Abstract 5692: Targeted inhibition of cancer stem cells by self-assembled miRNA-nanovectors

Abstract

Abstract Cancer stem cells (CSCs) are a subpopulation of tumorigenic cells capable of self-renewal and differentiation. These cells are highly resistant to chemo/radiation therapy and may be responsible for tumor recurrence and metastasis. MicroRNAs (miRNAs) are involved in cancer initiation and progression by regulating genes responsible for cell proliferation and/or death. The tumor suppressor miRNA miR-34a is directly regulated by p53. miR-34a targets Notch and Bcl-2, both of which are involved in the self-renewal and survival of CSCs. We recently showed that miR-34a potently inhibits tumorsphere growth and tumor-initiation of p53-mutant pancreatic cancer, accompanied by reduction of CSCs and inhibition of Bcl-2/Notch signaling pathways. However, like other gene therapeutics, tumor-targeted delivery of miRNA, especially targeting to CSCs, remains a great challenge. We have established a self-assembled nanovector system that shows promising tumor specificity and efficiency for tumor-targeted gene/siRNA delivery (US Patent No. 6,749,863 and 7,479,276 with modification). The nanovectors show promising specificity and efficacy for systemic p53 tumor suppressor gene therapy in human cancer models. The first-in-human Phase I clinical trial of nano-p53 (NCT00470613, ClinicalTrails.gov) by Chang EH group shows a promising safety profile, efficient therapeutic gene expression in tumors and early tumor response. We have modified this nanotechnology and established a nanovector delivery system to deliver miR-34a, which resulted in a high transfection efficiency and significant Bcl-2/Notch downregulation in pancreatic, breast and prostate cancer cell lines, accompanied with reduced tumorsphere growth in vitro and tumor formation in vivo. More importantly, systemic injection of nano-miR-34a can delivermiR-34a to the established pancreatic, breast and prostate cancer xenograft tumors and reduce Bcl-2/Notch expression in these tumors. CSC population was also reduced in the treated tumors. Our studies demonstrate that our nano-miR-34a may provide a novel and effective molecular therapy for human cancers with high Bcl-2 and p53 loss of function, potentially by modulating cancer stem cells. Molecularly targeted miRNA therapy delivered by nanovectors could be a powerful tool to correct the cancer stem cell dysregulation. Supported in part by NIH grant CA121830(S1). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5692. doi:1538-7445.AM2012-5692