Pancreatic ductal adenocarcinoma (PDAC) kills 72% of patients within one year of diagnosis and 94% of patients within five years. Curing PDAC is possible if the tumor is surgically resected before it has invaded surrounding tissues, but this is uncommon because MRI and CT routinely detect lesions that have already metastasized. Nearly half of symptomatic patients? diagnoses experience a delay of 6 weeks or more that directly affects survival regardless of the stage of disease. Given that tumor size at diagnosis is the single most important prognostic indicator in PDAC, we propose to develop a PET tracer to target a newly discovered molecule on the most abundant cell in PDAC ? the cancer associated fibroblast. Pancreatic CAFs far outnumber epithelial and endothelial cells by at least 100:1?in some cases 1000:1. The CAF are distinctly abnormal; they express a myofibroblast phenotype and mesenchymal stem cell markers. Through combinatorial library screening, we identified a CAF biomarker, a member of the taste receptor family, T2R9, that is expressed on CAFs and not on tumor epithelium or non- activated fibroblasts. It is our hypothesis that the high abundance of target per cell (~500,000) combined with the abundance of the CAFs will enable agent accumulation into the tumor at a high enough target to background ratio to facilitate imaging of small tumors that are in the radiologic window to diagnose and treat PDAC. In this proposal, we will use a multidisciplinary approach that includes a computational model based on the simplified Kogh cylinder model presented by Thurber et al. We have extended the model and incorporated our extensive pharmacokinetic and biodistribution data to enable rational design and to predict tumor accumulation of the proposed agents. Based on our previously published work in imaging agent development and in pancreatic cancer, we believe that we have the tools and the expertise to successfully complete the goals of this proposal, which in turn could have a major impact on the earlier diagnosis of pancreatic cancer in patients with high risk and in patients with suspected disease.
The overall goal of this proposal is to develop new methods for the imaging of pancreatic cancer associated fibroblasts. There are 100 ? 1000 more fibroblasts in a tumor than epithelial cancer cells. By targeting cancer associated fibroblasts, we have the potential to detect pancreatic cancer earlier, when it is curable. We will do this by engineering new imaging agents that will allow us to detect cancer associated stromal cells surrounding the tumors. The developed agents will ultimately be used to allow earlier detection of pancreatic precursor lesions as well as pancreatic cancer.
