EpigenOMic Determinants of the Neuroendocrine Phenotype As Biomarkers for Neuroendocrine Neoplasms

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Observational
Eligible Ages	18 Years and Over
Gender	All

More Inclusion & Exclusion 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

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT06785597
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	European Institute of Oncology
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Nicola Fazio, MD
Principal Investigator Affiliation	European Institute of Oncology
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	Italy
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Mixed Neuroendocrine-Non Neuroendocrine Neoplasm, Neuroendocrine Neoplasm

Additional Details

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.

Arms & Interventions

Arms

: 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

: Non-neuroendocrine neoplasm control

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

Interventions

Contact a Trial Team

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International Sites

European Institute of Oncology, Milan, Italy

Status

Recruiting

Address

European Institute of Oncology

Milan, , 20141

Site Contact

Nicola Fazio, MD,PhD

[email protected]

0257489258

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