Identification of New Theranostic Biomarkers of Pancreatic Tumor Progression

New Theranostic Biomarkers of Intraductal Mucinous Neoplasm (IPMN) Progression to Pancreatic Cancer for Patients' Outcome Improvement

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.

**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 Roma, Fondazione G. Pascale IRCCS Naples, Azienda Ospedaliera Universitaria Integrata Verona, and Azienda Ospedaliera Universitaria Integrata Messina.

Study Overview

• Status: Recruiting
• Conditions: IPMN, Pancreatic
• Intervention / Treatment: Other: Blood Collection Protocol for Patients with Indolent, Invasive, and Pancreatic Cancer-Associated IPMN Based on Clinical Course and Surgical Intervention

Detailed Description

**AIM1.**

1. **Identification** of genes and biological pathways associated with IPMN malignant transformation. The investigators aim to explore the molecular dynamics of tumor progression, focusing on cellular heterogeneity and phenotypic transitions.
2. **Characterization of the microenvironment** to understand its role in IPMN progression. The investigators will collect archival samples from 240 patients across four centers.
3. **Identification and validation in plasma** of selected patients of differentially expressed markers in indolent IPMN, invasive IPMN, and PDAC.

**AIM2.** The investigators will develop knowledge-based tools for diagnosing and treating IPMN and at-risk populations.

**AIM3.** The investigators will validate the role of key genes in IPMN carcinogenesis using in vitro study models.

• Study Type: Observational
• Enrollment (Estimated): 3600
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Carmine Carbone, PhD; Phone Number: 0630155894; Email: carmine.carbone@policlinicogemelli.it

Study Locations

• Italy
  • Roma, Italy, 00168
    • Recruiting
    • Fondazione Policlinico Gemelli
    • Contact: Carmine Carbone; Phone Number: 06301551; Email: carmine.carbone@policlinicogemelli.it
  • Rome, Italy, 00168
    • Not yet recruiting
    • IRCCS Fondazione Policlinico Universitario A. Gemelli
    • Contact: Carmine Carbone, PhD; Phone Number: +39 0630155259; Email: carmine.carbone@policlinicogemelli.it
    • Contact: Geny Piro, PhD; Phone Number: +39 0630155259; Email: geny.piro@policlinicogemelli.it
    • Principal Investigator: carmine carbone, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients >18 years old with Pancreatic IPMN. This cohort will consist of IPMN tissues collected via Formalin-Fixed Paraffin-Embedded from patients who have either developed or have never developed pancreatic cancer associated with IPMN.

Description

Inclusion Criteria:

• Diagnosis of indolent IPMN under monitoring;
• Diagnosis of malignant IPMN or resectable pancreatic adenocarcinoma with associated IPMN (previously untreated); Written informed consent; Male and female patients aged 18 years or older;

Exclusion Criteria:

-Inability to provide written informed consent or to trace patients for the retrospective study.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients with IPMN/pancreatic cancer diagnosis; Patients with indolent IPMN, invasive IPMN, and IPMN associated with pancreatic cancer, depending on their clinical course.

Other: Blood Collection Protocol for Patients with Indolent, Invasive, and Pancreatic Cancer-Associated IPMN Based on Clinical Course and Surgical Intervention; Blood will be collected from patients with indolent IPMN, invasive IPMN, and IPMN associated with pancreatic cancer, depending on their clinical course. Patients with indolent IPMN will be monitored by the gastroenterology units of their respective institutions, which will inform the patient. Patients with invasive IPMN and/or associated with cancer will undergo surgical resection as part of their standard clinical care, and blood will be collected after informed consent is obtained by the surgical teams at each institution.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association of IPMNs tumorigenic progression with a molecular profile	Identification of participants with malignant transformation and at least two-fold expression change of a specific molecular profile respect to indolent IPMN. All data will be collected and statistics will be done for the correlation between gene expression markers and malignant transformation.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Validation of the prognostic molecular profile identified in the primary objective in both archived tissue and plasma samples	Retrospective analysis.	2 years

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Collaborators: Azienda Ospedaliera Universitaria Integrata Verona; University of Messina; Istituto Nazionale Tumori IRCCS - Fondazione G. Pascale
• Investigators: Principal Investigator: Carmine Carbone, PhD, Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Publications and helpful links

General Publications

• Agostini A, Piro G, Inzani F, Quero G, Esposito A, Caggiano A, Priori L, Larghi A, Alfieri S, Casolino R, Scaglione G, Tondolo V, Cammarota G, Ianiro G, Corbo V, Biankin AV, Tortora G, Carbone C. Identification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms. Nat Commun. 2024 Mar 29;15(1):2764. doi: 10.1038/s41467-024-46994-2.
• Tanaka M, Fernandez-Del Castillo C, Kamisawa T, Jang JY, Levy P, Ohtsuka T, Salvia R, Shimizu Y, Tada M, Wolfgang CL. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology. 2017 Sep-Oct;17(5):738-753. doi: 10.1016/j.pan.2017.07.007. Epub 2017 Jul 13.
• Levink I, Bruno MJ, Cahen DL. Management of Intraductal Papillary Mucinous Neoplasms: Controversies in Guidelines and Future Perspectives. Curr Treat Options Gastroenterol. 2018 Sep;16(3):316-332. doi: 10.1007/s11938-018-0190-2.
• Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024 Jan-Feb;74(1):12-49. doi: 10.3322/caac.21820. Epub 2024 Jan 17.

Study record dates

Study Major Dates

• Study Start (Actual): May 29, 2025
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: August 26, 2024
• First Submitted That Met QC Criteria: August 26, 2024
• First Posted (Actual): August 27, 2024

Study Record Updates

• Last Update Posted (Estimated): September 3, 2025
• Last Update Submitted That Met QC Criteria: September 2, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Pancreatic cancer; IPMN; precancerous lesions
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Neoplasms, Ductal, Lobular, and Medullary; Pancreatic Intraductal Neoplasms; Pancreatic Neoplasms; Surgical Procedures, Operative
• Other Study ID Numbers: ID 6797; PNRR-MCNT2-2023-12377229 (Other Grant/Funding Number: Italian Ministry of Health)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No