Pancreatic Ductal Adenocarcinoma Targeted Ultrasound Contrast Agent Development

? DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is a deadly form of cancer and patient survival depends upon the stage of diagnosis. While overall survival at diagnosis is only about 4-6 months, 30-40% of patients with stage I disease survive 5 years. The best currently available diagnostic test which is routinely performed in patients at high risk for PDAC is endoscopic ultrasound (EUS). However, EUS has low specificity and poor interobserver reliability. One of the two PIs has identified and validated Thy1 as a novel, highly specific neoangiogenesis marker in patients with PDAC. In a preliminary study the PI tested an ultrasound contrast agent bearing antibodies to Thy1 and showed in a mouse model that contrast enhanced ultrasound could detect pancreatic tumors <2-mm in size. This PI has also identified a peptide that binds to both murine and human Thy1. The second and corresponding PI on this project developed the world's #1 selling ultrasound contrast agent and the chemist on this project previously developed the first clinical grade molecularly targeted contrast agent to enter clinical trials. The overall goal of this grant proposal is to develop a novel clinically translatableThy1-targeted ultrasound contrast agent to improve visualization and earlier detection of PDAC, thereby improving overall survival of patients with PDAC. We will create bioconjugates of the peptide to Thy1, incorporate them into ultrasound contrast agents (microbubbles), confirm binding to Thy1 in vitro, and then confirm efficacy in murine models of PDAC. Because PDAC often arises in the setting of chronic pancreatitis we will also confirm that the Thy1- targeted ultrasound contrast agent discriminates between PDAC and chronic pancreatitis. The new clinical grade Thy1-targeted contrast agent can enter formal development as a new drug candidate in Phase II.