Abstract 1592: Targeting proliferative signals in patient-derived pancreatic cancers propagated orthotopically in immunocompromised mice
Authors: Walters Dustin M. , Cowan Catharine R. , Adair Sara J. , Borgman Cheryl A. , Stokes Jayme B. , Stelow Edward B. , Lowrey Bryce T. , Gilmer Tona M. , Parsons J. Thomas , Bauer Todd W. 
Published: June 2012

Pancreatic ductal adenocarcinoma (PDAC) is associated with the shortest survival duration of any solid cancer. To improve treatment for this disease, better understanding of the proliferative signals that drive pancreatic cancer progression is imperative. To this end, we have established a transplantation model in which surgically resected human pancreatic cancers are propagated orthotopically in the pancreas of immunocompromised mice, permitting detailed molecular and cellular analysis. Approximately 70-85% of engrafted tumors grow and can be serially propagated in multiple generations of mice. Tumor architecture, desmoplastic character, and the metastatic properties of tumors are preserved between the original patient tumor and orthopically propagated tumors. The initial cohort of tumors reported herein was comprised of 4 early stage (Ib/IIb) and 3 late stage (IV) tumors. Five of 7 tumors had KRAS mutations in codon 12. Interrogation of tumor lysates with phospho-receptor tyrosine kinase arrays (R & D Systems) revealed activation of EGFR in all tumors, ERB2/HER2 receptors in 2 of 7 tumors, FGFR1/3 in 6 of 7 tumors, and Tie-2 receptor in 4 of 7 tumors. Based on the ubiquitous expression of EGFR family receptors and the presence of activated KRAS we assessed the efficacy of EGFR and MEK inhibitors on pancreatic cancer cell growth in culture and in the orthotopic xenograft model. A subset of patient-derived tumors adapted for growth in cell culture as well as 4 well established PDAC cell lines (MPanc96, L3.6pl, BxPC-3, PANC-1) were treated with erlotinib (EGFR inhibitor) or lapatinib (EGFR/HER2 inhibitor) and cell proliferation was assessed in a 5 day growth assay. None of the pancreatic cancer cell lines exhibited significant growth inhibition to either drug at concentrations known to be inhibitory in a sensitive cell line, SKBr3. In contrast, treatment of the pancreatic cancer cells with lapatinib in addition to a MEK inhibitor, GSK1120212, significantly inhibited cell growth in all but one of the cell lines tested. Three patient-derived tumors, including both KRAS wild type and mutant tumors, were tested in the orthotopic xenograft model for sensitivity to lapatinib, GSK1120212, or the combination of the two inhibitors. Treatment with lapatinib induced modest inhibition of tumor growth (approximately 30-50%), GSK1120212 treatment led to an approximate 60-80% reduction in tumor volume, whereas treatment with both lapatinib and GSK1120212 led to tumor regression in two tumors and greater than 80% inhibition in another. These data indicate that simultaneous inhibition of the EGF receptor and MAP kinase pathways may prove efficacious in inhibiting tumor proliferation in some primary PDACs. The effectiveness of this approach in inhibiting growth of other patient-derived tumors is under study. Supported by funding from NCI, ACS and UVa Cancer Center.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1592. doi:10.1158/1538-7445.AM2011-1592