Abstract 3862: OC201 and OC202e, potential inhibitors of cancer metastasis, suppress EMT in pancreatic cancer

Abstract Objective: Pancreatic cancer is among the most aggressive malignancies, associated with a very poor prognosis due to its rapid progression and resistance to conventional therapies, underscoring the urgent need for novel treatment approaches. Epithelial-mesenchymal transition (EMT) is a key process that enhances the migration and invasion capabilities of cancer cells and is recognized as a pivotal mechanism driving malignancy in pancreatic cancer. Inhibiting EMT is therefore a critical therapeutic strategy. This study aimed to evaluate the anti-metastasis efficacy and define the mode of action of OC201 and OC202e in EMT-induced pancreatic cancer cells. Method: EMT was induced in Panc-1 and MIA PaCa-2 cells through treatment with TGF-β1 (5 ng/ml) and TNF-α (10 ng/ml). Cell migration and invasion were assessed through functional assays, while EMT-related markers (E-cadherin, ZEB1, Snail, Vimentin, and MMP-2) were analyzed via qPCR and Western blot. The cells were subsequently treated with OC201 and/or OC202e, and changes in expression of EMT-related signaling proteins were evaluated. An in vivo hepatic metastasis model was also established using MIA PaCa-2 cells to evaluate the effects of OC201 and/or OC202e treatment on metastasis following four weeks of therapy. Results: Treatment with TGF-β1 and TNF-α significantly increased migration and invasion in both Panc-1 and MIA PaCa-2 cells, accompanied by decreased E-cadherin expression and increased expression of ZEB1, Snail, and Vimentin. Treatment with either OC201 or OC202e reduced cell migration and invasion, suppressed the expression of EMT markers (ZEB1, Snail, Vimentin, and MMP-2), and increased E-cadherin expression. Both compounds inhibited the activation of key EMT signaling proteins, AKT and IκBα, with combination treatment resulting in a stronger inhibition of AKT and IκBα activation and an enhanced E-cadherin expression compared to monotherapy. OC202e alone inhibited autophagy, while OC201 showed no significant effect. In the hepatic metastasis model, both OC201 and OC202e monotherapy significantly reduced liver metastatic nodules in mice compared to control, with combination therapy yielding a more substantial reduction, confirming the efficacy in reducing metastasis to the liver. Conclusion: This study demonstrated that OC201 and OC202e effectively inhibited TGF-β1- and TNF-α-induced EMT via the AKT and NF-κB signaling pathways, highlighting their potential to target critical mechanisms underlying pancreatic cancer metastasis. Both compounds effectively suppressed EMT while maintaining cell viability, with combination therapy exhibiting superior efficacy. These findings suggest that the combined use of OC201 and OC202e may serve as a promising therapeutic strategy for pancreatic cancer. Citation Format: Youngjin Kim, Dong Sub Jung, Sewon Kim, So Jung Sung, Yenny Kim, Yi Rang Kim, Jihoon Kang. OC201 and OC202e, potential inhibitors of cancer metastasis, suppress EMT in pancreatic cancer [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 3862.