Clinical trial NCT04464122: Rediscovering Biomarkers for the Diagnosis and Early Treatment Response in NEN (REBORN)
Official title: Rediscovering Biomarkers for the Diagnosis and Early Treatment Response in NEN. REBORN Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Neuroendocrine Tumors
Neuroendocrine Neoplasm
Neuroendocrine Tumor Grade 1
Neuroendocrine Tumor Grade 2
Neuroendocrine Carcinoma
Keywords: Neuroendocrine Tumours
Prognostic markers
Tumour educated platelets
angiogenesis
immune function
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2020-07-09
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with histologically-proven NENs, locally advanced or metastatic, originating from pulmonary or gastro-entero-pancreatic tract

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.

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.

Primary outcomes:
measure: To evaluate the modification of the angiogenetic mediator sTie2 after treatment.
timeFrame: baseline - + 1 month - +3 months
Secondary outcomes:
measure: To evaluate the difference in the angiogenetic mediator sTie2 between patients and controls
timeFrame: baseline
measure: To validate the use of circular RNAs from TEPs in NEN diagnosis
timeFrame: baseline
measure: To evaluate the changing in circular RNAs from TEPs in NEN patients after somatostatin analogs treatment
timeFrame: baseline - + 1 month - +3 months
measure: To compare circular and cellular angiogenesis mediators between patients and controls
timeFrame: baseline
measure: To evaluate the changing in circular and cellular angiogenesis mediators after treatment.
timeFrame: baseline - + 1 month - +3 months
measure: To quantify PBMC subpopulation in patients and controls
timeFrame: baseline
measure: To evaluate the modification of PBMC subpopulation in patients after treatment
timeFrame: baseline - + 1 month - +3 months
measure: To compare classical neuroendocrine markers serum levels between patients and controls
timeFrame: baseline
measure: To evaluate the modification of classical neuroendocrine markers in patients after treatment
timeFrame: baseline - + 1 month - +3 months
measure: To evaluate infectious diseases frequency and severity between patients and controls
timeFrame: baseline
measure: To evaluate the difference in quality of life questionnaire in patients and controls
timeFrame: baseline
measure: To evaluate the modification in quality of life questionnaire in patients after treatment
timeFrame: baseline - + 1 month - +3 months
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Andrea M Isidori
Study officials:
affiliation: Department of Experimental Medicine, Sapienza University of Rome
name: Andrea M Isidori, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.