Abstract 3750: miR-590-3p inhibits multiple oncogenic nodes within the TGFBR2:SMAD2/3 pathway in recurrent GBM cells

Abstract

Abstract Glioblastoma (GBM) is the most lethal and aggressive primary brain malignancy with high recurrence rates and virtually no long-term survival. Despite our expanding knowledge regarding GBM at the genomic/molecular level, we still don’t fully comprehend the molecular mechanisms responsible for GBM recurrence. Current knowledge implicates tumor-propagating Glioma Stem Cells (GSCs) in the evolution of treatment resistance and tumor recurrence. Understanding these cellular/molecular events will inform strategies for preventing and/or treating recurrent GBM (rGBM). Gene set enrichment analysis (GSEA) of RNA sequencing datasets obtained from GSCs and clinical rGBM specimens identified TGFBR2 signaling as a high frequency and potentially targetable pathway in rGBM. We show that SMAD2/3 signaling, a downstream effector of TGFBR2, is enriched in rGBM and that patients with elevated TGFBR2 have statistically shorter long-term survival outlooks. The functional relevance of these findings was supported using ITD1, a selective TGFBR2 inhibitor, which decreased the GSC phenotype and cell viability of cells derived from clinical rGBM (rGBM cells), while simultaneously re-sensitizing them to temozolomide (TMZ) in-vitro. Since GBM is known to efficiently develop resistance to receptor-targeting monotherapies, we sought to simultaneously target multiple putative oncogenic drivers downstream of TGFBR2. To achieve this, we applied an unbiased miRNA-based network analysis that identified miR-590-3p as an inhibitor of SMAD2/3 signaling at multiple nodes and thus a potential tumor suppressor in rGBM. Transgenic miR-590-3p robustly decreased the expression of >30 putative oncogenes, reduced the GSC phenotype and cell viability, as well as re-sensitized rGBM cells to TMZ. These results predict that blocking TGFBR2 signaling will negatively impact the tumor phenotype of rGBM as well as its GSC capacity. Ongoing directions for this research include comparing the efficacy of ITD1 monotherapy with miR-590-3p therapy in rGBM models in-vivo. These results identify a significant role of TGFBR2 signaling in both TMZ resistance and the GSC phenotype in rGBM and provide a miRNA-based strategy for simultaneously targeting multiple oncogenic nodes within the TGFBR2 and potentially other oncogenic signaling pathways. Citation Format: Sophie Sall, Jack Korleski, Amanda Johnson, Maya Johnson, Hernando Lopez-Bertoni. miR-590-3p inhibits multiple oncogenic nodes within the TGFBR2:SMAD2/3 pathway in recurrent GBM cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3750.