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[Objective] Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways., [Design and Methods] Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA)., [Results] Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs., [Conclusions] We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients.

Neuroendocrine tumors (NETs) are a heterogeneous family of neoplasms of increasing incidence and high prevalence due to their relatively indolent nature. Their wide anatomic distribution and their characteristic ability to secrete hormonally active substances pose unique challenges for clinical management. They are also characterized by the common expression of somatostatin receptors, a target that has been extremely useful for diagnosis and treatment (i.e., somatostatin analogues (SSAs) and peptide-receptor radionuclide therapy (PRRT)). Chemotherapy is of limited use for NETs of non-pancreatic origin, and the only approved targeted agents for advanced progressive NETs are sunitinib for those of pancreatic origin, and everolimus for lung, gastrointestinal and pancreatic primaries. Despite recent therapeutic achievements, thus, systemic treatment options remain limited. In this review we will discuss the state-of-the-art targeted therapies in the field of NETs, and also future perspectives of novel therapeutic drugs or strategies in clinical development, including recently presented results from randomized trials of yet unapproved antiangiogenic agents (i.e., pazopanib, surufatinib and axitinib), PRRT including both approved radiopharmaceuticals (177Lu-Oxodotreotide) and others in development (177Lu-Edotreotide, 177Lu-Satoreotide Tetraxetan), immunotherapy and other innovative targeted strategies (antibody-drug conjugates, bites,…) that shall soon improve the landscape of personalized treatment options in NET patients., Fac. de Medicina, TRUE, pub

This work was partially funded by Pfizer, Project G1808 from the Spanish National Taskforce on Neuroendocrine Tumors (GETNE), Ministry of Science, Innovation and Universities of Spain (MICINN) and FEDER funding (Ref. RTI2018-095166-B-I00) and Autonomous Community of Madrid (NOVELREN-CM. Ref: B2017/BMD3751). B.S. is funded by AECC (POSTDO46SOLD, Spain). A.L.-L. thanks CEU-International Doctoral School (CEINDO) for her fellowship. A.L.-P. is funded by CAM (PEJD-2019-PRE/BMD-17058, Progama de Empleo Juvenil (YEI), co-funded by European Union (ERDF/ESF, “Investing in your future”). C.C.-P. was partially funded by CAM (PEJD-2016-PRE/BMD-2666). B.R.-C. was partially funded by CAM (PEJD-2017-PRE/BMD-4981). ALS is funded by Instituto de Salud Carlos III (Contrato Rio Hortega). M.R.-M. is funded by AECC (CLSEN19003RIES)., Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research., Unión Europea, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, Grupo Español de Tumores Neuroendocrinos y Endocrinos (GETNE), Asociación Española Contra el Cáncer (AECC), Instituto de Salud Carlos III, Pfizer, Depto. de Medicina, Fac. de Medicina, TRUE, pub

Las neoplasias neuroendocrinas (NNEs) son una familia de tumores de una gran heterogeneidad biológica. Globalmente son neoplasias con un índice mutacional bajo y no se han identificado mutaciones genéticas conductoras o driver sobre las que se pueda actuar desde el punto de vista terapéutico. Sin embargo, los mecanismos epigenéticos juegan un papel determinante en la biología e historia natural de estos tumores. La expresión de los miRNAs está desregulada en cáncer a través de distintos mecanismos, incluidos la amplificación o delección de los genes que los codifican, alteraciones en la regulación de su transcripción, modificaciones epigenéticas y alteraciones en la maquinaria de su biogénesis, y pueden funcionar como oncogenes o como genes supresores de tumores dependiendo de los genes diana sobre los que actúen. Múltiples estudios han demostrado su utilidad como biomarcadores diagnósticos, pronósticos y terapéuticos en otras neoplasias, pero la evidencia en NNEs es escasa. La hipótesis que fundamenta este trabajo es que las NNEs presentan un perfil de expresión de miRNAs característico y que la identificación de estos miRNAs desregulados puede tener una utilidad clínica diagnóstica, pronóstica, y potencialmente terapéutica. En base a ello, el objetivo global fue caracterizar el perfil de expresión de miRNAs en NNEs de origen GEP y pulmonar, y evaluar su utilidad como potenciales biomarcadores en la clínica. Con este fin hemos analizado retrospectivamente en una cohorte de 128 pacientes con NNEs la expresión de un panel de 84 miRNAs relacionados con cáncer mediante PCR-arrays en muestras pareadas tumorales y no tumorales, con los siguientes objetivos específicos: 1) identificar el perfil de expresión diferencial de miRNAs en tejido tumoral respecto al tejido sano; 2) identificar el perfil de expresión de miRNAs en función de distintas variables clínicas y patológicas de interés, 3) evaluar su valor pronóstico añadido respecto a las variables pronósticas clínicas ya, Neuroendocrine neoplasms (NENs) are a family of tumors of great biological heterogeneity. Overall, they are neoplasms with a low mutational burden and no driver mutations have been identified that may be adequate targets for therapy. However, epigenetic mechanisms play a determining role in the biology and natural history of these tumors. The expression of miRNAs is deregulated in cancer through different mechanisms, including the amplification or deletion of the genes that encode them, alterations in the regulation of their transcription, epigenetic modifications and alterations in the machinery of their biogenesis. MiRNAs may function as oncogenes or as tumor suppressor genes depending on the target genes they regulate. Multiple studies have demonstrated their utility as diagnostic, prognostic, and therapeutic biomarkers in other malignancies, but the evidence in NENs is scarce. The hypothesis underlying this work is that NENs present a characteristic miRNA expression profile and that the identification of these deregulated miRNAs can be of potential diagnostic, prognostic or therapeutic utility. Based on this, the overall objective of this study was to characterize the expression profile of miRNAs in NENs of gastroentero-pancreatic (GEP) and pulmonary origin, and to evaluate their utility as potential biomarkers in the clinic. To this end, we have retrospectively analyzed in a cohort of 128 NENs patients the expression of a panel of 84 cancer-related miRNAs using PCR-arrays in paired tumor and non-tumor samples, with the following specific objectives: 1) to identify the differential miRNAs expression profile in tumor versus non-tumor tissue; 2) to identify the differential miRNA expression profile based on different clinical and pathological variables of interest, 3) to evaluate their added prognostic value with respect to the already known clinical prognostic variables, and 4) to explore the genes regulated by these miRNAs in order to identify the molecular path

Las neoplasias neuroendocrinas (NNEs) son una familia de tumores de una gran heterogeneidad biológica. Globalmente son neoplasias con un índice mutacional bajo y no se han identificado mutaciones genéticas conductoras o driver sobre las que se pueda actuar desde el punto de vista terapéutico. Sin embargo, los mecanismos epigenéticos juegan un papel determinante en la biología e historia natural de estos tumores. La expresión de los miRNAs está desregulada en cáncer a través de distintos mecanismos, incluidos la amplificación o delección de los genes que los codifican, alteraciones en la regulación de su transcripción, modificaciones epigenéticas y alteraciones en la maquinaria de su biogénesis, y pueden funcionar como oncogenes o como genes supresores de tumores dependiendo de los genes diana sobre los que actúen. Múltiples estudios han demostrado su utilidad como biomarcadores diagnósticos, pronósticos y terapéuticos en otras neoplasias, pero la evidencia en NNEs es escasa. La hipótesis que fundamenta este trabajo es que las NNEs presentan un perfil de expresión de miRNAs característico y que la identificación de estos miRNAs desregulados puede tener una utilidad clínica diagnóstica, pronóstica, y potencialmente terapéutica. En base a ello, el objetivo global fue caracterizar el perfil de expresión de miRNAs en NNEs de origen GEP y pulmonar, y evaluar su utilidad como potenciales biomarcadores en la clínica. Con este fin hemos analizado retrospectivamente en una cohorte de 128 pacientes con NNEs la expresión de un panel de 84 miRNAs relacionados con cáncer mediante PCR-arrays en muestras pareadas tumorales y no tumorales, con los siguientes objetivos específicos: 1) identificar el perfil de expresión diferencial de miRNAs en tejido tumoral respecto al tejido sano; 2) identificar el perfil de expresión de miRNAs en función de distintas variables clínicas y patológicas de interés, 3) evaluar su valor pronóstico añadido respecto a las variables pronósticas clínicas ya