NF-κB as potential target in the treatment of melanoma

The RAS/MAP kinase pathway has attracted attention because activating mutations of the BRAF serine/threonine kinase was described in over 50% of melanomas. Very recently, selective and potent BRAF inhibitors have been developed. Several other signal transduction pathways have been found to be constitutively active or mutated in other subsets of melanoma tumors that are potentially targetable with new agents. Among these, NFκB is another pathway that melanoma tumors use to achieve survival, proliferation and resistance to apoptosis. Inhibition of NF-κB activation appears to be a very promising option for anti-cancer therapies

ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma. Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin

In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy

MMP-9 as a Candidate Marker of Response to BRAF Inhibitors in Melanoma Patients With BRAFV600E Mutation Detected in Circulating-Free DNA

The BRAFV600E mutation is associated with melanoma development and its detection in circulating-free DNA cannot be observed in all melanoma patients harboring this mutation in tumor specimens. Beside the circulating-free DNA BRAFV600E mutation, other markers of therapeutic response should be identified. Matrix metalloproteinase-9 (MMP-9) could be one of them as its role as indicator of invasiveness in melanoma have been explored. In this study, MMP-9 was evaluated in melanoma cells after treatment with dabrafenib. In vitro data were validated in 26 melanoma patients, of which 14 treated with BRAF inhibitor alone and 12 treated with both BRAF and MEK inhibitors, by ELISA assay and droplet digital PCR for measuring MMP-9 serum levels and circulating-free DNA BRAFV600E mutation, respectively. Statistical analyses were performed to evaluate the prognostic significance of MMP-9, progression-free survival (PFS) and overall survival (OS) according to the BRAFV600E mutation and MMP-9 levels. The performed analyses showed that MMP-9 and pEKR1-2 were statistically down-regulated in melanoma cells after treatment with dabrafenib. Circulating-free DNA BRAFV600E mutation was detected in 11 out of 26 melanoma patients showing higher levels of MMP-9 compared to those with undetectable BRAFV600E mutation. Furthermore, higher levels of MMP-9 and circulating-free DNA BRAFV600E mutation were associated with lower PFS and OS. Finally, the monitoring of therapy showed that MMP-9 significantly decreased at T1 and T2, but not at T-last, for the patients with detectable circulating-free DNA BRAFV600E mutation. In conclusion, high levels of MMP-9 and circulating-free DNA BRAFV600E mutation are associated with poor PFS and OS. MMP-9 may represent a promising indicator of response to BRAF inhibitors in combination with the detection of BRAFV600E mutation

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. Funding: This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen

Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors.

BACKGROUND Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung cancer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identifying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. METHODS In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 peripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs. FINDINGS When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predictive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon-γ (IFN-γ) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs. CONCLUSIONS We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs. FUNDING This work was primarily funded by the European Research Council, the Swiss National Science Foundation, the Swiss Cancer League, and the Forschungsförderung of the Kantonsspital St. Gallen

EVALITA Evaluation of NLP and Speech Tools for Italian - December 17th, 2020

Welcome to EVALITA 2020! EVALITA is the evaluation campaign of Natural Language Processing and Speech Tools for Italian. EVALITA is an initiative of the Italian Association for Computational Linguistics (AILC, http://www.ai-lc.it) and it is endorsed by the Italian Association for Artificial Intelligence (AIxIA, http://www.aixia.it) and the Italian Association for Speech Sciences (AISV, http://www.aisv.it)

Biomarcatori Circolanti Indicativi di Risposta al Trattamento con Immunoterapia in Pazienti Affetti da Melanoma Metastatico: Ruolo del CD73

Nonostante i passi in avanti nel trattamento della patologia neoplastica, per alcune di esse, la prognosi rimane nefasta soprattutto nelle fasi avanzate. Esempio calzante è il melanoma maligno, il tumore più aggressivo della pelle, il cui tasso di sopravvivenza a 5 anni resta compreso tra 5-19%. A contrastare queste statistiche, negli ultimi anni ha contribuito l’ampliamento del panorama dei trattamenti terapeutici per il melanoma con l'introduzione di anticorpi immunomodulanti e di farmaci a bersaglio molecolare, che hanno mostrato una attività clinica obiettiva. Nonostante gli enormi progressi, lo sviluppo da parte delle cellule tumorali di meccanismi di resistenza ai trattamenti farmacologici e le eterogenee risposte cliniche ottenute dai pazienti sono tuttora grandissimi fattori limitanti il successo delle terapie. Nell’era della medicina personalizzata, al fine di superare questi ostacoli, è evidente la necessità di identificare marcatori prognostici e predittivi di risposta alle terapie, che permettano un’appropriata selezione dei pazienti che possano realmente beneficiare dal trattamento indirizzando in modo specifico le scelte terapeutiche. Negli ultimi anni, uno dei pathway di segnalazione studiato più a fondo e diventato argomento di grande interesse nella ricerca sul cancro, a causa di un numero crescente di evidenze che mostrano un suo coinvolgimento nella progressione tumorale e nelle metastasi, è il pathway dell'adenosina. In particolare, si è approfondito il ruolo del CD73, enzima coinvolto nella via di segnalazione dell’adenosina, nell'immunosoppressione e progressione tumorale, In tale contesto, ho fissato come obiettivo del percorso di Dottorato di Ricerca la valutazione del ruolo delle molecole coinvolte nel pathway dell’Adenosina, con particolare attenzione al CD73, quali potenziali biomarcatori di risposta all’immunoterapia con anti-PD-1 (Pembrolizumab e Nivolumab) in pazienti affetti da melanoma metastatico e quindi determinarne il ruolo prognostico e predittivo. Nello specifico, è stata valutata l’attività basale ed eventuali oscillazioni in corso di trattamento del CD73 solubile (sCD73) e la sua espressione proteica nel sangue periferico, è stata analizzata l’espressione del CD73 sulle sottopopolazioni linfocitarie circolanti CD8+ (linfociti T) in pazienti trattati con anti-PD-1 al fine di correlare i risultati ottenuti alla risposta terapeutica

A Dynamical Systems Characterisation of Atmospheric Jet Regimes

International audienceAtmospheric jet streams are typically separated into primarily “eddy-driven” (or polar-front) jets and primarily “thermally driven” (or subtropical) jets. Some regions also display “merged” jets, resulting from the (quasi-)collocation of the regions of eddy generation with the subtropical jet. The different locations and driving mechanisms of these jets arise from very different underlying mechanisms and result in very different jet characteristics. Here, we link the current understanding of dynamical jet maintenance mechanisms, mostly arising from conceptual or idealized models, to the phenomena observed in reanalysis data. We specifically focus on developing a unitary analysis framework grounded in dynamical systems theory, which may be applied to both idealized models and reanalysis, as well as allowing for direct intercomparison. Our results illustrate the effectiveness of dynamical systems indicators to diagnose jet regimes.Atmospheric jet streams are typically separated into primarily "eddy-driven", or "polar-front", jets and primarily "thermally-driven", or "subtropical" jets. Some regions also display "merged" jets, resulting from the (quasi) co-location of the regions of eddy generation with the subtropical jet. The different locations and driving mechanisms of these jets issue from very different underlying mechanisms, and result in very different jet characteristics. Here, we link the current understanding of the dynamical jet maintenance mechanisms, mostly issuing from conceptual or idealised models, to the phenomena observed in reanalysis data. We specifically focus on developing a unitary analysis framework, grounded in dynamical systems theory, which may be applied to both idealised models and reanalysis, and allow for direct intercomparison. Our results illustrate the use of dynamical systems indicators to diagnose jet regimes