SBIR FY25 CONCEPT AWARD, TARGETING PLOD2 IN UNDIFFERENTIATED PLEOMORPHIC SARCOMA

Soft tissue sarcoma (STS) comprises a group of rare tumors accounting for ~1% of adult cancers. Undifferentiated pleomorphic sarcoma (UPS) is a relatively common and aggressive STS subtype predominantly arising in adult skeletal muscle. UPS and other sarcomas feature extensive deposition of extracellular matrix (ECM) proteins, which is associated with tumor progression, therapeutic resistance, and poor clinical outcomes. However, these features have not been targeted for therapeutic intervention. We propose to pursue collagen-interacting proteins as novel targets in UPS. Overexpression of the collagen lysine hydroxylase PLOD2 promotes tumor progression, T cell dysfunction, and immune evasion in human UPS. Reinforcing its potential as a target, PLOD2 expression correlates with poor human UPS patient survival. Thus, the overall goals of this proposal are to 1) validate PLOD2 as a therapeutic target and 2) use Cell Painting, a machine learning-driven phenotypic assay, to identify chemical starting matter for development of a PLOD2-targeting small molecule inhibitor. PLOD2-targeting compounds will then be evaluated in novel in vitro models of the UPS microenvironment and in vivo, setting the stage for future medicinal chemistry optimization and IND-enabling studies. This work will define a new class of novel therapeutic strategies for UPS/STS, and potentially other matrix-rich tumors.