Biomarkers For Sensitivity To Gamma Secretase Inhibitors In Mouse Models Of Pancreatic Adenocarcinoma

Background: The Notch pathway is important in carcinogenesis and maintenance of pancreatic adenocarcinoma through its effects on cancer stem cells, cell differentiation and neoangiogenesis. RO4929097 is a novel oral inhibitor of the Notch pathway through its effects on γ-secretase, a key enzyme in this pathway. Several clinical trials are currently in progress with RO4929097 including a CTEP sponsored phase II trial in gemcitabine resistant metastatic pancreas cancer by our group. However, there are no biomarkers of sensitivity available currently for therapy with RO4929097 or other γ-secretase inhibitors (GSIs). Methods: We intend to treat 12 human pancreas cancer cell line mouse xenografts and 6 human primary pancreas tumor explants with RO4929097 (alone or in combination with gemcitabine) to identify sensitive (defined as tumors with ≥ 50% relative tumor growth inhibition with treatment) and resistant tumors. Subsequently, we propose to identify differences in gene expression by RT-PCR (Notch pathway), gene array or gene copy number by FISH between the resistant and sensitive tumors as potential biomarkers. Results: Of the eight pancreas cell line xenografts treated so far, four are sensitive to RO4929097. Comparison between sensitive and resistant tumors by gene array suggests that the sensitive cell lines exhibit higher levels of mesenchymal markers. In addition, two of the four human primary pancreatic explants treated thus far show intermediate sensitivity. RO4929097 in combination with gemcitabine in the four explants reveals a significant decrease in tumor growth inhibition for the combination compared to RO4929097 alone but the additive effect appears to be entirely due to gemcitabine. Similar effects were observed on tumor regrowth, upon observation after an initial period of treatment with either agents alone or in combination. In addition, future experiments to identify stem cell and/or angiogenesis specific biomarkers are also planned. Updated results will be presented at the meeting. Acknowledgements: This work was supported by Roche Pharmaceuticals 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 5050. doi:10.1158/1538-7445.AM2011-5050