An integrated strategy using a serum and imaging biomarker for the early detection of pancreatic cancer.

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 6% and diagnosis at an earlier resectable stage improves survival rates: andgt; 30% for node negative tumors andlt; 2 cm; up to 60% for tumors andlt; 1 cm; and, essentially curative for carcinoma in situ. Currently, at diagnosis only 20% of pancreatic cancers are resectable due to locoregional infiltration and distant metastases. Hence early detection of PDAC can have a dramatic impact on survival. Tumor associated MUC1 (tMUC1) is present on over 90% of PDAC examined by immunohistochemistry. Since tMUC1 is also released into circulation, given the high prevalence in PDAC, the antigen can be used as both a blood based and imaging biomarker in an integrated strategy designed to detect pancreatic cancer early. We have developed a tumor specific antibody, TAB004, which specifically detects tMUC1. Variants of this antibody (murine and chimeric) have been used to develop a serum ELISA test called the Agkura® Personal Score (APS) that uses a novel patent pending process to accurately measure small increases in tMUC1 concentration which are associated with the progression of PDAC. In a Phase II clinical study, this test accurately differentiated patients with disease progression from those with stable disease. The TAB004 antibody has also been fully humanized (hTAB004) to develop radionuclide imaging. In this project we propose to use three novel mouse models that have human MUC1 in the entire epithelia: MUC1.Tg, spontaneous PDA.MUC1.Tg that spontaneously develops PDAC and a non- spontaneous PDA.MUC1.Tg model that requires tamoxifen injection to initiate PDAC progression. The PDA.MUC1.Tg models have the KRASG12D mutation and mimic the onset and progression of pancreatic cancer in humans. The mice will be maintained at UNCC and be subjected to blood draws every two weeks. Blood samples will be provided to OncoTAb in a blinded fashion (association with mouse model will be withheld) to test the ability of the APS test to detect PDAC at a carcinoma in situ stage. Mice flagged positive will be shipped to Invicro for imaging with hTAB004 labeled with Indium-111. To ensure the imaging study is also blinded, twice as many mice without PDAC (MUC1.Tg and non- spontaneous PDA.MUC.Tg models) will also be shipped without model association being disclosed. The three mouse models are on the C57BL/6 background and are indistinguishable from each other. Successful demonstration of the integrated serum and imaging biomarker approach to detect PDAC at a carcinoma in situ stage in the proposed blinded study will be a major breakthrough. Establishing early detection in the proposed novel mouse model that mimics human PDAC progression will set the stage to conduct a clinical trial to screen people at high risk for pancreatic cancer using the APS test.Narrative: The proposed research will evaluate an integrated serum and imaging biomarker strategy for the early detection of pancreatic ductal adenocarcinoma (PDAC). A blinded study is proposed using novel mouse models that mimic the progression of human PDAC that releases a biomarker (tMUC1) that is present in over 90% of PDAC patients. The study will evaluate the performance of a blood test, the Agkura® Personal Score (APS), that accurately detects circulating tMUC1, to detect the growth of pancreatic cancer at a carcinoma in situ stage. The study will include mice that do not have PDAC and the blood test will be used to identify the mice that should be imaged with a tMUC1 targeting antibody, hTAB004. By blinding the status of the mice (PDAC positive/negative), the study will simulate screening for pancreatic cancer in a high-risk cohort in the clinic. Successful demonstration of the integrated serum and imaging biomarker approach to detect PDAC at a carcinoma in situ stage in the proposed blinded study will be a major breakthrough and will set the stage to conduct a clinical trial to screen people at high risk for pancreatic cancer using the APS test.