Abstract CN01-02: Targeting basal-like TNBCs and epithelial tumor-initiating cells with aptamer-siRNA chimeras.

RNA interference (RNAi) offers the exciting therapeutic possibility of selectively knocking down disease-causing genes. Recent Phase I and II clinical trials of small interfering RNAs (siRNAs) have shown promising gene knockdown and clinical benefit in a handful of diverse diseases caused by aberrant liver gene expression. In these studies siRNAs were targeted to the liver by encapsulation in lipoplexes or by conjugation with a sugar selectively recognized by hepatocytes. The major obstacle to harnessing RNAi for treating cancer is the difficulty delivering RNAs into disseminated cancer cells. Giangrande, McNamara and Gilboa developed a flexible and effective multifunctional RNA delivery platform using aptamer-siRNA chimeras (AsiC), to accomplish this goal. RNA aptamers, structured RNAs that bind with high affinity to a protein, covalently linked to siRNAs, cause knockdown selectively in cells bearing the receptor recognized by the aptamer. Although treatment for breast cancer has improved with the development of targeted therapeutics, there is still a need for new approaches for poor prognosis breast cancers. In particular, there is no targeted therapy for triple negative breast cancers (TNBC), which often relapse after current therapy; Her2+ breast cancers frequently develop resistance to targeted therapy with trastuzumab or lapatinib. We chose EpCAM as the receptor for aptamer-targeted treatment of basal-like TNBC because EpCAM is highly expressed on the most malignant epithelial cancers and their tumor-initiating cells (T-ICs). In normal epithelia, EpCAM is only expressed on basolateral gap junctions, where it may not be accessible to drugs. In epithelial cancers, it is not only much more abundant (by several orders of magnitude), but is also distributed along the whole cell membrane. All basal-A TNBC and luminal breast cancer cell lines examined were strongly EpCAM+, while a normal breast cancer epithelial line and mesenchymal TNBCs had close to background EpCAM levels. RNA uptake, gene knockdown and the cytotoxic effect of EpCAM-AsiCs that knockdown PLK1 were robust in basal-like TNBC and luminal breast cancer lines, but not in normal epithelial cells and mesenchymal cells. In fact gene knockdown and antitumor effect correlated with EpCAM expression. EpCAM-AsiCs targeting PLK1, but not control siRNAs, eliminated T-ICs from epithelial TNBC and luminal breast cancer cell lines as assessed by in vitro assays for T-IC function-mammosphere and colony formation and survival of Aldefluor+ cells. These results suggest that EpCAM-AsiCs could be used to treat epithelial breast tumors and the T-ICs within them, sparing normal cells. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN01-02. Citation Format: Adi Gilboa-Geffen, Lee Adam Wheeler, Anders Wittrup, Fabio Petrocca, Judy Lieberman. Targeting basal-like TNBCs and epithelial tumor-initiating cells with aptamer-siRNA chimeras. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN01-02.