Gastro-Entero-Pancreatic-Neuroendocrine-Tumors (GEP-NETs) overexpresses Somatostatine receptors (SSTRs). Peptide Receptor Radionuclide Therapy (PRRT) target SSTRs. Although GEP-NETs show SSTRs overexpression, about 30% of patients do not respond to PRRT. It has been demonstrated that 18FDG –PET, reflects higher glucose uptake and represent a prognostic marker in GEP-NETs. MiRNAs are involved several mechanisms, including cell metabolism. In this scenario it would be pivotal to find new prognostic and/or predictive markers able to correlate with 18FDG/PET status.
Platelet free plasma from 66 GEP-NET patients was collected. Whole miRNOME NGS analysis was performed on exome enriched small-RNAs fraction of 24 patients: 12 18PET/FDG+ and 12 18PET/FDG-. MiRNAs significantly associated with 18PET/FDG outcome were identified and validated by RT/qPCR on overall case series. Target miRNAs fold enrichment were then combined to create predictors (pAB, pAC, pBC and pABC). Man-Whitney test was applied and validated miRNAs were correlated with clinical outcome and parameters (ki-67, grading, tumor burden and 68Gallium-PET SUVmax).
NGS profiling revealed 7 miRNAs able to distinguish 18FDG/PET positive from negative Pancreatic-NETs (PNETs). Mir-A, mir-B, mir-C (patent pending) had been then validated on overall case series by multiplex RT/qPCR (p < 0,0109, p < 0,0033 and p < 0,0002, respectively) on PNETs case series and pBC resulted to be the best predictor (p < 0,0002). All validated miRNAs and derived predictors, expecially mir-B, result significantly increased in small intestine (SINETs) and in PNETs patients when compared to healthy controls. Correlation analysis between target miRNAs and clinical parameters also revealed that mir-B negatively correlates with 68Ga-PET SUVmax (p < 0,0351).
We defined a 3 miRNAs signature able to correlate with 18FDG/PET status. Over expression of mir-A, mir-B, mir-C or combined predictors in PNETs with the same SSTR status might help to identify PRRT non-responders. In addition mir-B negatively correlates with clinical outcome and 68Ga-PET SUVmax. We are investigating if mirB interfere with SSTR expression, affecting PRRT efficacy.
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) Srl - IRCCS.
Has not received any funding.
All authors have declared no conflicts of interest.