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

[Cardiac sympathetic innervation imaging with myocardial MIBG scintigraphy]. FT Studio dell'innervazione cardiaca mediante scintigrafia miocardica con MIBG.

Metaiodobenzylguanidine (MIBG) was developed initially as a tracer for oncological imaging; when labeled with 123 I or 131 I, it may detect APUDomas, such as pheochromocytomas and paragangliomas. In the last years, MIBG has found an important role also in neurology and cardiology, as cardiac innervation tracer. Actually, MIBG cardiac imaging is a universally accepted method to estimate cardiac sympathetic innervations. This review covers the role of MIBG cardiac imaging in Parkinson disease and parkinsonisms, from the pathophysiological premises for cardiac denervation to new emerging data

Soluble CD73 in the peripheral blood: a potential biomarker in patients with advanced melanoma receiving nivolumab

Background: Anti-PD1 agents are successfully used in therapy to treat patients with advanced melanoma. Here, we retrospectively analysed the CD73 enzyme activity in the peripheral blood of in patients with metastatic melanoma receiving nivolumab. CD73 is an ectonucleotidase able to generate adenosine from AMP. Adenosine in the tumor microenvironment is a potent immune-suppressive mediator, so that inhibition of CD73-generating enzyme or blockade of adenosine receptors is a promising therapeutic strategy to fight cancer. Materials and methods: CD73 enzyme activity was retrospectively analysed in the plasma of patients before receiving nivolumab. Levels of CD73 enzyme activity was correlated with the survival and progression-free survival of the patients analysed in this study and a multivariate analysis was performed to evaluate the prognostic value of this factor. Results: 70% of the patients analysed in this study presented detectable CD73 activity in the plasma. High basal levels of sCD73 enzyme activity in serum were significantly associated with poor overall survival and progression-free survival in melanoma patients. In multivariate analysis, levels of CD73 significantly impact on both, overall survival and progression-free survival. Interestingly, we found that low levels of CD73 in the peripheral blood determined before treatment, were significantly associated with disease control rate to nivolumab. Patients who do not respond to nivolumab therapy instead presented higher levels of CD73 enzyme activity in the blood. Conclusion: Although our results need to be confirmed and validated, they suggest that the activity of CD73 in the peripheral blood of patients with metastatic melanoma might be useful as prognostic factor and potentially as predictor of response to nivolumab treatment. We also postulate that increased levels of CD73 may contribute to affect the response of immunotherapeutic agents in cancer patients

Expression of CD73 on CD8+/PD-1+cells as a new possible biomarker for advanced melanoma patients treated with nivolumab

Background: Anti-programmed death (PD)-1 monoclonal antibodies have changed the prognosis of metastatic melanoma, improving overall survival [1]. However, still a proportion of patients is unresponsive to these compounds, indicating the presence of other immunosuppressive mechanisms. Thus, the identification of reliable biomarkers to predict the response to checkpoint blockades is still an unmet need. Recent findings showed a tumor-induced immunosuppressive pathway, in which the extracellular adenosine produced by tumor-derived enzyme CD73 (5′-ectonucleotidase) promotes tumor growth by inhibiting immunosuppressive T-cell action [2]. Targeting adenosine generation by blockade of CD73 significantly enhances anti-tumor activity of anti-PD-1 drugs, inducing full regression in some tumor models [3]. The aim of the study was to investigate whether baseline levels of CD73+ on circulating CD8+, CD4+ and MDSCs cells could be considered as potential biomarkers in stage IV melanoma patients treated with nivolumab. Materials and methods: Blood samples from 36 advanced melanoma patients were taken before nivolumab treatment; blood populations were measured in frozen peripheral blood mononuclear cells (PBMCs) that were thawed and then rested briefly, and subjected to flow cytometry analysis for myeloid-derived suppressor cells (MDSCs: CD14+ CD33+ CD11b+ HLA-DR-/low), CD8+ and CD4+, alone or in association with PD-1 and CD73+. Results: Our data demonstrated that patients with lower baseline values of CD8+/PD-1+/CD73+ had high OS and PFS (34.8 and 19.2 months, respectively); conversely, patients with higher baseline frequency of these cells experienced lower OS and PFS (9.5 and 2.8 months, respectively; OS p < 0.003, PFS p < 0.007) (Tables 1, 2). In addition, increasing number of total CD8+ cells (p < 0.05) and especially of CD8+/PD-1+ cells (p < 0.04) were negatively correlated with survival (Table 1). Furthermore, the baseline values of MDSCs/CD73+ and CD4+/CD73+ cells showed no significant differences in survival. Conclusions: Our work indicates that the analysis of CD8+/PD-1+/CD73+ baseline levels in advanced melanoma patients treated with nivolumab could be associate to treatment outcome. Also, these preliminary results strengthen the therapeutic potential of anti-CD73 inhibitors, which are still in phase I of clinical trials, increasing the development of new treatment combinations strategies with other immune checkpoint monoclonal antibodies. Further studies on a larger number of patients are ongoing to confirm the data obtained

Baseline neutrophil-to-lymphocyte ratio (NLR) and derived NLR could predict overall survival in patients with advanced melanoma treated with nivolumab

Abstract Background Previous studies have suggested that elevated neutrophil-to-lymphocyte ratio (NLR) is prognostic for worse outcomes in patients with a variety of solid cancers, including those treated with immune checkpoint inhibitors. Methods This was a retrospective analysis of 97 consecutive patients with stage IV melanoma who were treated with nivolumab. Baseline NLR and derived (d) NLR were calculated and, along with other characteristics, correlated with progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. The best cutoff values for NLR and dNLR were derived using Cutoff Finder software based on an R routine which optimized the significance of the split between Kaplan-Meier survival curves. Results In univariate analysis, increasing absolute neutrophil count (ANC), NLR, dNLR and lactate dehydrogenase (LDH) (continuous variables) were all significantly associated with OS. Only NLR (hazard ratio [HR] = 2.85; 95% CI 1.60–5.08; p < 0.0001) and LDH (HR = 2.51; 95% CI 1.36–4.64; p < 0.0001) maintained a significant association with OS in multivariate analysis. Patients with baseline NLR ≥5 had significantly worse OS and PFS than patients with NLR < 5, as did patients with baseline dNLR ≥3 versus < 3. Optimal cut-off values were ≥ 4.7 for NLR and ≥ 3.8 for dNLR. Using this ≥4.7 cut-off for NLR, the values for OS and PFS were overlapping to the canonical cut-off for values, and dNLR< 3.8 was also associated with better OS and PFS. Conclusion Both Neutrophil-to-lymphocyte ratio (NLR) and derived (d) NLR were associated with improved survival when baseline levels were lower than cut-off values. NLR and dNLR are simple, inexpensive and readily available biomarkers that could be used to help predict response to immunotherapy in patients with advanced melanoma