Targeting Extra Domain A of Fibronectin to Improve Noninvasive Detection of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) lags behind other breast cancer types in targeted therapeutic and diagnostic imaging agent development, largely due to high disease heterogeneity. Noninvasive imaging is essential for diagnosing and staging TNBC and predicting and measuring treatment response. This study targeted a conserved disease-specific extracellular matrix protein domain (the extra domain A of fibronectin [EDA-FN]), with a monoclonal antibody (F8) to overcome tumor cell marker heterogeneity and develop an imaging agent to detect multiple TNBC subtypes and improve diagnostic capacity. Methods: [89Zr]Zr-desferrioxamine [DFO]-F8 was synthesized and evaluated in vitro and in vivo for EDA-FN binding capacity to detect TNBC by PET/CT in several preclinical xenograft models. Results: [89Zr]Zr-DFO-F8 exhibited specific, blockable EDA-FN binding activity in vitro. In vivo experiments demonstrated high tumor uptake in preclinical TNBC xenograft models. [89Zr]Zr-DFO-F8 detected EDA-FN in subcutaneous and orthotopic TNBC xenografts and accumulated in aggressive disease concordantly with EDA-FN expression. Conclusion: EDA-FN imaging with [89Zr]Zr-DFO-F8 exhibits powerful tumor delineation in preclinical tumor delineation across TNBC molecular subtypes in vivo.