1,720,985 research outputs found
The potential of BRAF-associated non-coding RNA as a therapeutic target in melanoma
No full textThe advent of targeted therapies and immune checkpoints inhibitors has enhanced the treatment of metastatic melanomas. Despite striking improvements of patients' survival, drug resistance continues to limit the efficacy of such treatments. Genetic and nongenetic/adaptive mechanisms of resistance could be involved; in the latter mechanism, noncoding RNAs (ncRNAs) are emerging as key players. Areas covered: This article outlines the current knowledge of ncRNA involvement in BRAF-mutant melanomas and the development of resistance to targeted/immunotherapies. We also discuss how ncRNAs can be exploited for the development of therapeutic and diagnostic approaches. Expert opinion: ncRNAs can be envisaged as powerful diagnostics and therapeutics. Despite progress in our knowledge about their deregulation in cancer, it is still difficult to derive universal and robust ncRNAs unique signatures of malignancy for diagnostic purposes, which need validation in large cohort of patients. Also, ncRNA specific targeting to melanoma cells in vivo requires the development of improved systemic delivery tools. In this regard, the development of stable nanodelivery particles seems to offer renewed hope for success in the clinic
Drug tolerance to target therapy in melanoma revealed at single cell level: What next?
No full textDrug resistance strongly impairs the efficacy of virtually every kind of anticancer therapy. This phenomenon is commonly fueled by intrinsic or acquired mechanisms. In this mini-review, focusing on BRAF-mutated melanoma as prototypical example, we analyze how recent studies that make use of single cell analysis identify the involvement of distinct transcriptional trajectories as the common thread at the basis of drug tolerance. The identification of these transcriptional trajectories provide a mechanistic basis for the development of both intrinsic and acquired drug resistance. These studies also suggest that hitting these transcriptional trajectories through personalized adaptive treatments can delay or abrogate the onset of drug resistance
Cancer stem cells and the slow cycling phenotype. how to cut the gordian knot driving resistance to therapy in melanoma
Get PDFCancer stem cells (CSCs) have historically been defined as slow cycling elements that are able to differentiate into mature cells but without dedifferentiation in the opposite direction. Thanks to advances in genomic and non-genomic technologies, the CSC theory has more recently been reconsidered in a dynamic manner according to a “phenotype switching” plastic model. Transcriptional reprogramming rewires this plasticity and enables heterogeneous tumors to influence cancer progression and to adapt themselves to drug exposure by selecting a subpopulation of slow cycling cells, similar in nature to the originally defined CSCs. This model has been conceptualized for malignant melanoma tailored to explain resistance to target therapies. Here, we conducted a bioinformatics analysis of available data directed to the identification of the molecular pathways sustaining slow cycling melanoma stem cells. Using this approach, we identified a signature of 25 genes that were assigned to four major clusters, namely 1) kinases and metabolic changes, 2) melanoma-associated proteins, 3) Hippo pathway and 4) slow cycling/CSCs factors. Furthermore, we show how a protein−protein interaction network may be the main driver of these melanoma cell subpopulations. Finally, mining The Cancer Genome Atlas (TCGA) data we evaluated the expression levels of this signature in the four melanoma mutational subtypes. The concomitant alteration of these genes correlates with the worst overall survival (OS) for melanoma patients harboring BRAF-mutations. All together these results underscore the potentiality to target this signature to selectively kill CSCs and to achieve disease control in melanoma
MicroRNA-driven deregulation of cytokine expression helps development of drug resistance in metastatic melanoma
No full textmicroRNAs are major components of the eukaryotic post-transcriptional machinery and are frequently deregulated during cancer development. Increasing evidence points to them also as key players in the establishment of drug resistance. In this review, we provide an updated overview of the role of miRNAs in melanoma development and drug resistance and postulate that they are able to drive these processes in concert with deregulation of inflammatory and angiogenic cytokine expression. Notably, we have identified by querying the Cancer Genome Atlas database, a defined set of miRNAs which mostly have an impact on the development of melanoma and have recognized the main downstream pathways controlled by them. Most importantly, these miRNAs, which are down-regulated in metastatic melanomas as compared to primary tumors, are also able to predict prognosis of BRAF-mutated melanoma patients. Finally, we discuss the possibility that a common miRNA signature characterizes not only acquired resistance to MAPKi but also innate resistance to anti-PD-1 immunotherapy, since these conditions are both associated with alterations of the same pro-angiogenetic and pro-inflammatory pathways
Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: an in vitro study
No full textBackground: BRAF + MEK inhibitors have become the standard of care for melanoma patients (approximately 50%) harboring BRAF-V600 mutations. However, drug resistance often impairs the efficacy of this combinatorial approach. Hence, the need to identify additional therapeutic approaches capable to control the development of drug resistance and to avoid disease relapse. Towards this goal, our group has been largely involved in the last years in the study of non-mutational mechanisms involved in the acquisition of drug resistance. For example, we reported that monoclonal antibodies targeting ErbB3 receptor are able to delay the emergence of resistance to target therapy in vitro and in vivo. More recently, we have also demonstrated that microRNAs are key players of resistance to target therapy in melanoma and that their targeting is able to restore drug sensitivity. Here, we have started to investigate whether reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS can act in combination with target therapy to fight the development of drug resistance.
Material and methods: Human melanoma cell lines, namely M14 and A375 harboring BRAF-V600E mutation have been treated with different concentration of either BRAFi and/or MEKi in the presence or not of the non-nucleoside RTI, i.e. SPV122. MTT and colony formation assays have been used to determine cell proliferation. Annexin V assay for apoptosis, cell cycle and mitochondrial membrane depolarization have been tested through FACS analyses. DNA double-strand breaks have been determined through Western Blot and Immunofluorescence analyses.
Results: Our present work has reported for the first time the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas in vitro. We show that the novel non-nucleoside RTI, SPV122 synergizes with BRAF and MEK inhibitors to: 1) impair BRAF-mutant melanoma cell growth; 2) induce apoptosis; 3) block cell cycle progression and 4) delay the emergence of resistance in vitro. Mechanistically, we also show that this combination provokes DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels.
Conclusions: Our in vitro results pave the way for the combinatorial use of RTi + BRAFi + MEKi as a novel therapeutic option for BRAF-mutant melanoma patients and warrant further investigation in in vivo models
Single cell analysis to dissect molecular heterogeneity and disease evolution in metastatic melanoma
Get PDFOriginally described as interpatient variability, tumour heterogeneity has now been demonstrated to occur intrapatiently, within the same lesion, or in different lesions of the same patient. Tumour heterogeneity involves both genetic and epigenetic changes. Intrapatient heterogeneity is responsible for generating subpopulations of cancer cells which undergo clonal evolution with time. Tumour heterogeneity develops also as a consequence of the selective pressure imposed by the immune system. It has been demonstrated that tumour heterogeneity and different spatiotemporal interactions between all the cellular compontents within the tumour microenvironment lead to cancer adaptation and to therapeutic pressure. In this context, the recent advent of single cell analysis approaches which are able to better study tumour heterogeneity from the genomic, transcriptomic and proteomic standpoint represent a major technological breakthrough. In this review, using metastatic melanoma as a prototypical example, we will focus on applying single cell analyses to the study of clonal trajectories which guide the evolution of drug resistance to targeted therapy
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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