Abstract 2231: CY-101 inhibits the tumor growth and improves anti-PD-1 immunotherapy in beta-catenin-driven tumors

Abstract CY-101 is a bi-functional peptide with a dual mechanism of action. It selectively targets cancer cell membranes, forming pores that release neoantigens to the tumor microenvironment, thereby triggering a robust anti-tumor immune response. In addition, CY-101 inhibits the oncogenic Wnt/beta-catenin signaling pathway, which is frequently dysregulated in several cancers such as colorectal carcinoma (CRC), adrenocortical carcinoma (ACC), and melanoma. Given the high prevalence of beta-catenin mutations in these tumors, targeting this pathway offers significant therapeutic potential. We show that CY-101 induces a dose-dependent cell death across mouse and human beta-catenin-driven CRC, ACC, and melanoma cell lines in vitro following suppression of the Wnt/beta-catenin pathway. In preclinical animal models, CY-101 elicited a potent anti-tumor activity by completely eradicating ACC tumors and significantly enhancing the efficacy of anti-PD-1 therapy in CRC and melanoma models. Notably, CY-101 treatment reshaped the tumor immune landscape by modulating cytokine expression, leading to increased infiltration of cytotoxic CD8+ T cells. Mechanistically, CY-101-treated tumors exhibited downregulation of Wnt/beta-catenin downstream target genes, emphasizing its role as a potent Wnt/beta-catenin inhibitor. These preclinical findings support the observations seen in the first in human CICILIA Phase 1/2a trial, which reported clinical activity in ACC and melanoma patients. Collectively, our study demonstrates the therapeutic potential of CY-101 in beta-catenin-driven tumors, both as monotherapy and in combination with anti-PD1 checkpoint inhibitors. Citation Format: Margaux Poussard, Muhammad Zaeem Noman, Kris Van Moer, Jubayer Hossain, Ruize Gao, Ege Solel, Federico Grego, Lars Prestegarden, Rolf Bjerkvig, Bassam Janji. CY-101 inhibits the tumor growth and improves anti-PD-1 immunotherapy in beta-catenin-driven tumors [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 2231.