The role of preclinical models in radiopharmaceutical therapy

Radiopharmaceutical therapy (RPT) is a treatment modality that involves the use of radioactively labeled targeting agents to deliver a cytotoxic dose of radiation to tumor while sparing normal tissue. The biologic function of the target and the biologic action of the targeting agent is largely irrelevant as long as the targeting agent delivers cytotoxic radiation to the tumor. Preclinical RPT studies use imaging and ex vivo evaluation of radioactivity concentration in target and normal tissues to obtain biodistribution and pharmacokinetic data that can be used to evaluate radiation absorbed doses. Since the efficacy and toxicity of RPT depend on radiation absorbed dose, this quantity can be used to translate results from preclinical studies to human studies. The absorbed dose can also be used to customize therapy to account for pharmacokinetic and other differences among patients so as to deliver a prespecified absorbed dose to the tumor or to dose-limiting tissue. The combination of RPT with other agents can be investigated and optimized by identifying the effect of other agents on tumor or normal tissue radiosensitivity and also on how other agents change the absorbed dose to these tissues. RPT is a distinct therapeutic modality whose mechanism of action is well understood. Measurements can be made in preclinical models to help guide clinical implementation of RPT and optimize combination therapy using RPT.