10177-CB-5 Cracking the Code of ZFTA Ependymoma: L1CAM-YAP1 Signaling as a Druggable Pathway

Abstract ZFTA fusion-positive ependymomas, which account for approximately 70% of supratentorial ependymomas, are highly aggressive tumors with extremely poor prognosis. Despite their clinical severity, no effective molecularly targeted therapies are currently available, highlighting the urgent need for new therapeutic strategies. In 2021, we identified a set of ZFTA fusion genes essential for tumor initiation and proposed GLI2 as a common downstream effector and potential therapeutic target (Zheng et al. Cancer Discovery 2021). However, translation into clinical application remains challenging. In this study, we focused on L1CAM, a membrane protein transcriptionally regulated downstream of ZFTA fusions, as a novel therapeutic candidate. Silencing L1CAM significantly suppressed tumor cell proliferation and induced apoptosis in ZFTA ependymoma cells. To uncover the underlying mechanisms, we performed high-throughput drug screening using an FDA-approved drug library and identified involvement of the Hippo pathway, specifically implicating YAP1 as a downstream effector of L1CAM signaling. Using patient-derived xenograft (PDX) models of ZFTA ependymoma, in vivo knockdown of L1CAM by shRNA reduced YAP1 expression and its nuclear localization, thereby attenuating transcriptional activity of YAP1 target genes. Furthermore, pharmacological inhibition of YAP1 alone effectively suppressed tumor growth, establishing a proof-of-concept (POC) for targeting this pathway. Ongoing studies are now investigating the potential synergistic effects of combining YAP1 inhibition with radiotherapy. In this presentation, we will share our latest findings supporting the L1CAM-YAP1 axis as a promising and druggable pathway in ZFTA fusion-positive ependymoma.