Therapeutic potential of targeting micro RNA ‐10b in established intracranial glioblastoma: first steps toward the clinic

Abstract

MicroRNA-10b (miR-10b) is a unique oncogenic miRNA that is highly expressed in all GBM subtypes, while absent in normal neuroglial cells of the brain. miR-10b inhibition strongly impairs proliferation and survival of cultured glioma cells, including glioma-initiating stem-like cells (GSC). Although several miR-10b targets have been identified previously, the common mechanism conferring the miR-10b-sustained viability of GSC is unknown. Here, we demonstrate that in heterogeneous GSC, miR-10b regulates cell cycle and alternative splicing, often through the non-canonical targeting via 5 0 UTRs of its target genes, including MBNL1-3, SART3, and RSRC1. We have further assessed the inhibition of miR-10b in intracranial human GSC-derived xenograft and murine GL261 allograft models in athymic and immunocompetent mice. Three delivery routes for the miR-10b antisense oligonucleotide inhibitors (ASO), direct intratumoral injections, continuous osmotic delivery, and systemic intravenous injections, have been explored. In all cases, the treatment with miR-10b ASO led to targets' derepression, and attenuated growth and progression of established intracranial GBM. No significant systemic toxicity was observed upon ASO administration by local or systemic routes. Our results indicate that miR-10b is a promising candidate for the development of targeted therapies against all GBM subtypes.

A combined microRNA-based targeted therapeutic approach to eradicate glioblastoma stem-like cells

“…When grown in 3-dimensional cultures as spheroids U87MG cells expressed the transcription factors Sox-2 and Nanog, which are involved in maintaining the pluripotency of stem-cells, and an increased expression of PDGFRβ, downregulated the neuronal differentiation [44]. Further, in the spheroids the levels of miR-137 are downregulated while those of miR-10b upregulated as described for GSCs [15,18].…”

“…Here we focused on two miRNAs that have been implicated in GSC propagation: the miR-137, downregulated in GSCs, considered as a putative tumor suppressor miRNA implicated in cell cycle arrest and neuronal differentiation in primary GBM [43] and miR-10b considered an oncomiR required for GSC self-renewal and proliferation [18]. Since the aptamer conjugates are internalized through a receptor mediated manner whose effectiveness is thus limited by the amount of available receptor present on the cell surface [21], we conjugated the miR-137 and the single chain miR-10b antagonist to two different aptamers in order to deliver them separately into the target cell by targeting two distinct RTKs.…”

“…As shown in Fig. 1A, both the miR-137 mimic and the antimiR-10b alone and in double transfections retain functional activity as determined by the simultaneous downregulation of the miR-137 validated target, glioma pathogenesis-related protein 1 (GLIPR-1) [15], and up-regulation of the miR-10b validated target, BH3-only protein, (Bim) [18]. Further, both molecules synergize to inhibit cell migration ( 1D).…”

“…To this end, we investigated the combination of miR-137 and the antagonist of the miR-10b. The miR-137 is a brain-enriched miRNA that acts as an oncosuppressor in several tumors, including GBMs, leading to decreased cell proliferation and invasion, [15] whereas miR-10b acts as an oncomiR and is highly expressed in GBMs and low expression is observed in normal human brain [18]. Antagonizing miR-10b expression has been shown to reduce glioma cell growth by cell cycle arrest and apoptosis [18].…”

“…In GSCs the combined deregulation of a characteristic pattern of miRNA expression has been described by several groups where elevated expression of a subset of miRNAs, including both miR-10a and miR-10b and downregulation of tumor suppressor miRNAs, such as miR-124, miR-9, miR-137, miR-135 have been observed in several cancer types [14][15][16][17][18]. Despite the potential held by miRNA-based therapeutics, major hurdles to the translation to clinic include the lack of safe and effective carriers able to penetrate and to accumulate into tumor selectively…”