Abstract LB321: Identification of a novel mode of action and scaffold for modulation of cancer-associated fibroblast through Chip-seq analysis

Abstract

Abstract Cancer microenvironment (CME) possess a crucial function in tumor mass, in which it control tumor growth, progression, metastasis, and even chemotherapy resistance. The CME is a complex and dynamic system that is an integral part of the entire tumor. Among the components of CME, in particular, CAFs promote cancer progression and directly stimulate cancer cell proliferation. Thus, targeting CAF would be a promising approach for the treatment of cancer. Looking at models of the evolution of CAFs during tumor progression, CAFs have heterogeneous and dynamic properties. Tumor progression may be associated with a decrease in the tumor inhibitory CAF/tumor supporting CAF ratio, with tumor inhibitory CAF occurring at the highest levels in early tumor stages in response to tumor emergence and gradually switching to tumor support CAFs towards tumor progression/metastatic process. In other words, in order to suppress solid tumors accompanied by desmoplastic stroma, it is necessary to regulate CAFs, a key component. We performed ChiP-seq using an antibody against H3k27ac with CAFs that have a strong ability to promote cancer and NFs that do not. As result, we identified a novel mode of action and scaffold (ARC2-002 and ARC2-003) for modulating CAF via suppressing CAF proliferation, contraction, and collagen deposition. Finally, through 3D co-culture, we confirmed that the two novel scaffolds had excellent anticancer effects when administered alone as well as in combination with an existing anticancer drug. The compounds identified in this study may represent a new therapeutic agent targeting fibroblasts with abnormal activation, and their efficacy may be increased when combined with existing anticancer drugs. Citation Format: So-Young Yeo, Mohamed Farh, InSuk Sohn, Seok-Hyung Kim, Keun-Woo Lee. Identification of a novel mode of action and scaffold for modulation of cancer-associated fibroblast through Chip-seq analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB321.