The low rate of approval of novel anti-cancer agents underscores the need for better preclinical models of therapeutic response as neither xenografts nor early-generation genetically engineered mouse models (GEMMs) reliably predict human clinical outcomes. Whereas recent, sporadic GEMMs emulate many aspects of their human disease counterpart more closely, their ability to predict clinical therapeutic responses has never been tested systematically. We evaluated the utility of two state-of-the-art, mutant Kras-driven GEMMs—one of non-small-cell lung carcinoma and another of pancreatic adenocarcinoma—by assessing responses to existing standard-of-care chemotherapeutics, and subsequently in combination with EGFR and VEGF inhibitors. Standard clinical endpoints were modeled to evaluate efficacy, including overall survival and progression-free survival using noninvasive imaging modalities. Comparisons with corresponding clinical trials indicate that these GEMMs model human responses well, and lay the foundation for the use of validated GEMMs in predicting outcome and interrogating mechanisms of therapeutic response and resistance.
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We would like to thank S. Kelsey, J. Hambleton, O. Rosen, S. Erickson, F. Borellini, D. Colburn and G. Evan for critically evaluating the manuscript as well as F. de Sauvage, B. Mass and M. Benyunes for invaluable input. J. Bower, V. Javinal, A. Arrazate, L. Nguyen and A. Wong provided excellent technical assistance. We also received extensive and able technical support from the in-house genotyping and murine reproductive technology core groups. A special note of gratitude to H. Wong, L. Salphati, B. Liederer and L. Damico for pharmacokinetic support and analyses. L. Berry and B. Hollister supervised the xenograft studies shown here. B. Tong, J. Yi and J. Wacker provided statistical information and feedback. The graphics and layout were ably provided by J. Wood and D. Wood.
The authors are current or past employees of Genentech, Inc. and/or may have stocks or shares in Roche, Inc.
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Singh, M., Lima, A., Molina, R. et al. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nat Biotechnol 28, 585–593 (2010) doi:10.1038/nbt.1640
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