Identification of New Theranostic Biomarkers of Pancreatic Tumor Progression
NCT Number: NCT06574373
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: NA
Conditions: Population of Patients with IPMN And/or Pancreatic Cancer
Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 3600
Study Design: Allocation: NON_RANDOMIZED|Intervention Model: SINGLE_GROUP|Masking: NONE|Primary Purpose: PREVENTION
Start Date: 2024-10-01
Completion Date: 2026-12-31

Summary:
Intraductal papillary mucinous neoplasms (IPMN) are one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC), a lethal disease predicted to become the second leading cause of cancer-related deaths in Western societies within a decade. The mechanisms underlying IPMN progression are poorly understood. The goal of IPMN management is to reduce the risk of patient death due to progression to PDAC through primary and secondary prevention (namely, early diagnosis and risk-reducing surgery). High-risk IPMNs (i.e., high-grade or main duct IPMNs, which account for 57-90% of cases) are referred for surgical resection, while low-risk IPMNs (6-46%) undergo periodic follow-up aimed at monitoring the acquisition of morphological features associated with malignancy over time. However, the clinical management of IPMN remains a significant challenge because the distinction between high and low-risk progression is based on imaging and histological criteria that are not unequivocally recognized and do not take into account the underlying biology of lesions that appear similar but are associated with different clinical behaviors. Consequently, patient risk stratification is often inaccurate, leading to suboptimal treatment. Approximately 1-11% of low-risk IPMN patients assigned to clinical follow-up have developed PDAC. Therefore, it is of paramount importance to improve the understanding of the biology and malignant potential of IPMN to improve prognosis and clinical management of affected patients and guide them toward personalized therapeutic approaches. The availability of markers capable of stratifying IPMN based on their risk of progression to PDAC could enhance the current malignancy criteria assessed in clinical settings by more accurately identifying patients who strongly need surgical resection.

\*\*2 - Study Objective\*\* The aim of this study is to identify and validate biomarkers capable of distinguishing between low-risk and high-risk IPMN progression to PDAC. These biomarkers would help more accurately identify IPMN patients who could benefit from therapeutic intervention and/or surgical resection in the future. The study will include patients with IPMN followed at Fondazione Policlinico Gemelli IRCCS, Fondazione G. Pascale IRCCS, Azienda Ospedaliera Universitaria Integrata Verona, and Azienda Ospedaliera Universitaria Integrata di Messina.

Primary Outcome Measures: to identify pathways and molecular profiles associated with the tumorigenic progression of IPMNs., To identify genes or pathways associated with the malignant transformation of IPMNs, we will conduct an epithelial-specific characterization of IPMNs from both gene expression (single nuclei) and epigenomic changes (ATAC-seq), both with single-cell resolution. Applying a multi-omics approach with single-cell resolution to patient groups at risk of developing pancreatic cancer (normal population, those with a family history of this cancer, or associated with obesity/diabetes), differing histologies (gastric, intestinal, pancreaticobiliary), and dysplasia (high grade and low grade) will allow us to identify stage-specific cellular heterogeneity, different cell transitions, and their cellular fate during tumorigenic progression, as well as characterize the surrounding microenvironment during malignant transformation. A total of 48 IPMN samples and 12 pancreatic cancer samples will be analyzed according to the workflow., 2 years
Secondary Outcome Measures: To validate the markers identified in the primary objective and their role as prognostic factors in both archived tissue samples and plasma., To achieve these objectives, a retrospective analysis will be conducted on a cohort of IPMN patients from the four institutions involved in the project. This analysis will be performed on Formalin-Fixed Paraffin-Embedded (FFPE) samples (n=240) that include all the aforementioned risk groups, histotypes (gastric, pancreaticobiliary, and intestinal), and grades of dysplasia (high or low grade). The identified markers will be validated at both transcriptomic and proteomic levels, using spatial transcriptomics with single-cell resolution (XENIUM, 10X Genomics) and AKOYA Phenocycler, respectively., 2 years