STEM-23. miR-486-5p REGULATES TUMOR SUPPRESSOR NETWORKS AND ITS INHIBITION REDUCES TUMOR VOLUME AND SENSITIZES TO RADIATION TREATMENT IN A PDX MOUSE MODEL OF GBM. (5th November 2018)

• Record Type: Journal Article
• Authors: Kotchetkov, Ivan; Lopez-Berotni, Hernando; Michelson, Nicole; Rui, Yuan; Lal, Bachchu; Li, Yunqing; Green, Jordan; Laterra, John
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi248
• Page End: vi248
• 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/noy148.1030
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Glioblastoma multiforme (GBM) is a heterogeneous malignancy that contains a subpopulation of tumor cells with stem-like features. These GBM stem cells (GSCs) have the ability to self-renew and establish tumors. As such, they are thought to disproportionately contribute to re-growth and resistance to therapy, and targeting mechanisms that underlie stemness may lead to development of more effective treatments. Work from the Laterra lab has shown that the transcription factors (TFs) Oct4 and Sox2 drive GBM cells toward a stem-like phenotype, in part by regulating subsets of microRNAs (miRNAs). One commonly overlooked mechanism by which these TFs can promote tumorigenesis is by inhibiting repressors of cell stemness and tumor propagation through miRNAs. This study demonstrates that miR-486-5p is induced by Sox2 12-fold and regulates GSC self-renewal as measured by limiting dilution and sphere formation assays by inhibiting tumor suppressors PTEN and FOXO1 in established glioma cell lines and patient-derived neurospheres. Inhibition of endogenous miR-486-5p in these lines leads to cell death. Furthermore, in vivo delivery of miR-486-5p inhibitor via a novel nanoparticle complex to pre-established patient-derived GBM xenografts (PDX) in mice decreases tumor volume by 61% (p < 0.001) and sensitizes to the effects of ionizing radiation 9-fold (p < 0.001). Thus, the Sox2:miR-486-5p axis offers a promising translational target for therapies aimed at depleting GBMs of stem-like cells in combination with standard therapies.