Preclinical In Vivo Evaluation of Novel Radiosensitizers by Local Tumor Control Experiments

Screening and Validation of Molecular Targeted Radiosensitizers

“…9,15,16 The preclinical evaluation of drug and radiation effects is challenging because of the need to measure the probability of local tumor control (tumor control probability [TCP]), integrate standard-of-care chemotherapy, and model the impact of the microenvironment. 62 Mouse models for the study of radiosensitizing agents have been reviewed recently, 63,64 and some controversy exists regarding the best in vivo models for this purpose. Every model has strengths and shortcomings, but heterotopic xenografts in nude mice have distinct advantages in that they readily allow testing of tumors from different genomic backgrounds, such as those derived from screened cell lines, and assessments of local control after fractionated radiation therapy.…”

“…The specific endpoint of tumor growth delay (TGD) compares the different times needed for treated (eg, drug plus radiation) versus control (radiation) tumors to reach a specified volume. 64 TGD is suitable for studies such as initial drug screening, proof-of-concept experiments, and investigations of mechanism of action or pharmacodynamics. 64 However, standard TGD experiments are able to assess only the treatment effects on bulk tumor cell kill, but not the inactivation of CSCs or clonogenic tumor cells.…”

“…64 TGD is suitable for studies such as initial drug screening, proof-of-concept experiments, and investigations of mechanism of action or pharmacodynamics. 64 However, standard TGD experiments are able to assess only the treatment effects on bulk tumor cell kill, but not the inactivation of CSCs or clonogenic tumor cells. Because of this limitation, TGD studies might fail to predict the ability of a targeted drug to improve local tumor control in patients, which requires eradication of all CSCs or clonogenic tumor cells that could give rise to a local recurrence.…”

“…In vivo validation of screening "hits" remains indispensable for rational drug development, and science-based choices regarding the most appropriate tumor and mouse models and experimental endpoints, including normal tissue toxicity, need to be made. 64 Because of the importance of local tumor control in the clinic, TCD50 experiments are invaluable for assessing the efficacy of targeted radiosensitizers. Furthermore, the design of these studies should consider intertumoral heterogeneity, include biomarker assessment, and incorporate clinically relevant dosing and scheduling of drug and radiation regimens to achieve a suitable preclinical body of data for further optimization and clinical translation of the most promising candidate drugs.…”

“…These curves are similar to dose-response relationships observed previously in patients. 64 The radiation dose needed to cure 50% of the mice can then be calculated (TCD50, tumor control dose 50%). The dose-modifying factor, which is calculated from the TCD50 values of different dose-response curves, represents the decrease in radiation dose after adding a drug to reach the same TCP compared with radiation alone.…”