Abstract LB457: Suppressing liver metastasis growth by inducing the endogenous expression of the tumor suppressor miR-34a by small synthetic molecules

Abstract Background and Aims: Metastasis are responsible for over 90% of cancer related mortality and remain the major challenge for successful management of malignant diseases. The liver is a preferred site of metastatic disease and a major cause of death from various malignancies, including colon, gastric, and pancreatic carcinomas as well as melanoma, breast cancer, and sarcomas. Recent evidence has indicated the role of microRNAs in modulating the metastatic processes. MicroRNAs (miRs) constitute a class of short noncoding RNAs which regulate gene expression by targeting messenger RNA (mRNA), including translational repression and mRNA degradation. There are specific miRs that exhibit tumor-suppressive activity by targeting cancer driver genes. miR-34a is a well-known tumor suppressor and anti-metastatic miR. However, the administration, and particularly the delivery of miR-34a, constitutes a major challenge. To overcome this major hurdle of translating miR-34a into a therapeutic molecule, we hypothesize that induction of endogenous expression and secretion of the tumor-suppressive miR-34a, in the vicinity of metastasis, using small synthetic molecules, could be a new strategy for metastasis therapy. Method: To identify small molecules which activate miR-34a expression and secretion, we generated a PmiR-34a-EGFP reporter system in vitro and performed high throughput screening of synthetic small molecule libraries, searching for compounds that induce the miR-34a promoter. Once compounds were identified by our high-through-put system that we established, validation experiments in vitro and in vivo followed. Results: The readout of the first high-through-put screening helped us to identify 15, out of over 8000 compounds, which induce miR-34a promoter activity. However, when validating these compounds, only 6 (AT7519, A-674563, BBI503, PCM0240249, KRIBB and SB273005) out of 9 compounds that were tested -induced miR-34a promoter activation and only 2 (AT7519 and A-674563) out of the 6, also caused miR-34a secretion from HepG2, a human hepatoblastoma cell line. As both AT7519 and A-674563 are known as multi-Cyclin Dependent Kinase (CDK) inhibitors, we searched for more potent CDK inhibitors, and we identified two compounds: Dinaciclib and A51. Both compounds induced miR-34a expression and secretion in vitro. Dinaciclib exhibited a better miR-34a dependent anti-tumoral effect in vitro whereas, A51 exhibited a better anti-metastatic effect in the forced colorectal cancer (CRC) liver metastasis model in vivo. Conclusion: Induction of miR-34a using small synthetic molecules is a novel therapeutic approach to eradicate CRC liver metastasis. Citation Format: Dayana Yaish, Auerlia Markezana, Alexander Plotnikov, Nofar Rosenberg, Shanny Barnoy, Emma Klahr, Moshe Oren, Yinon Ben-Neriah, Haim Barr, Hilla Giladi, Eithan Galun. Suppressing liver metastasis growth by inducing the endogenous expression of the tumor suppressor miR-34a by small synthetic molecules [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB457.