P18.22.b Hur-Rna Complexes: Emerging Targets for Innovative Glioblastoma Therapeutics

Abstract BACKGROUND Glioblastoma (GBM) is an aggressive and fatal brain tumor, with a median survival of 15 months. This poor prognosis is largely due to the limited efficacy of current therapies, including chemotherapy and radiotherapy. A major challenge in treating GBM is its complex tumor microenvironment, which comprises various cell types such as glioma stem cells (GSCs), glioma tissue cells (GTCs), and tumor-associated macrophages (TAMs). These cell populations interact through a dense network of signaling molecules, many of which are regulated by the RNA-binding protein HuR (ELAVL1). HuR was found to regulate genes linked to major cancer hallmarks, including proliferation, invasion, metastasis, apoptosis resistance, angiogenesis, metabolic reprogramming, and immune evasion. HuR is also a key post-transcriptional regulator that stabilizes messenger RNAs (mRNAs) encoding pro-inflammatory cytokines (e.g., IL6, IL8, TGFβ, TNFα, IFNγ), inflammatory enzymes (COX-2, iNOS), and acute-phase proteins like C-reactive protein. Given its central role in tumor progression, the HuR-mRNA interaction has emerged as a promising therapeutic target. Small-molecule inhibitors that disrupt this interaction may offer a novel and effective strategy for GBM and other resistant cancers. MATERIAL AND METHODS Thirty novel HuR ligands, classified in resorcinol-benzil-ammide (RBA) and substituted lactam (ABOPC) series were tested on several commercial cancer cell lines representing lung, breast, pancreatic, colorectal, and liver tumors, as well as on a GBM panel including both commercial and patient-derived cell lines. Cytotoxicity was assessed via MTS assay, apoptosis by AnnexinV/FITC assay. RESULTS Among the thirty novel HuR ligands, RBA compounds showed broad-spectrum efficacy (IC50 values from 37 to 86 uM). The lead compound of the RBA series (RBA1) demonstrated efficacy in two GBM patient-derived cell lines and in two lung cancer cell lines, as well as in two breast cancer cell lines (IC50 value from 56 uM to 82 uM). Structural analogs of RBA1 were also found to be active in pancreatic and colon cancer cell lines (IC50 value from 53 and 74 uM). Furthermore, RBA1 and its structural analogs were tested for their ability to induce apoptosis in GBM cells, showing pro-apoptotic activity (ranging from 30% to 80%). CONCLUSION These early findings are encouraging, identifying active compounds—including some effective ones against resistant cancers. Future work will explore their mechanisms of action. This study supports the development of novel, epigenetics-based therapies for GBM. This work was supported by the National Recovery and Resilience Plan (PNRR), funded by the European Union - NextGenerationEU: PNRR-POC-2023-12377405