Cancer Therapy: Preclinical A Spontaneous Acinar Cell Carcinoma Model for Monitoring Progression of Pancreatic Lesions and Response to Treatment Through Noninvasive Bioluminescence Imaging

Purpose: We have generated an EL1-luc/TAg transgenic mouse model that develops spontaneous and bioluminescent acinar cell carcinomas. We applied this model to noninvasively monitor tumor development and drug response. Experimental Design: EL1-luc/TAg transgenic mice of 11 weeks of age were treated with rapamycin (5 mg/kg, i.p.) or vehicle for 6 to 12 weeks. Tumor development was monitored through bioluminescence imaging and necropsy at the study end point. Results: EL1-luc/TAg transgenic mice showed pancreas-specific bioluminescence signal before tumor progression and produced increasing light emission from the onset of the pancreatic acinar cell carcinomas. The latency of tumor development ranged from 10 to >20 weeks of age in these mice. Progression of the primary acinar cell carcinoma was accompanied by emergence of metastatic lesions in the abdominal organs, including liver and gastrointestinal fat tissues. Rapamycin treatment suppressed tumor development. Conclusions: The EL1-luc/TAg mouse provides a noninvasive approach for monitoring spontaneous acinar cell carcinoma development and comprises a convenient tool for the evaluation of novel therapeutics against pancreatic cancers. Tumor growth suppression through inhibition of the mammalian target of rapamycin pathway further validates this model as clinically relevant. Pancreatic cancer is one of the leading causes of cancer deaths in the United States, with a 5-year survival from the time of diagnosis of <5% (1). The aggressiveness, the lack of effective treatments, and late detection of only advanced symptomatic pancreatic cancers due to their anatomic location behind other organs contribute to such poor outcomes (2). Lack of effective treatment for pancreatic tumors prompted development of preclinical models for evaluation of novel therapeutics. Spontaneous mouse tumor models have been used for two decades in preclinical drug development to better understand many critical components of tumor development, such as tumor-stromal interactions, the role of the immune system, metastasis, angiogenesis, and tumor cell proliferation in immunocompetent animals (3–5). Most pancreatic epithelial neoplasms recapitulate to some degree one or more of the normal cell types of the pancreas: ductal, acinar, and endocrine. Most pancreatic neoplasms (>90%) have ductal differentiation, including the most common tumor, infiltrating ductal adenocarcinoma. The small group of “nonductal” pancreatic neoplasms includes endocrine and acinar neoplasms, as well as those with mixed or undetermined differentiation (6). Spontaneous pancreatic tumor models wherein tumor development in the acinar cells of the pancreas is mediated by expression of SV40 T antigens (7, 8) or mutant Kras (9) has been previously reported. These studies increased our understanding of the molecular, physiologic, and histologic aspects of tumorigenesis. However, the use of such models in the evaluation of novel therapeutics is complicated by the variable onset of pancreatic tumor development, as well as a lack of methods to assess tumor burden without sacrificing the animal. As a result, these models usually required relatively large cohorts of animals and extensive invasive endpoint analyses to produce statistically significant drug response data. Recent advances within the field of bioluminescence imaging have added a new tool for monitoring tumor development noninvasively in preclinical cancer models (10, 11). Bioluminescence imaging allows sensitive and rapid analysis of light emitted from luciferase-labeled cells and can be used to measure tumor burden from otherwise nonvisible deep tissue locations when caliper-based measurements are not possible. Firefly luciferase has been widely used as a bioluminescence reporter for in vitro and in vivo applications. Its activity is ATP and O2 dependent; thus, only viable cells bioluminesce. This approach allows the researcher to noninvasively measure Authors' Affiliations: Caliper Life Sciences, Alameda, California and Department of Molecular Imaging, Cancer Research UK, Cambridge Research Institute, Cambridge, United Kingdom Received 9/2/08; revised 4/23/09; accepted 4/27/09; published OnlineFirst