Pancreatic cancer is a lethal disease. Empirical development of new drugs has not resulted in any meaningful improvement in survival. New strategies are urgently needed to combat this disease. We have developed and optimized a low-passage xenograft model that may permit an individualized approach to the treatment of patients with pancreatic cancer. Fresh pancreatic cancer tissues obtained at the time of surgical resection are implanted in nude mice. Xenografted tumors can be treated with anticancer agent to determine their in vivo activity. In previous studies we have mastered this model and have obtained a high take on rate and excellent in vivo results. We have also shown that the xenografted tumors closely resemble at the histology, gene mutation, and selected gene expression levels the biological features of the primary tumor from which they were generated. Sucessive passage in mice does not influence the resistance/susceptibility properties of the tumors to the drugs we have preliminarily tested and does not result in mayor changes in biological features. Because tumors can be indefinitely propagated in the mice the model is also very well suited to investigate biological markers that predict response and/or resistance to drugs. This translational application is to utilize the above mentioned preclinical model to individualize the development of new drugs for patients with pancreatic cancer. The hypothesis to be tested is that model-based selection of drugs for patient's treatment will result in better outcome than expected with random selection. We propose the following three Specific Aims: 1) to determine the activity of a series of novel anticancer agents against a set of xenografted tumors obtained from patients with resected pancreatic cancer;b) to conduct a phase II clinical trial in which patients whose tumor was xenografted in the mice will be treated at the time of progression with model-selected new agents and;3) to explore biological markers of response to treatment agents in tumor tissues. We expect this approach will validate the use of the low-passage xenograft model to predict susceptibility to a drug. If correct, this model will then be invaluable to discover biomarkers predicting drug response and as a screening model to select drug for clinical development in pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129963-05
Application #
7912947
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (02))
Program Officer
Timmer, William C
Project Start
2007-09-21
Project End
2013-07-31
Budget Start
2011-09-15
Budget End
2013-07-31
Support Year
5
Fiscal Year
2011
Total Cost
$121,828
Indirect Cost
Name
Spanish National Cancer Center
Department
Type
DUNS #
465637457
City
Madrid
State
Country
Spain
Zip Code
28029
Martinez-Garcia, Raquel; Lopez-Casas, Pedro P; Rico, Daniel et al. (2014) Colorectal cancer classification based on gene expression is not associated with FOLFIRI response. Nat Med 20:1230-1
Ruppen-Cañás, Isabel; López-Casas, Pedro P; García, Fernando et al. (2012) An improved quantitative mass spectrometry analysis of tumor specific mutant proteins at high sensitivity. Proteomics 12:1319-27
Garrido-Laguna, Ignacio; Uson, Maria; Rajeshkumar, N V et al. (2011) Tumor engraftment in nude mice and enrichment in stroma- related gene pathways predict poor survival and resistance to gemcitabine in patients with pancreatic cancer. Clin Cancer Res 17:5793-800
Rajeshkumar, N V; De Oliveira, Elizabeth; Ottenhof, Niki et al. (2011) MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clin Cancer Res 17:2799-806
Von Hoff, Daniel D; Ramanathan, Ramesh K; Borad, Mitesh J et al. (2011) Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol 29:4548-54
Villarroel, Maria C; Rajeshkumar, N V; Garrido-Laguna, Ignacio et al. (2011) Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol Cancer Ther 10:3-8
Messersmith, Wells A; Rajeshkumar, N V; Tan, Aik Choon et al. (2009) Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts. Mol Cancer Ther 8:1484-93
Jimeno, Antonio; Feldmann, Georg; Suárez-Gauthier, Ana et al. (2009) A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development. Mol Cancer Ther 8:310-4
Jimeno, Antonio; Tan, Aik Choon; Coffa, Jordy et al. (2008) Coordinated epidermal growth factor receptor pathway gene overexpression predicts epidermal growth factor receptor inhibitor sensitivity in pancreatic cancer. Cancer Res 68:2841-9