Abstract 5429: Therapeutic targeting of oncogenic long non-coding RNAs utilizing antisense oligonucleotides

Abstract

Abstract Non-coding RNAs (ncRNAs) are emerging as potent regulators of biological process including human diseases such as cancer. Long non-coding RNAs (lncRNAs) are a dynamic and versatile class of ncRNAs for which there is extensive evidence of these transcripts modulating epigenetic programs to affect cellular phenotypes. Our initial studies using a model of glioblastoma (GBM) tumor recurrence has revealed a number of oncogenic lncRNAs associated with therapy resistance and/or tumor recurrence. We have validated the expression of these oncogenic lncRNAs in another cancer, pediatric rhabdomyosarcoma (RMS). There have been few effective therapeutic advances made in past decades for either RMS or GBM. Radiation therapy is commonly employed alongside surgery and standard chemotherapy, especially in the case of unresectable disease, advanced disease, or upon tumor recurrence. Tumors may inherently possess or acquire resistance to radiation therapy and other treatment modalities over the course of disease. Tumor therapy resistance and recurrence are mediated by complex epigenetic programs which lead to increased capacity for DNA damage repair or tolerance of double stranded breaks. LncRNAs may regulate mechanisms of tumor recurrence and therapy resistance across multiple cancer types. The functional roles of ZFAS1 modulating epithelial to mesenchymal transition in colon cancers and SAMMSON which drives aberrant mitochondrial function in melanoma have been described. CASC19/PCAT2, ZFAS1, DUXAP9, and SOX2-OT are overexpressed in multiple cancers with CASC19 having a significant negative association with GBM patient survival. In silico analysis identifies DNA-binding capacities harbored by these lncRNA transcripts, and their predicted binding sites are proximal to several cancer hallmark genes. We have verified the expression of isoforms of these lncRNA transcripts that contain DNA-binding domains through sequencing and qPCR. We hypothesize that these lncRNAs regulate transcriptional networks via recruitment of transcriptional or epigenetic machinery to genomic loci to modulate oncogenic programs and/or tumor suppressor pathways. As potent epigenetic regulators, lncRNAs present an attractive class of therapeutic targets that could complement standard treatments to reduce disease burden and improve patient survival. It is possible that acquired radiation resistance mediated by lncRNAs is conserved across multiple malignancies. We are developing chemically modified, novel antisense oligonucleotides to target these transcripts in GBM and RMS patient-derived xenografts. Using these systems, we hope to reveal novel associations with disease progression and oncogenic mechanisms that could be exploited through the direct targeting of lncRNAs. We hope our work will lead to the development of novel clinical agents to treat patients with RMS, GBM, and potentially other intractable cancers. Citation Format: Christian Tyler Stackhouse, Corinne Linardic, Malaika Kimmons, Samantha Weitzel. Therapeutic targeting of oncogenic long non-coding RNAs utilizing antisense oligonucleotides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5429.