(P 125) TARGETING LCP1-MEDIATED METASTASIS IN CHONDROSARCOMA WITH OROXYLIN A

Objective: Chondrosarcoma, the second most common bone sarcoma, is chemo/radiotherapy-resistant. Standard treatment, en-bloc resection, is often ineffective for metastatic disease, highlighting an urgent need for new therapies. Our lab linked dysregulated actin-binding protein LCP1 to metastatic cell behavior. We aimed to validate LCP1 as a metastatic driver and assess LCP1 inhibition, specifically with oroxylin A, to suppress chondrosarcoma metastasis.

Methods: To confirm LCP1's role, two patient-derived high-grade metastatic chondrosarcoma cell lines (725 & 731) underwent CRISPR/Cas9 LCP1 knockout (KO), confirmed by western blot. LCP1 KO effects were assessed via in vitro assays (viability, wound healing, invasion). In vivo, metastatic mouse models compared lung tumor burden and bioluminescent signaling (14 weeks post-tail-vein injection) of luciferase-labeled wild-type (WT) vs. KO cells in immunodeficient mice. Pharmacologic inhibition with 50 µM oroxylin A was assessed in WT cells via functional assays.

Results: In vitro, LCP1 KO significantly impaired chondrosarcoma cell migration and invasion without affecting viability. Scratch wound assays showed reduced motility (725: p=0.0003; 731: p< 0.0001). Invasion assays showed reduced invasive potential (725: p< 0.001; 731: p< 0.01). In vivo, LCP1 KO tumors showed reduced bioluminescent signal (p=0.0026) and lower lung metastatic burden at 14 weeks. Oroxylin A similarly suppressed migration (p < 0.0001) and invasion (p < 0.0001) without affecting viability

Conclusion: LCP1 is a key mediator of chondrosarcoma metastatic migration and invasion, in vitro and in vivo. Pharmacologic LCP1 inhibition with oroxylin A effectively mimicked LCP1 KO's anti-metastatic phenotype, crucially without impacting cell viability. LCP1 is a druggable driver of chondrosarcoma metastasis. Oroxylin A is a promising therapeutic candidate to prevent or delay metastatic disease progression.