Abstract A07: Identification of endocrine/metabolic biomarkers associated to early PDC in a transgenic mouse model
Authors: Valentina Pasquale, Erica Dugnani, Daniela Liberati, Paolo Marra, Tamara Canu, Antonio Esposito, Lorenzo Piemonti1
Journal: Cancer Research (2016)

Abstract Background: Pancreatic ductal adenocarcinoma (PDC) is a deadly disease, even surgery contributes little to survival if PDC is not diagnosed at an initial stage. Glucose homeostasis alteration associated to PDC was described to identify an high risk population for screening. Moreover the weight loss often manifests several months before cachexia. The crosstalk between metabolism and cancer could be a key to early diagnosis. Our aim is to find endocrine/metabolic biomarkers of early PDC development in a gold standard murine model. Materials and Methods: Candidate markers were investigated using LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse, a genetically-engineered model that develops PDC with 100% penetrance. KPC has been fed with standard diet (SD) or high fat diet (HFD) introducing a further risk factor for diabetes and metabolic alterations. To overcome the problem of asynchronous development of PDC in KPC, 7T-MRI was used to classify mice in actual pathological stage: normal (S1); cystic degeneration (S2); small tumor (S3) and advanced pancreatic cancer (S4). We performed metabolic test (OGTT) and serum endocrine/metabolic profile (xMAP technology and clinical biochemistry) in n=27 KPC (and control mice PDX-1 Cre) fed with HFD vs n=26 KPC (and control mice PDX-1 Cre) fed with SD. To prioritize markers we computed the ROC curve analysis. Results: i) Glucose metabolism: KPC were normoglycemic regardless of the diet; the AUC in OGTT increases in KPC fed with HFD (HFD vs SD: S1 p&amp;lt;0,001, S2 p&amp;lt;0,001, S3 p=0,002, Cre p&amp;lt;0,001) ii) Serum levels of 29 endocrine/metabolic biomarkers were assessed during disease progression. The more relevant results are: increase of PYY (p&amp;lt;0,003) and decrease of leptin (p&amp;lt;0,02), GIP (p&amp;lt;0.005) albumin (p&amp;lt;0.001) both in HFD and SD fed KPC (Cre vs S2); increase of amylase in stage 1 HFD-fed KPC (p=0,037). Moreover PYY was able to discriminate control from stage 2 KPC with an AUC=0,929 in the ROC curve analysis (p&amp;lt;0,001). Conclusions: Unlike human, in the mouse model the development of PDC is not associated with an hyperglycemic status, regardless of the diet. However KPC fed with HFD experience a mild impairment of glucose metabolism (as well as in control mice) and a mild pancreatic damage. Our results identify Leptin, PYY, GIP and albumin as markers of early stage PDC in a preclinical model with a diagnostic potential to be validated in human patients. Citation Format: Valentina Pasquale, Erica Dugnani, Daniela Liberati, Paolo Marra, Tamara Canu, Antonio Esposito, Lorenzo Piemonti1.{Authors}. Identification of endocrine/metabolic biomarkers associated to early PDC in a transgenic mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A07.