Pancreatic cancer medicine in mice.

CS04-02

Pancreatic ductal adenocarcinoma (PDA) is a common and extremely lethal malignancy that eludes early detection and is refractory to current therapies. This grim situation prompted a "think tank" conference to convene in 1999 to discuss the biology and therapy of human pancreatic cancer and prioritize areas for future research. A primary recommendation emanating from this conference was that relevant animal models of pancreatic cancer are needed to explore the biology of pancreatic cancer and accelerate the pace of discovery (1).

Accordingly, our laboratory has produced two mouse models of early and advanced PDA through endogenous gene targeting in embryonic stem cells. First, a model of Pancreatic Intraepithelial Neoplasia (PanIN) was generated by expressing an oncogenic Kras^G12D allele in the developing pancreas (2). Murine PanINs shared similar biochemical and cellular features of human PanIN, and were present across the entire spectrum of human PanIN. Mice with PanIN slowly developed and succumbed to invasive and metastatic PDA with a median survival of 16 months, confirming that PanINs are the preinvasive state for PDA. This model is appropriate for the development of novel detection methods for PanIN and the evaluation of potential chemoprevention modalities for PDA. Second, a distinct model of metastatic PDA was generated by concomitantly expressing oncogenic Kras^G12D and a mutant Trp53^R172H allele in the developing pancreas (3). By all available criteria, this model closely mimicked the cognate human condition. In particular, heterogeneous molecular and histological features prompted the discovery that chromosomal instability (CIN) was present in this model, a process postulated to play a causal role in human epithelial tumorigenesis. This model is a suitable platform for the investigation of potential therapeutic strategies in PDA. Indeed, we have evaluated Gemcitabine, the standard of care systemic agent for advanced PDA, and find that this agent demonstrates preferential activity in ectopic tumor models as compared to our autochthonous model. Given their obvious utility in basic tumor biological studies and the aforementioned preclinical applications, these models should contribute meaningfully to tremendous progress in PDA cancer medicine over the next several years.

1. Kern S, Hruban R, Hollingsworth MA, et al. A white paper: the product of a pancreas cancer think tank. Cancer Res 2001;61:4923-4932.

2. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4:437-450.

3. Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005;7:469-483.