EpigenOMic Determinants of the Neuroendocrine Phenotype As Biomarkers for Neuroendocrine Neoplasms

NCT ID: NCT06785597

Last Updated: 2025-01-21

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 130 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-10-21
• Study Completion Date: 2026-10-21

Brief Summary

For GEP mixed neuroendocrine (NE) non-neuroendocrine neoplasms (MiNENs) a key issue affecting prognosis is sometimes the difficulty in obtaining a timely diagnosis, as the NE component is often localized in deeper anatomical locations and/or becomes prevalent over time. The tissue material of biopsies may be not enough to define the NE component when this is particularly small and this could impact on therapeutic decision. Furthermore GEP NENs need to be characterized for potentially druggable biomarkers and liquid biopsy has clear advantage to the solid one to this aim. Here, we will exploit epigenetic differences characterizing NE tumors to build a DNA methylation-based liquid biopsy assay able to detect circulating tumor DNA of NE derivation, to enable the non-invasive diagnosis and monitoring of GEP-MiNENs.

Detailed Description

GEP-NENs are a heterogeneous group of diseases that encompasses relatively indolent and more aggressive tumors, sometimes with mixed exocrine/endocrine components (MINENs). Due to persistent uncertainties in diagnosis and treatment, prognosis of the mixed and more aggressive forms remains poor. Non-invasive tests would enable timely identification and monitoring over time. A better understanding of their biology and of the phenotypic differentiation process may pave the way for novel therapies. Differentiation follows, and can be inferred from, changes in the epigenetic landscape that shape transcriptional programs. Among epigenetic markers, DNA methylation is particularly well suited for non-invasive detection as it can be measured in circulating tumor DNA (ctDNA). New technologies like Oxford Nanopore Technologies (ONT) enable simultaneous analysis of DNA sequence and methylation, as we recently showed by Magi et al Nat Comms Biol 2022. Previous studies identified distinct neuroendocrine epi-transcriptomic landscapes but were conducted on tumor specimens (Yachida et al Cancer Discov 2022), impeding the discrimination of signals specifically generated within neuroendocrine tumor cells from the noise due to surrounding nontumoral or exocrine tumoral cells. This is now potentially solved by methods allowing single-cell sequencing directly from frozen or paraffin-embedded patient samples.

The main expected outcome is the development of a novel liquid biopsy assay for the detection and monitoring of GEP-NENs and MiNENs. To this end, we will exploit the ability of Oxford Nanopore Technologies (ONT) sequencing to simultaneously yield sequencing and methylated DNA profiles. Importantly, assessment of cell of origin from ctDNA requires the comparison of methylation and fragmentomics signals with previously generated maps of reference cells and tissues (Katsman et al 2022 Genome Biology). For rare tumors like NENs, these maps are not available in the literature; the few studies that have characterized the epigenomic features of NENs are likely contaminated by the surrounding stroma, so epigenetic signals (including both DNA methylation and tumor-specific transcription factor binding sites, essential for fragmentomics) may be uninformative for detection in the blood.

Conditions

Mixed Neuroendocrine-Non Neuroendocrine Neoplasm; Neuroendocrine Neoplasm

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: PROSPECTIVE

Study Groups

Neuroendocrine neoplasm case

patient with histologically confirmed neuroendocrine neoplasm and onfirmed Mixed Neuroendocrine-non neuroendocrine neoplasm with each component \> 30%) and high-grade Neuroendocrine Carcinomas

No interventions assigned to this group

Non-neuroendocrine neoplasm control

patient with histologically confirmed non-neuroendocrine gastrointestinal tumors (including gastric, pancreatic, colorectal, small intestine).

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Patient with histologically confirmed diagnosis of NEC/MINEN amenable to surgery with radical intent
• Patient with histologically confirmed diagnosis of NET amenable to surgery with radical intent
• Patient with metastatic NET/NEC, amenable to biopsy or surgery, including palliative intent
• Patient histologically confirmed non-NEN histotype:

1. Colorectal carcinoma

2. Small intestine carcinoma

3. Gastric or oesophageal carcinoma

4. Pancreatic ductal adenocarcinoma

5. Metastasectomy from any non-NEN GI carcinoma

Exclusion Criteria

• Grading G1 and G2 <=10% Ki67
• Presence of concomitant neoplasm (within 3 years)
• Concomitant major haematological alteration
• Concomitant major organ dysfunction (e.g. G3/4 liver or kidney failure)
• Ongoing chemotherapy

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone Palermo

OTHER

Sponsor Role: collaborator

European Institute of Oncology

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nicola Fazio, MD

Role: PRINCIPAL_INVESTIGATOR

European Institute of Oncology

Locations

European Institute of Oncology

Milan, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Nicola Fazio, MD

Role: CONTACT

divisione.gastrointestinale@ieo.it

0257489258

Francesca Spada, MD

Role: CONTACT

divisione.gastrointestinale@ieo.it

0257489258

Facility Contacts

Nicola Fazio, MD,PhD

Role: primary

divisione.gastrointestinale@ieo.it

0257489258

Nicola Fazio, MD,PhD

Role: backup

Francesca Spada, MD

Role: backup

Luca Mazzarella, MD

Role: backup

Lorenzo Gervaso, MD

Role: backup

Chiara Alessandra Cella, MD

Role: backup

Elenora Pisa, MD

Role: backup

Chiara Maria Grana, MD

Role: backup

Emilio Bertani, MD

Role: backup

Giuseppe Badalamenti, MD

Role: backup

Laura Algeri, MD

Role: backup

Other Identifiers

L2-154

Identifier Type: -

Identifier Source: org_study_id