Abstract 6563: Network potential identifies therapeutic miRNA cocktails in Ewings Sarcoma
Authors: Weaver Davis T. , Pishas Kathleen I. , Williamson Drew , Scarborough Jessica , Lessnick Stephen L. , Dhawan Andrew , Scott Jacob G. 
Published: September 2020

Introduction: Micro-RNA (miRNA)-based therapies are an emerging class of cancer therapies with many potential applications in the field owing to their ability to repress multiple, predictable targets and cause widespread changes in a cell signaling network. New miRNA-based oligonucleotide drugs have have shown significant promise for the treatment of cancer in pre-clinical studies. Because of the broad effects miRNAs can have on different cells and tissues, a network science-based approach is well-equipped to evaluate and identify miRNA candidates and combinations of candidates for the repression of key oncogenic targets.

Methods: In this work, we present a novel network science-based approach for identification of potential miRNA therapies, using Ewings Sarcoma as a model system. We first characterized 6 Ewings cell lines using paired mRNA and miRNA sequencing. We then estimated a measure of tumor state, which we term network potential, based on both the mRNA gene expression and the underlying protein-protein interaction network in the tumor. Next, we ranked mRNA targets based on their contribution to network potential, aiming to approximate the relative importance of each protein to network stability in decreasing the network potential. After identifying these mRNA targets, we sought to identify miRNAs and combinations of miRNAs that preferentially act to repress these targets, with the aim of defining synthetic miRNA-based therapy for down-regulation of these targets.

Results: We identified TRIM25, APP, ELAV1, RNF4, XPO1 as ideal protein targets for therapy for each of the six cell lines based on the degree of network disruption induced when each gene was modeled as repressed. The expanded list of targets was enriched for genes involved in the canonical miRNA biogenesis pathway, suggesting a link between signaling network disruption and miRNA production. Using miRNA-mRNA target mappings, we identified miR-3613-3p, let-7a-3p, miR-300, miR-424-5p, and let-7b-3p as the optimal miRNAs for preferential repression of these targets.

Discussion: In this work, we applied a novel pipeline for identification of miRNAs candidates for cancer therapy. Using a measure of network state, network potential, we identified potential mRNA targets crucial to the stability of the Ewings Sarcoma signaling network, including known drivers of tumor progression and genes involved in miRNA biogenesis. Applying mRNA-miRNA mappings, we successfully identified miRNAs and combinations of miRNAs that, if introduced synthetically, are predicted to preferentially and dramatically disrupt the Ewings Sarcoma signaling network.

Citation Format: Davis T. Weaver, Kathleen I. Pishas, Drew Williamson, Jessica Scarborough, Stephen L. Lessnick, Andrew Dhawan, Jacob G. Scott. Network potential identifies therapeutic miRNA cocktails in Ewings Sarcoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6563.