Abstract 5926: YB-1 inhibition as an effective approach for the treatment of osteosarcoma

Abstract Background: Osteosarcoma (OS) is a bone cancer primarily affecting adolescents and young adults, with about 20% of patients having detectable metastatic disease at the time of diagnosis. Despite a large number of clinical trial efforts, metastatic sarcoma remains a lethal disease, and there have been no meaningful advances in therapy or improvements in patient outcomes for decades. Y-box binding protein 1 (YB-1) is a multifunctional cold-shock protein that translationally activates diverse stress response factors with pro-metastatic activities in many cancer types. Importantly, YB-1 is strongly associated with poor outcomes in sarcoma patients and is a major metastatic driver in high-risk sarcomas. Methods: We recently described a novel compound, CET056, that inhibits cancer progression via YB-1 inhibition. We hypothesized that CET056 had the potential to suppress the progression of OS and could provide a new treatment for this disease. We screened osteosarcoma human and mouse cell lines for YB-1 protein expression. OS cells were functionally characterized for responses to CET056 in vitro and in vivo. Results: YB-1 expression was seen in nearly all cell lines tested. CET056 treatment of OS cells resulted in reduced cell viability and YB-1 protein expression in a dose- and time- dependent manner, as well as reduced formation of colonies and spheroids. In vivo efficacy studies, which employed a syngeneic subcutaneous tumor model, revealed that CET056 effectively inhibited tumor progression and enhanced overall survival in contrast to vehicle treated control mice. Conclusion: These results support our hypothesis and illustrate that YB-1 inhibition by CET056 is a promising candidate for further development as a therapy for OS. Citation Format: Kirsten Stefan, Arpit Dheeraj, Dhanir Tailor, Lara E. Davis, Sanjay V. Malhotra. YB-1 inhibition as an effective approach for the treatment of osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5926.