siRNA Chimeras Suppresses Epithelial Breast Cancers and Their Tumor-Initiating Cells

Mol Cancer Ther. 2015 Oct;14(10):2279-91. doi: 10.1158/1535-7163.MCT-15-0201-T. Epub 2015 Aug 11.

Authors

Adi Gilboa-Geffen¹, Peter Hamar², Minh T N Le¹, Lee Adam Wheeler¹, Radiana Trifonova¹, Fabio Petrocca¹, Anders Wittrup¹, Judy Lieberman³

Affiliations

¹ Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
² Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.
³ Cellular and Molecular Medicine Program, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts. judy.lieberman@childrens.harvard.edu.

PMID: 26264278
DOI: 10.1158/1535-7163.MCT-15-0201-T

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism
Aptamers, Nucleotide / administration & dosage*
Aptamers, Nucleotide / genetics
Aptamers, Nucleotide / metabolism
Base Sequence
Breast Neoplasms / metabolism
Breast Neoplasms / pathology*
Carcinogenesis / metabolism
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Epithelial Cell Adhesion Molecule
Female
Gene Expression
Gene Knockdown Techniques
Humans
Mice, Nude
Neoplasm Transplantation
Neoplasms, Glandular and Epithelial / metabolism
Neoplasms, Glandular and Epithelial / pathology*
Neoplastic Stem Cells / physiology*
Polo-Like Kinase 1
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism
RNA Interference
RNA, Small Interfering / administration & dosage*
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Tumor Burden

Substances

Antigens, Neoplasm
Aptamers, Nucleotide
Cell Adhesion Molecules
Cell Cycle Proteins
EPCAM protein, human
Epithelial Cell Adhesion Molecule
Proto-Oncogene Proteins
RNA, Small Interfering
Protein Serine-Threonine Kinases

Grants and funding

R01 CA184718/CA/NCI NIH HHS/United States