Rediscovering Biomarkers for the Diagnosis and Early Treatment Response in NEN (REBORN)

NCT ID: NCT04464122

Last Updated: 2025-04-03

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 60 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-09-14
• Study Completion Date: 2025-12-31

Brief Summary

This is a multicentre, controlled, observational prospective study on new biomarkers, as immune profiling, angiogenetic markers and circRNA from TEPs in the diagnosis and in the evaluation of treatment response in pulmonary and gastro-entero-pancreatic NENs.

Detailed Description

Neuroendocrine Neoplasm (NEN) are heterogeneous disease in terms of origin, localization and clinical presentation. Annual incidence of NEN is increasing in the last 30 years, even if the reasons underlying this rise have not been completely identified.

Many biomarkers have been used in the diagnosis and follow-up of patients with NEN. In non-functioning NEN general tumor markers, such as chromogranin A (CgA) and neuron specific enolase (NSE), are commonly used but their sensibility and specificity are quite low.

Recently, high-throughput tissue microarray and immunohistochemistry assessments have been performed to observe the expression pattern of new potential markers for NEN. In order to overcome limitations of tissue acquisition, the use of liquid biopsies has been advocated. It has been reported that tumor-educated platelets (TEPs) may easily enable blood-based cancer diagnostics. TEPs take up tumor-derived secreted membrane vesicles containing RNAs, of which circular RNAs (circRNAs) that can serve as a potential biomarker source for cancer diagnostics. This innovative approach in cancer detection has not yet been transferred to the NEN field.

Flow cytometric analysis furnishes important insights into the immune status by providing information about the numbers and phenotypes of the immune cells, which are known to be altered in many types of neoplasms. In NEN, leukocytes subpopulations and peripheral blood mononuclear cells (PBMCs) are not been completely investigated but immunological alterations could represent a signal of neoplastic spread.

Inflammatory and angiogenetic pathways' involvement in NEN behavior has recently received increasing attention. It is well known that NEN are known to be highly vascularized neoplasms and somatostatin analogues (SSA), used as first line drugs for most well differentiated NEN, can reduce tumour proliferation by various direct and indirect mechanism including the inhibition of angiogenesis.

Tumor angiogenesis is a complicated process consisting of several steps, the angiogenesis cascade, regulated by endogenous and exogenous factors, including the system Angiopoietin-1 (Ang-1) and -2 (Ang-2) / Tie2 and Prokineticins. These systems are involved in neoplastic angiogenesis and inflammation in various types of cancer. Despite these evidences, the role of inflammatory and angiogenic factors in NEN detection and follow-up has not been completely clarified.

The aim of the study is to evaluate immune profiling, angiogenetic markers and circularRNA sequencing in patients affected by locally advanced or metastatic pulmonary or GEP NENs and controls. Moreover, NENs patients will be evaluated also after 1 and 3 months of first line medical treatment.

Conditions

Neuroendocrine Tumors; Neuroendocrine Neoplasm; Neuroendocrine Tumor Grade 1; Neuroendocrine Tumor Grade 2; Neuroendocrine Carcinoma

Study Design

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

Study Groups

Neuroendocrine toumor group

30 patients (18-80 years, males and females) affected by histologically-proven neuroendocrine neoplasms, locally advanced or metastatic, originating from pulmonary or gastro-entero-pancreatic (GEP) tract, candidate to medical therapy.

Somatostatin analog; chemotherapy

Intervention Type: DRUG

According to current ENETS guidelines, patients will be treated by somatostatin analogs or chemotherapy, recommended respectively as first line therapy in neuroendocrine tumours or neuroendocrine neoplasms.

Control group

Patients affected by other non-malignant endocrine disease, e.g. benign thyroid disfunction (18-80 years, males and females)

No interventions assigned to this group

Interventions

Somatostatin analog; chemotherapy

According to current ENETS guidelines, patients will be treated by somatostatin analogs or chemotherapy, recommended respectively as first line therapy in neuroendocrine tumours or neuroendocrine neoplasms.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Histologically-proven NENs, locally advanced or metastatic, originating from pulmonary or gastro-entero-pancreatic (GEP) tract, candidate to first line medical therapy (study group);
• Patients affected by other non-malignant endocrine disease, e.g. benign thyroid disfunction (control group).

Exclusion Criteria

• Severe chronic kidney disease (stage 4-5);
• Clinical or laboratory signs of significant respiratory, cardiological and hepatobiliary disease;
• Other non-neuroendocrine malignancies.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Roma La Sapienza

OTHER

Sponsor Role: lead

Responsible Party

Andrea M. Isidori

Full Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrea M Isidori, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Department of Experimental Medicine, Sapienza University of Rome

Locations

Andrea M Isidori

Rome, Italy, Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Andrea M Isidori, MD, PhD

Role: CONTACT

andrea.isidori@uniroma1.it

+390649970540

Elisa M Giannetta, MD, PhD

Role: CONTACT

elisa.giannetta@uniroma1.it

+390649970540

Facility Contacts

Andrea M Isidori, MD, PhD

Role: primary

andrea.isidori@uniroma1.it

00390649970540

References

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Reference Type: BACKGROUND

PMID: 28681241 (View on PubMed)

Joosse SA, Pantel K. Tumor-Educated Platelets as Liquid Biopsy in Cancer Patients. Cancer Cell. 2015 Nov 9;28(5):552-554. doi: 10.1016/j.ccell.2015.10.007.

Reference Type: BACKGROUND

PMID: 26555171 (View on PubMed)

Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol. 2006 Dec;27(12):552-8. doi: 10.1016/j.it.2006.10.004. Epub 2006 Oct 12.

Reference Type: BACKGROUND

PMID: 17045842 (View on PubMed)

Monnier J, Samson M. Prokineticins in angiogenesis and cancer. Cancer Lett. 2010 Oct 28;296(2):144-9. doi: 10.1016/j.canlet.2010.06.011. Epub 2010 Jul 14.

Reference Type: BACKGROUND

PMID: 20633984 (View on PubMed)

Best MG, Sol N, Kooi I, Tannous J, Westerman BA, Rustenburg F, Schellen P, Verschueren H, Post E, Koster J, Ylstra B, Ameziane N, Dorsman J, Smit EF, Verheul HM, Noske DP, Reijneveld JC, Nilsson RJA, Tannous BA, Wesseling P, Wurdinger T. RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics. Cancer Cell. 2015 Nov 9;28(5):666-676. doi: 10.1016/j.ccell.2015.09.018. Epub 2015 Oct 29.

Reference Type: BACKGROUND

PMID: 26525104 (View on PubMed)

Harris AL, Reusch P, Barleon B, Hang C, Dobbs N, Marme D. Soluble Tie2 and Flt1 extracellular domains in serum of patients with renal cancer and response to antiangiogenic therapy. Clin Cancer Res. 2001 Jul;7(7):1992-7.

Reference Type: BACKGROUND

PMID: 11448916 (View on PubMed)

Other Identifiers

Reborn Study

Identifier Type: -

Identifier Source: org_study_id