Molecular imaging has evolved into an important clinical tool to visualize the expression and activity of specific molecules in diseased states and to provide insight towards effective diagnosis and treatment of patients. However, a significant bottleneck has emerged for the development and translation of molecular imaging agents, with the process of developing a single compound into an imaging agent being extremely time consuming and costly. Current limitations for the rapid development and translation of targeted molecular imaging agents for PET include but are not limited to; the complex design, synthesis and screening approaches for both ligand identification and imaging agent development as well as the burdensome administrative documentation associated with preparing the agent for clinical use. We propose to mitigate some of these challenges by leveraging academic and industry expertise and resources to develop a high- throughput multiplex approach, initially focusing on Plectin-1 targeted peptides (PTPs) for pancreatic ductal adenocarcinoma (PDAC). Plectin-1 is a marker for multiple cancers including ovarian, esophageal, head and neck squamous cell carcinoma, and pancreatic ductal adenocarinoma (PDAC). PDAC is a devastating disease with a median survival rate of 6 months and a 5-year survival rate of only 5%. The only curative treatment for PDAC is surgery for localized disease; however, only 20% of patients will present with surgically resectable disease. There is a clear unmet need for the development of novel molecular markers and imaging agents that would enable earlier detection and provide a rational guide for treatment regimens. We will utilize the advances made in combinatorial chemistry and microfluidic flow chemistry to rapidly identify, screen and optimize PTPs. Specifically we will use OBOC to affinity mature the plectin binding peptide PTP-01 (identified by Kelly) and microfluidic flow chemistry for rapid radiolabeling of lead peptides with fluorine- 18 for subsequent PET imaging in vivo in both mouse and non-human primate (NHP) studies. Through the industrial partnership with iTi Health Inc. we will advance a lead candidate through IND-enabling studies towards a first-in-human clinical study. This strategic alliance brings together an interdisciplinary team of investigators with expertise in combinatorial chemistry, radiochemistry, high-throughput in vivo screening and molecular imaging (Sutcliffe, PI), PDAC biology, chemical biology and proteomics (Kelly, co-investigator) biostatistics (Beckett), nonhuman primate imaging (Tarantal), and surgical oncology (Bold). In additional to the unique expertise this partnership leverages the unique resources including state of the art preclinical imaging resources (including nonhuman primate), new radiochemistry and GMP resources at UC Davis.
Tools for earlier diagnosis of malignancies such as ovarian, esophageal and pancreatic cancer are critical to improve patient outcomes. With the identification of plectin, a molecule that is found on many of these cancers we now have the opportunity to develop such tools. We will use advances in technologies and through an industry-academic partnership we will catalyze the translation of tools from the bench to the bedside.
