Julie L. Sutcliffe, Ph.D.
Principal Investigator (contact): Julie L. Sutcliffe, Ph.D.
Institution: University of California, Davis
Co-Investigator: Richard J. Bold, M.D.
Institution: University of California, Davis
Synopsis of Research and Network Resources
Title of the PCDC Project
PEPTIDE-BASED TARGETED MOLECULAR IMAGING FOR EARLY DETECTION IN PANCREATIC CANCER
One of the major challenges of pancreatic ductal adenocarcinoma (PDAC) is the identification, development and validation of novel molecular markers and imaging probes that would enable earlier detection and provide a rational guide for treatment regimens. We are proposing the integrin subtype αvβ6 as a novel molecular imaging marker for further development and validation combined with a non-invasive peptide-based molecular imaging strategy for in vivo detection of disease progression. αvβ6 is an epithelial-specific cell surface receptor that is undetectable in healthy adult epithelium but is significantly upregulated in a wide range of epithelial derived cancers. This receptor is often localized to the invasive front of tumors and plays a key role in invasion and metastasis. αvβ6 was initially identified in pancreatic cancer with the majority of human PDAC samples tested receiving the maximum score from IHC. Dr. Sutcliffe has developed an αvβ6-directed molecular imaging agent, 18F-αvβ6-binding-peptide (18F-αvβ6-BP), which has high affinity and selectivity for αvβ6 integrin and demonstrated favorable pharmacokinetics in tumor-bearing mice and non-human-primates. The overall goal of this is to validate αvβ6 integrin as a non-invasive molecular imaging target for the early detection of PDAC with PET using 18F-αvβ6-BP.
Description of the Project
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the United States, shows a rapid clinical course, has a dismal median survival of 6 months and the 5-year survival rate remains at only 3%. One major challenge is the identification, development and validation of novel molecular markers and imaging probes for incipient PDAC that would enable earlier detection and provide a rational guide for treatment regimens. We are proposing the integrin subtype αvβ6 as a novel molecular marker for further development and validation combined with a non-invasive peptide-based molecular imaging strategy for in vivo detection of disease progression. Three specific aims are proposed.
Specific Aim 1: Characterization of αvβ6 as a molecular imaging target to evaluate progression of PDAC. We propose to characterize the expression of the integrin αvβ6 in both human and mouse tissue. We will characterize expression levels in resected specimens of IPMN, MCNs and PDAC in addition to analyzing cyst fluid content. Immunohistochemical analysis will be performed on paraffin embedded specimens and Immunoprecipitation will be performed on cyst fluid. In addition we will utilize small animal PET/CT imaging to non-invasively characterize the expression of the integrin αvβ6 during the progression of the normal pancreatic ductal epithelium to PDAC a) through precursor IPMNs and b) through precursor MCNs.
Specific Aim 2: First-in-human molecularly targeted imaging of αvβ6 in PDAC, IPMN and MCN. We propose to use the well characterized peptide 18F-αvβ6-BP to perform the first-in-human imaging of αvβ6 expression in PDAC patients and further validate the utility of 18F-αvβ6-BP-PET/CT to evaluate the concordance of imaging, cytologic and molecular assessment of patients with either suspected PDAC (Cohort 1; 5 patients) or asymptomatic pancreatic cystic lesions (Cohort 2; 10 patients). 18F-αvβ6-BP is a peptide that has high affinity (nM) and selectivity for the integrin αvβ6 and demonstrated favorable pharmacokinetics in tumor-bearing mice and non-human-primates (NHP) and was recently approved by the FDA for first-in-human imaging under the auspices of an exploratory Investigational New Drug (eIND).The primary objectives of this study are to determine the association of 18F-αvβ6-BP-PET/CT imaging results with resected specimen pathology and to determine the association of 18F-αvβ6-BP-PET/CT imaging results with CT/EUS/molecular testing for risk stratification of pancreatic cystic lesions.
Specific Aim 3: Development of a multiplex approach for the rapid development and screening of novel molecular imaging agents for the early detection of PDAC. This approach will enable interrogation of multiple molecular imaging markers simultaneously in vivo using PET. We have selected αvβ6 and Plectin-1 as our initial model as both targets have been identified in PDAC, expression levels are very low or undetectable in normal pancreatic tissue and peptide-based targeted molecular imaging agents already exist for each target. Peptides will be synthesized using solid-phase peptide synthesis and click chemistry. Affinities and selectivity’s will be tested both in vitro using cell binding assays and in vivo using small animal PET/CT imaging. When successfully completed, this will also demonstrate the ability to function as a Consortium through the integration of externally-developed agents in our platform for the development of imaging agents in PDAC.
Resources for Sharing (e.g., description of cohorts, technologies)
All major research findings from this study will be made publicly available via presentations at conferences and publication in peer-reviewed literature. We will publish all the techniques and results with sufficient detail to allow for replication of our work. Results will be published promptly. Data will be shared under confidentiality agreements with all collaborators and researchers interested in this project. Additional agreements, such as non-disclosure Agreements may also be used to protect intellectual property rights while exchanging information with collaborators, partners and the wider scientific community.
We will share our expertise in molecular probe development and translational molecular imaging studies as well as provide access to our unique imaging resources at UC Davis. In addition we are committed to helping with patient recruitment, collecting biospecimens and developing a diverse set of imaging technologies.