Validation of a panel of fibroblast activation protein expressing cell line derived xenograft models as a platform for the development of targeted radioligand therapeutics

Targeted radioligand therapy (RLT) has emerged as a promising strategy for precision oncology, enabling selective tumor targeting while reducing collateral damage to healthy tissue. A major challenge in advancing novel RLT agents, however, is the limited availability of well-validated preclinical models for assessing target-specific efficacy. Fibroblast Activation Protein (FAP), a membrane-bound protein with minimal expression in normal tissues but high prevalence in cancer-associated fibroblasts and glioblastoma (GBM) cells, represents an attractive therapeutic target. FAP-2286, a FAP-binding peptide radiolabeled with lutetium-177 ( 177 Lu), offers potential as both an imaging and therapeutic agent. In this study, we evaluate target expression and compare the anti-tumor efficacy of 177 Lu-FAP-2286 across multiple immunocompromised mouse models bearing subcutaneous, cell line-derived tumors. Our findings underscore the critical role of model selection in preclinical development and highlight its importance for rational decision-making in RLT programs.