CADD-04. NANOPARTICLE DELIVERY OF miRNAs TO INHIBIT GBM STEM CELLS. (5th November 2018)

• Record Type: Journal Article
• Authors: Lopez, Hernando; Kozielski, Kristen L; Rui, Yuan; Lal, Bachchu; Vaughan, Hannah; Wilson, David R; Mihelson, Nicole; Eberhart, Charles G; Green, Jordan J; Laterra, John
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi277
• Page End: vi277
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.1153
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Cancer cells arise from complementary genomic and epigenomic abnormalities that deregulate pathways that control cell proliferation and tissue homeostasis. Epigenetic modifications, involving deregulation of non-coding RNAs, are emerging as critical determinants of gene expression and essential drivers of neoplastic phenotypes. Our knowledge of how these complex epigenetic mechanisms operate in the context of cancer cell phenotype regulation remains limited. Non-coding RNAs, in particular miRNAs, are emerging as critical epigenetic regulators of cell fate and oncogenesis. MiRNAs act by selectively inhibiting gene expression primarily by targeting mRNA for degradation. Numerous miRNAs have been found to regulate tumorigenesis and cancer cell stemness by virtue of their capacity to target tumor-suppressing or tumor promoting transcripts. We recently showed that the coordinated actions of Oct4 and Sox2 induce a tumor-propagating stem-like state in GBM cells through a mechanism that involves the induction of DNMTs and down-regulation of a network of miRNAs through promoter DNA methylation. Two of the miRNAs repressed by Oct4/Sox2, miR-148a and miR-296-5p, efficiently inhibit the tumor propagating capacity of GBM stem-like, making them excellent candidates for therapeutic intervention. Options for treating high-grade brain tumors remain limited. Recent developments in nanomedicine provide new and exciting opportunities to treat and manage brain tumors. Cationic polymers are a class of biomaterials with great promise for targeted molecular therapeutics. We combined this cutting-edge technology with our newly discovered stem cell inhibiting miRNAs to develop nanoparticles to treat gliomas. We show these nano/miRs distribute throughout an established tumor in vivo, and more importantly, delivering these tumor-suppressing miRNAs using PBAE polymers inhibits the growth of established GBM tumor and prolongs survival in mouse models. Our findings demonstrate that identifying stem cell-inhibitory miRNAs in combination with current advances in nanomedicine will impact the development of novel therapies for treating GBM.