Abstract A060 Investigating underlying efficacy and mechanism of action of the KIF11 inhibitor filanesib in Ewing and clear cell sarcomas

Abstract Ewing (ES) and clear cell (CCS) sarcomas are bone and soft tissue malignances and in advanced and relapsed disease overall survival rates remain dismal. For metastatic ES, five-year survival rates are between 15% and 30%. In CCS, the five-year survival rates are between 30% and 67%. Accordingly, there is a critical need for the development of novel targeted therapeutics for the treatment of these rare cancers. Both cancers are driven by fusion proteins; EWS-FLI1 in ES and EWS-ATF1 in CCS, which arise from separate chromosomal translocations: t(11;22)(q24;q12) and t(12;22)(q13;q12) respectively. Current approaches for developing new treatments focus on targeting the fusion proteins or their downstream targets. We performed a small molecule compound library screen of clinically used drugs and identified ES and CCS cells to be extremely sensitive to filanesib, a kinesin spindle protein (KIF11) inhibitor. KIF11 is known to play roles in cell cycle progression and mitotic spindle stability. Our preclinical efficacy studies demonstrated that filanesib promotes potent tumor growth inhibition in both EWS-FLI1 and EWS-ATF1 xenograft models in mice. We are currently investigating the mechanism underlying the relationship between KIF11 and EWS-FLI1 and EWS-ATF1. Prior studies have identified KIF11 within a EWS-ATF1 transcriptional complex and KIF11 has been shown to interact with the histone acetyltransferase (HAT) p300/CBP-Associated Factor (PCAF). HATs are necessary components for chromatin remodeling, which the oncogenic fusion proteins regulate. Future research directions involve elucidating the role of KIF11 in regulating the EWS-ATF1 and EWS-FlI1 transcriptional complexes. Additionally, to further improve the therapeutic response to filanesib, we are investigating potential synergistic relationships with other compounds. This work has been supported in part by the Flow Cytometry and the Molecular Genomics Cores at the H. Lee Moffitt Cancer Center & Research Institute, a comprehensive cancer center designated by the National Cancer Institute and funded in part by Moffitt’s Cancer Center Support Grant (P30-CA076292) Citation Format: Hannah L. Walker-Mimms, Nicole Londono, Yi Liao, Neelkamal Chaudhary, Mingxiang Teng, Fumi Kinose, Xueli Li, Andrii Monastyrskyi, Uwe Rix, Derek Duckett. Investigating underlying efficacy and mechanism of action of the KIF11 inhibitor filanesib in Ewing and clear cell sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A060.