Pancreatic cancer is an aggressive disease without currently effective therapies and with poor prognosis. The ability to develop improved therapies for this invariably fatal disease would benefit significantly from animal models that recapitulate the disease in patients and allow for non-invasively monitoring and following pancreatic ductal adenocarcinoma (PDAC) development and progression. Investigators studying PDAC biology and therapy extensively use the KPC transgenic mouse, which contains an activated K-ras oncogene and deletion of one or both p53 tumor suppressor genes in the pancreas. This animal model follows the course of the human disease and thereby provides a useful and potentially predictive system for evaluating therapeutic intervention. However, as with human patients, this mouse shows great variability in the timing and kinetics of tumor development and effectively monitoring tumor and metastatic growth is challenging. Our research seeks to remedy this situation and develop a PDAC model permitting more accurate staging and evaluation of therapy than the existing KPC mouse model. We tested the hypothesis that integrating a cancer-selective promoter driving the luciferase reporter gene, a CCN1-Luc gene construct, in all tissue of a transgenic mouse could serve as a means of imaging primary tumors and metastases non-invasively by bioluminescence imaging (BLI) following crossing of the CCN1-Luc mouse with the KPC mouse. Proof-of-principle has been obtained with several double transgenic animals, CCN1-Luc-KPC mice, indicating that administering luciferin allows for detection of primary tumors and metastases by BLI, as confirmed by fluorescence in isolated organs and immunohistochemistry (IHC). These results are innovative and significant, supporting further studies using this unique double transgenic mouse model, called PanMetView or PMV mice, to evaluate PDAC development and progression to metastasis, and the potential of therapy to impact on these processes. Studies characterizing the PMV mouse model will be performed in Specific Aim 1 of our grant. To confirm utility of the PMV mice for evaluating therapeutic intervention, we have chosen a novel therapeutic approach that involves delivery of polyinosinic-polycytidylic acid (pIC), a synthetic dsRNA that activates the immune system and when administered into the cytosol of cancer cells, using polyethyleneimine (PEI), [pIC]PEI, causes apoptosis and toxic autophagy. Preliminary studies indicate that [pIC]PEI displays potent pancreatic antitumor effects in vitro as well as in multiple immune deficient animal models in vivo, including xenografts and quasi-orthotopic administration of human pancreatic cancer cells. Proof-of-principle for therapeutic efficacy of [pIC]PEI in the PMV mice will be tested in Specific Aim 2 of our grant. Successful completion of our studies will be transformative in how PDAC is studied using transgenic mice with wide applications as a global technique for generating double transgenic mice to follow development, progression and therapy in other cancer models.
Despite medical advances including new pathway-targeted drugs, pancreatic cancer remains a very aggressive neoplasm without long-term effective therapies. Improved genetically engineered mouse (GEM) models hold significant promise for defining the mechanism of pancreatic cancer development and progression, as well as systems for evaluating new cancer therapeutics. Studies focus on developing and evaluating the next generation of GEMs in which animals are created that can recapitulate pancreatic cancer as observed in patients and also contain a gene encoding a reporter that allows visualization of primary tumor development and metastasis non-invasively through bioluminescence imaging.
|Menezes, M E; Das, S K; Minn, I et al. (2016) Detecting Tumor Metastases: The Road to Therapy Starts Here. Adv Cancer Res 132:1-44|
|Quinn, Bridget A; Lee, Nathaniel A; Kegelman, Timothy P et al. (2015) The Quest for an Effective Treatment for an Intractable Cancer: Established and Novel Therapies for Pancreatic Adenocarcinoma. Adv Cancer Res 127:283-306|
|Wu, Bainan; Wang, Si; De, Surya K et al. (2015) Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells. Chem Biol 22:876-887|
|Quinn, Bridget A; Dash, Rupesh; Sarkar, Siddik et al. (2015) Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline. Cancer Res 75:2305-15|
|Bhoopathi, Praveen; Quinn, Bridget A; Gui, Qin et al. (2014) Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine-polycytidylic acid. Cancer Res 74:6224-35|