| Colorectal cancer (CRC) continues to be one of the most prevalent cancers and leading causes of cancer-related deaths in Western societies. Molecule-targeted therapies are being developed and tested in preclinical and clinical studies, with some promising results. One such class of therapeutics targets EGFR signaling, a pathway often deregulated in epithelial cancers. While these inhibitors have shown some effectiveness in clinical trials, the results have not been as promising and consistent as those reported in preclinical trials. The current study addresses these inconsistencies, expanding preclinical investigation to include multiple mouse models, genetic strains, and diet in an effort to better predict human response to these therapies. Two mouse models for CRC, ApcMin/+ and AOM, are used on distinct inbred strains as well as a shared F1 strain and are maintained on either a standard mouse chow (STD) or Western-style diet (WD). The efficacy of small molecule EGFR inhibitor AG1478 varies with respect to model, strain and diet. Additionally, human dietary supplementation is addressed, assessing the effect of supplementing a Western-style diet with high levels of calcium on AG1478 treatment of CRC. The two mouse models mentioned as well as an in vitro system including two human CRC cell lines, Caco-2 and HCT116, were used to evaluate the impact of low (0.05%) versus high (5%) calcium in vivo and increasing calcium concentrations in vitro (0.424--5.5mM) on AG1478-mediated tumor reduction. Calcium consistently impacts AG1478 with an additive effect on tumor growth reduction across each model system, however, with potentially toxic side effects in vivo. In addition, gender influences are revealed in response to diet and AG1478 inhibition of EGFR activity. We conclude that the diet consumed during cancer treatment, including the use of dietary supplements, may impact response to conventional therapies, and that understanding gene-environment-therapy interactions will be critical in developing and testing new therapies for CRC. |
