Abstract 259: Targeted STEAP2 knockdown with self-delivering antisense oligonucleotide reduces cancer malignant behavior.

Abstract Background: The STEAP (Six-Transmembrane Epithelial Antigen of Prostate) family encodes metalloreductases involved in iron and copper metabolism, with increasing evidence linking dysregulated metal homeostasis to tumor progression. Increased STEAP2 expression has been implicated in the development and progression of several cancers, with enhanced cellular proliferation, migration, but its precise role in cancer remains obscure. The goal of this project is to investigate the significance and prognostic potential of targeting STEAP2 in oncogenesis. Methods: Our study investigated a self-delivering antisense oligonucleotide (ASO) targeting STEAP2 in cancer. Human liver cancer SNU398 and prostate cancer PC3 cells were treated with increasing ASO concentrations (0.25, 0.5, 1 and 5 μM) for 92 hours, followed by assessment of cell viability (WST-1), migration (transwell), and anchorage-independent growth (soft agar). For the in vivo study, orthotopic xenografts were created by injecting SNU398-luc/GFP cells into the livers of immunodeficient mice. Beginning on day 7, mice received 12 doses of the STEAP2-ASO or scrambled control (5 mg/kg, every two days). Tumor growth was monitored non-invasively via IVIS imaging. Upon treatment completion, tumors and adjacent liver tissues were harvested. Expression of EMT markers (Vimentin and SNAIL1) was evaluated in cell and tissue lysates using western blot analysis. Results: ASO mediated KD of STEAP2 induced a dose dependent reduction in STEAP2 expression, leading to significantly reduced cell viability, migration, and anchorage-independent growth in both SNU398 and PC3 cell lines. In addition, STEAP2 knockdown resulted in decreased expression of key EMT markers, including Vimentin and SNAIL1. In vivo analysis demonstrated that treatment with STEAP2 targeting ASOs resulted in a substantial decrease in tumor size, together with downregulation of STEAP2 levels, highlighting a clear association between STEAP2 suppression and inhibition of cancer progression. Consistent with the in vitro findings, tumors from ASO-treated mice also showed reduced Vimentin and SNAIL1 expression, further supporting EMT attenuation. Thus, our findings emphasize STEAP2 as an essential regulator of cancer development and progression as well as the therapeutic promise of the ASO-based STEAP2 silencing for abrogating the progression of liver and prostate cancer. Conclusion: Overall, these findings establish STEAP2 as a potential biomarker and therapeutic target for the intervention of various cancers. Citation Format: Nagesh K. Panchal, Araceli Bernal, Brittany Michelle Barre, Francisco Cigarroa, LuZhe Sun. Targeted STEAP2 knockdown with self-delivering antisense oligonucleotide reduces cancer malignant behavior abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 259.