(P 59) TARGETING ADORA2B TO HALT METASTASIS IN UNDIFFERENTIATED PLEOMORPHIC SARCOMA: FROM MULTI-OMICS TO THERAPEUTIC INHIBITION

Objective: Undifferentiated pleomorphic sarcoma (UPS) is an aggressive soft tissue sarcoma with poor prognosis, especially in metastatic cases. The biological mechanisms underlying metastasis remain poorly defined, hindering therapeutic progress.The aim of our study was to elucidate these mechanisms with the goal of use them for therapeutic purposes.

Methods: We employed a multi-omics approach to analyze matched primary and metastatic UPS tumor samples. Spatial transcriptomics, bulk RNA sequencing, and computational deconvolution analyses were used to explore molecular pathways and immune microenvironment alterations associated with UPS metastatic evolution. We identified interesting potential therapeutic targets and we performed functional validation, including CRISPR-Cas9-mediated gene knockouts in UPS cell lines and in vivo tumor models. To explore therapeutic relevance of one of the most interesting target we found, we tested a pharmacological inhibitor, currently in early-phase trials for advanced solid tumors.

Results: Transcriptomic profiling revealed enrichment of hypoxia, epithelial-mesenchymal transition (EMT), and immune-suppressive pathways in metastatic UPS. Among these, ADORA2B emerged as a key driver, with elevated expression correlating with shorter disease-free survival. Loss-of-function studies demonstrated that ADORA2B promotes cell proliferation, migration, invasion, and extracellular matrix remodeling via metalloprotease regulation. Pharmacological inhibition with M1069, a dual ADORA2A/ADORA2B inhibitor, recapitulated these effects in vitro, significantly reducing UPS cell proliferation, migration, and invasion. ADORA2B knockout also impaired tumor growth and metastasis in vivo. Ongoing in vivo experiments with M1069 will provide further insight into its translational potential and suitability for clinical evaluation in UPS.

Conclusion: Our findings identify ADORA2B as a central regulator of metastatic progression in UPS and support adenosine signaling as a viable therapeutic target. The efficacy of the dual ADORA2A/ADORA2B inhibitor M1069 reinforces its potential as a candidate for future clinical trials in UPS patients.
Even more, our transcriptomic analyses provide a large database for further target identification.