Development of a panel of multiplex biomarkers for the early detection of pancreatic ductal adenocarcinoma and high-risk lesions

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with an overall 5-year survival of 11%. Due to its asymptomatic nature and lack of methods for early detection, the majority of PDAC patients (> 85%) present with non-localized tumors. This highlights the need to detect PDAC at an earlier, localized stage. Intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN) offer a unique opportunity to identify premalignant lesions to serve as targets for early detection strategies. Dr. Randall Brand and others proposed a two-step surveillance approach for early detection of PDAC: 1) identification of high-risk populations through clinical evaluation with an elevated PDAC prevalence close to or above 1% and 2) development of serum biomarker(s), for repeated testing at intervals to detect subjects in surveillance with a rising risk of PDAC (prevalence ~ 10%) for additional imaging. The goal of this proposal is to identify serum biomarkers and develop in vitro diagnostic multivariate index assays (IVDMIAs) and incorporate them into an “early detection through surveillance” workflow for the detection of early-stage PDAC and its precursor lesions. The intended use of these IVDMIAs are 1) to assist in the clinical evaluation of high-risk subjects to be included in surveillance for the early detection of PDAC, and 2) to detect rising risk of PDAC or high-risk IPMN in the longitudinal evaluation of subjects in surveillance. The project has five specific aims: 1. To discover and develop serum-based PDAC early detection biomarkers through integrated proteomic analysis of serum/tissue samples from early-stage PDAC, IPMN, and benign and healthy controls using a multimodal and phased approach with corroborative supporting evidence from tissue-based proteomic analysis and immunohistochemical (IHC) verification. 2. To use a by-design approach driven by predefined intended uses that are both clinically meaningful and practically feasible to develop and evaluate serum biomarkers for IVDMIAs. 3. To develop and optimize multiplex analytical assays for selected biomarkers and apply them to generate high-quality biomarker data for IVDMIA development and clinical evaluation. 4. To collect and assemble large clinical specimen sample sets for both IVDMIA algorithm development and independent validation. 5. To participate in collaborative activities with other PCDC-RUs. To be successful, the proposed project requires a multi-disciplinary, systems approach and the support of critical technology, data science, and clinical specimen resources. Our team is a unique ensemble of experts in PDAC and IPMN pathology for early detection, clinical chemistry/assay development, clinical proteogenomics, and statistical/machine learning for IVDMIA development. Most importantly, the team members individually and collectively all have a long-standing history of active research with accomplishments in biomarker development and translation into clinical tests, including the first proteomic IVDMIA test cleared by the FDA. We believe with these innovative yet practical approaches, our RU offers the best opportunity to make significant contributions to the PCDC network and address critical clinical unmet needs.