Abstract 1186: microRNA-targeted small molecule inhibitors in metastatic cancers

Background: Gastric carcinoma is a highly heterogeneous disease with diverse subtypes, each with distinct histopathological and clinical characteristics, complicating prognosis and treatment. High mortality is driven by molecular and microenvironmental changes, often leading to peritoneal carcinomatosis. MicroRNAs (miRs), particularly miR-10b, play key roles in gastric cancer by promoting drug resistance, migration, and invasiveness. Targeting miR-10b with Small Molecule Inhibitors of miRNAs (SMIRs) offers a novel approach to disrupting RNA-small molecule interactions, presenting promising strategies for halting cancer progression and improving outcomes. Methods: We investigated the expression of miRNAs in patients with peritoneal carcinomatosis using miRNA sequencing, followed by RT-qPCR for validation, identifying miR-10b as a candidate therapeutic target. SMIR-10b, a small-molecule inhibitor of miR-10b, was employed to suppress miR-10b expression, leading to increased expression levels of PTEN and HOXD10 post-treatment. The antiproliferative effects of SMIR-10b were assessed in GA0518 cells, with miR-10b and precursor miR-10b expression, as well as target protein levels, evaluated using RT-qPCR, western blotting, and immunofluorescence. To examine the in vivo effects of SMIR-10b, GA0518 cells were xenografted into nude mice. Results: We analyzed miRNA sequencing data and identified miR-10b as a specific target associated with peritoneal carcinomatosis, distinguishing it from normal and tumor tissues. In this context, a gradual increase in the concentration of SMIR-10b resulted in significant downregulation of miR-10b expression, which corresponded to an increase in PTEN and HOXD10 protein levels. Furthermore, SMIR-10b was found to target nuclear precursor miR-10b, suppressing its maturation into mature miR-10b. This led to an accumulation of precursor miR-10b in the nucleus and a concomitant reduction in mature miR-10b levels in the cytoplasm. Our in vivo studies demonstrated that SMIR-10b improved survival rates by reducing the tumorigenicity of GA0518 peritoneal carcinomatosis xenograft tumors. Collectively, these findings suggest that miR-10b is a promising therapeutic target in peritoneal carcinomatosis, contributing to tumorigenesis at least partially by regulating the expression of PTEN and HOXD10. Discussion: Through specificity analysis, we identified miR-10b, among other miRNAs, as a potential biomarker for peritoneal carcinomatosis. These findings support the therapeutic potential of targeting miR-10b to suppress gastric cancer progression and inhibit the dissemination of cancer cells within the peritoneal cavity, a primary driver of peritoneal carcinomatosis. This approach offers valuable insights into novel therapeutic strategies aimed at combating this aggressive malignancy and improving patient outcomes. Citation Format: Maria-Ancuta Jurj, Michael A. Attathikhun, Meng Chen, Corina Minciuna, Venkata Narayana Vidadala, Gabriele Varani, Jaffer A. Ajani, George A. Calin. microRNA-targeted small molecule inhibitors in metastatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1186.