91P Targeting leucine-rich repeat-containing protein 15 (LRRC15): SOT106 antibody-drug conjugate for soft tissue sarcoma and osteosarcoma therapy

Methods: Kaplan-Meier survival and pathway analysis was conducted on publicly available soft tissue (TCGA) and osteosarcoma (TARGET) RNAseq datasets using R. Patient data was dichotomised into low DMD and high DMD expressing groups.Functionally, we characterised DMD expression across a panel of sarcoma cell lines as well as the effect of Dp71 variant overexpression on various cellular functions including proliferation.Results: For both SARC (P 0.031) and OS (P 0.0015), overall survival was improved in patients expressing high DMD.Isoform level data was available for SARC and revealed that Dp40, Dp71a, Dp71ab and Dp427m were highly expressed.Significant survival differences were found for Dp40 (P 0.023) and Dp71a (P0.034).In functional experiments cell lines were transfected with plasmids containing Dp71a and Dp71ab and for the OS cell line U2OS, Dp71ab overexpression resulted in reduced cellular proliferation (P0.0057).Differentially expressed genes (DEGs) for SARC were enriched for GO terms highlighting myogenesis.This included sarcomere structure and function with key components including the I band, Z disc, myofibrils, and actin binding.A 35-gene set identified through WGCNA differentiated DMD-high and DMD-low tumours in SARC, suggesting distinct molecular profiles linked to dystrophin expression and its potential role in tumour biology.The GO terms for OS highlighted immune processes, membrane components, and signalling activities, emphasising the role of immune regulation and transmembrane signalling in its biology.Conclusions: This study demonstrates a significant association between high DMD expression and better survival outcomes in SARC and OS patients.We are exploring these mechanisms by developing novel 3D sarcoma models using bio-printed scaffolds and microdroplets.These findings underscore a potential role for DMD in the pathogenesis of sarcoma.