Abstract Purpose. Triple negative breast cancer (TNBC) is highly aggressive and heterogeneous with high rates of disease recurrence and poor treatment outcomes. The extra domain A of fibronectin (EDA-FN) is an extracellular matrix protein with high abundance in TNBC stroma and limited expression in healthy human tissues. Theranostic approaches have demonstrated improved patient outcomes by utilizing identical targeting vectors for patient stratification by targeted positron emission tomography imaging and radioligand therapy, however no targeted radiopharmaceuticals are currently approved for TNBC. Experimental Design. 89ZrZr-DFO-F8 and 177LuLu-CHX-A’’-DTPA-F8 were synthesized and characterized in vitro and in vivo for comparability in binding and biodistribution. Dosimetry estimation identified optimal dosing parameters for therapeutic benefit with limited off-target toxicities. 177LuLu-CHX-A’’-DTPA-F8 was assessed as a therapeutic against two triple negative breast cancer xenograft mouse models. Weekly health and hematological assessment with terminal serum chemistry and histopathology analysis was performed to evaluate toxicities. Results. 89ZrZr-DFO-F8 and 177LuLu-CHX-A’’-DTPA-F8 exhibited similar in vitro characteristics, and similar tumor accumulation in two different xenografted mouse models of triple negative breast cancer. 177LuLu-CHX-A’’-DTPA-F8 treatment significantly prolonged survival in both mouse models with only transient myelosuppression and off-target myelotoxicity only in Rag2-/- mice receiving the highest dose of radiolabeled F8 antibody, as determined by blood measurements and terminal histopathology. Conclusion. The 89Zr/177Lu theranostic nuclide coupling successfully identified triple negative breast cancer xenografts, and significantly extended survival of xenografted mice.
Hachey et al. (Thu,) studied this question.
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