Abstract
Noninvasive detection of both early pancreatic neoplasia and metastases could enhance strategies to improve patient survival in this disease that is notorious for an extremely poor prognosis. There are almost no identifiable targets for non-invasive diagnosis by positron emission tomography (PET) for patients with pancreatic ductal adenocarcinoma (PDAC). Over-expression of the receptor for advanced glycation end products (RAGE) is found on the cell surface of both pre-neoplastic lesions and invasive PDAC. Here, a RAGE-specific single chain (scFv) was developed, specific for PET imaging in syngeneic mouse models of PDAC. An anti-RAGE scFv conjugated with a sulfo-Cy5 fluorescence molecule showed high affinity and selectivity for RAGE expressing pancreatic tumor cells and genetically engineered KRASG12D mouse models of PDAC. An in vivo biodistribution study was performed with the 64Cu-radiolabled scFv in a syngeneic murine pancreatic cancer model, demonstrating both the feasibility and potential of an anti-RAGE scFv for detection of PDAC. These studies hold great promise for translation into the clinic.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the U.S and associated with an extremely poor clinical outcome
receptor for advanced glycation end products (RAGE) is upregulated in a number of pathogenic diseases such as neurodegeneration, diabetes, vascular disease, and cancer [18]
The overexpression of RAGE is a direct link to the survival of premalignant epithelial precursors and tumor cells in PDAC [5]
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in the U.S and associated with an extremely poor clinical outcome. The 5-year patient survival rate for all patients in aggregate is less than 5%, thought to be due to late diagnosis, early metastasis, and resistance to chemotherapy [1]. Treatment options for patients with PDAC are limited. Surgical removal of the tumor at an early stage before invasion is the only currently available therapy with curative intent [2]. Detection of PDAC, or its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), could potentially improve treatment outcomes [2]. Non-invasive diagnostic imaging by positron emission tomography (PET) is an ideal tool for assessing the functional tumor status within the pancreas.
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