TORward AKTually useful mouse models


For over half a century, the preclinical evaluation of cancer therapeutics has relied on cancer cell lines and patient tumor samples implanted into immunodeficient mice. Though these cancer models provide a convenient and unlimited source of human cancer cells in which to compare the potency of various chemotherapeutics, their genetic complexity and variability has limited their utility for predicting outcome in patient trials. In recent years the US National Cancer Institute has orchestrated a large effort by academic institutions to develop mouse models to allow the systematic study of human carcinogenesis1. How these genetically engineered mouse models, burdened by high breeding costs and phenotypes of variable onset and penetrance, can be integrated into the streamlined process of drug development remains an important question for the cancer community. A study by Majumder et al.2 in this issue suggests that these models could play an important role in the discovery of biomarkers—molecular signatures of the effect of a drug on a tumor—which are currently the Achilles heel for optimal clinical deployment of many targeted agents. In the transgenic mouse model used for this study, an activated allele of the serine/threonine kinase Akt was selectively expressed in the ventral prostate. This expression resulted in a highly penetrant prostate intraepithelial neoplasia (PIN) phenotype, a prostate cancer precursor lesion characterized by epithelial cell hyperplasia, abnormal cell morphology and disorganization of the luminal architecture. Encouraged by the previous observation that the kinase mammalian target of rapamycin (mTOR) mediates Akt-driven cellular prolifer-

DOI: 10.1038/nm0604-579

Cite this paper

@article{Mellinghoff2004TORwardAU, title={TORward AKTually useful mouse models}, author={Ingo K. Mellinghoff and Charles L Sawyers}, journal={Nature Medicine}, year={2004}, volume={10}, pages={579-580} }