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Advances and Novel Treatment Options in Metastatic Melanoma
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Advances and Novel Treatment Options in Metastatic Melanoma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 August 2020) | Viewed by 88054

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Antonio Facchiano

E-Mail Website
Guest Editor
Laboratory of Molecular Oncology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome, Italy
Interests: melanoma markers; angiogenic factors; melanoma therapy and diagnosis; autophagy
Special Issues, Collections and Topics in MDPI journals
Dr. Donatella Del Bufalo

E-Mail Website
Co-Guest Editor
Preclinical Models and New Therapeutic Agents Unit, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
Interests: melanoma; bcl-2; microenvironment; angiogenesis
Dr. Alessandra Carè

E-Mail Website
Co-Guest Editor
Center for Gender-Specific Medicine Oncology Unit, Istituto Superiore di Sanità, Rome, Italy
Interests: microRNAs; fatty acids; gender differences; melanoma therapeutic targets

Special Issue Information

Dear Colleagues,

The field of cancer treatments is experiencing a revolutionary age, with the continuous release of new effective drugs gradually changing the prognosis of several cancer types. This is true in the melanoma field as well. An unprecedented scenario is likely opening regarding melanoma treatment, where effective approaches, such as different drug or different strategy combinations may be available in a relatively short time.

An open view at the options available, at the different new research-lines going on, and at the bottlenecks is needed.

In the present Special Issue, manuscripts reporting original data or updated literature reviews in the melanoma field are sought. Manuscripts should focus on the known new effective molecular approaches or on the possible new molecular targets, strong candidates for future prognostic/therapeutic strategies. The molecular basis of the novel toxic/side effects and possible drawbacks related to the new drugs currently under clinical use are also a hot topic that will be addressed in the Special Issue. In addition, solid-based nutrition interventions and new acquisitions on microbiome-related melanoma studies are sought, as well as studies regarding how to improve quality of life in metastatic melanoma patients.

Manuscripts reporting at least one cartoon to be used as a visual-abstract are encouraged.

Dr. Antonio Facchiano
Dr. Donatella Del Bufalo
Dr. Alessandra Carè
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • melanoma
  • new drugs
  • biomarkers
  • microbiome
  • nutrition-based approaches
  • toxic effects
  • drug combination
  • strategy combination
  • quality of life

Published Papers (25 papers)

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Editorial

Jump to: Research, Review

4 pages, 211 KiB  
Editorial
Editorial on Special Issue “Advances and Novel Treatment Options in Metastatic Melanoma”
by Alessandra Carè, Donatella Del Bufalo and Antonio Facchiano
Cancers 2022, 14(3), 707; https://doi.org/10.3390/cancers14030707 - 29 Jan 2022
Cited by 2 | Viewed by 1095
Abstract
Investigating mechanisms controlling melanoma setup, development and progression is currently an extremely hot and rapidly evolving topic [...] Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)

Research

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19 pages, 2858 KiB  
Article
Molecular Targeting of HuR Oncoprotein Suppresses MITF and Induces Apoptosis in Melanoma Cells
by Rebaz Ahmed, Ranganayaki Muralidharan, Akhil Srivastava, Sarah E. Johnston, Yan D. Zhao, Suhendan Ekmekcioglu, Anupama Munshi and Rajagopal Ramesh
Cancers 2021, 13(2), 166; https://doi.org/10.3390/cancers13020166 - 06 Jan 2021
Cited by 13 | Viewed by 2823
Abstract
Background: Treatment of metastatic melanoma possesses challenges due to drug resistance and metastases. Recent advances in targeted therapy and immunotherapy have shown clinical benefits in melanoma patients with increased survival. However, a subset of patients who initially respond to targeted therapy relapse and [...] Read more.
Background: Treatment of metastatic melanoma possesses challenges due to drug resistance and metastases. Recent advances in targeted therapy and immunotherapy have shown clinical benefits in melanoma patients with increased survival. However, a subset of patients who initially respond to targeted therapy relapse and succumb to the disease. Therefore, efforts to identify new therapeutic targets are underway. Due to its role in stabilizing several oncoproteins’ mRNA, the human antigen R (HuR) has been shown as a promising molecular target for cancer therapy. However, little is known about its potential role in melanoma treatment. Methods: In this study, we tested the impact of siRNA-mediated gene silencing of HuR in human melanoma (MeWo, A375) and normal melanocyte cells in vitro. Cells were treated with HuR siRNA encapsulated in a lipid nanoparticle (NP) either alone or in combination with MEK inhibitor (U0126) and subjected to cell viability, cell-cycle, apoptosis, Western blotting, and cell migration and invasion assays. Cells that were untreated or treated with control siRNA-NP (C-NP) were included as controls. Results: HuR-NP treatment significantly reduced the expression of HuR and HuR-regulated oncoproteins, induced G1 cell cycle arrest, activated apoptosis signaling cascade, and mitigated melanoma cells’ aggressiveness while sparing normal melanocytes. Furthermore, we demonstrated that HuR-NP treatment significantly reduced the expression of the microphthalmia-associated transcription factor (MITF) in both MeWo and MITF-overexpressing MeWo cells (p < 0.05). Finally, combining HuR-NP with U0126 resulted in synergistic antitumor activity against MeWo cells (p < 0.01). Conclusion: HuR-NP exhibited antitumor activity in melanoma cells independent of their oncogenic B-RAF mutational status. Additionally, combinatorial therapy incorporating MEK inhibitor holds promise in overriding MITF-mediated drug resistance in melanoma. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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22 pages, 3111 KiB  
Article
BCL2L10 Is Overexpressed in Melanoma Downstream of STAT3 and Promotes Cisplatin and ABT-737 Resistance
by María Josefina Quezada, María Elisa Picco, María Belén Villanueva, María Victoria Castro, Gastón Barbero, Natalia Brenda Fernández, Edith Illescas and Pablo Lopez-Bergami
Cancers 2021, 13(1), 78; https://doi.org/10.3390/cancers13010078 - 30 Dec 2020
Cited by 14 | Viewed by 2864
Abstract
The anti-apoptotic proteins from the Bcl-2 family are important therapeutic targets since they convey resistance to anticancer regimens. Despite the suspected functional redundancy among the six proteins of this subfamily, both basic studies and therapeutic approaches have focused mainly on BCL2, Bcl-xL, and [...] Read more.
The anti-apoptotic proteins from the Bcl-2 family are important therapeutic targets since they convey resistance to anticancer regimens. Despite the suspected functional redundancy among the six proteins of this subfamily, both basic studies and therapeutic approaches have focused mainly on BCL2, Bcl-xL, and MCL1. The role of BCL2L10, another member of this group, has been poorly studied in cancer and never has been in melanoma. We describe here that BCL2L10 is abundantly and frequently expressed both in melanoma cell lines and tumor samples. We established that BCL2L10 expression is driven by STAT3-mediated transcription, and by using reporter assays, site-directed mutagenesis, and ChIP analysis, we identified the functional STAT3 responsive elements in the BCL2L10 promoter. BCL2L10 is a pro-survival factor in melanoma since its expression reduced the cytotoxic effects of cisplatin, dacarbazine, and ABT-737 (a BCL2, Bcl-xL, and Bcl-w inhibitor). Meanwhile, both genetic and pharmacological inhibition of BCL2L10 sensitized melanoma cells to cisplatin and ABT-737. Finally, BCL2L10 inhibited the cell death upon combination treatments of PLX-4032, a BRAF inhibitor, with ABT-737 or cisplatin. In summary, we determined that BCL2L10 is expressed in melanoma and contributes to cell survival. Hence, targeting BCL2L10 may enhance the clinical efficacy of other therapies for malignant melanoma. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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27 pages, 5829 KiB  
Article
Investigating Serum and Tissue Expression Identified a Cytokine/Chemokine Signature as a Highly Effective Melanoma Marker
by Marco Cesati, Francesca Scatozza, Daniela D’Arcangelo, Gian Carlo Antonini-Cappellini, Stefania Rossi, Claudio Tabolacci, Maurizio Nudo, Enzo Palese, Luigi Lembo, Giovanni Di Lella, Francesco Facchiano and Antonio Facchiano
Cancers 2020, 12(12), 3680; https://doi.org/10.3390/cancers12123680 - 08 Dec 2020
Cited by 12 | Viewed by 3411
Abstract
The identification of reliable and quantitative melanoma biomarkers may help an early diagnosis and may directly affect melanoma mortality and morbidity. The aim of the present study was to identify effective biomarkers by investigating the expression of 27 cytokines/chemokines in melanoma compared to [...] Read more.
The identification of reliable and quantitative melanoma biomarkers may help an early diagnosis and may directly affect melanoma mortality and morbidity. The aim of the present study was to identify effective biomarkers by investigating the expression of 27 cytokines/chemokines in melanoma compared to healthy controls, both in serum and in tissue samples. Serum samples were from 232 patients recruited at the IDI-IRCCS hospital. Expression was quantified by xMAP technology, on 27 cytokines/chemokines, compared to the control sera. RNA expression data of the same 27 molecules were obtained from 511 melanoma- and healthy-tissue samples, from the GENT2 database. Statistical analysis involved a 3-step approach: analysis of the single-molecules by Mann–Whitney analysis; analysis of paired-molecules by Pearson correlation; and profile analysis by the machine learning algorithm Support Vector Machine (SVM). Single-molecule analysis of serum expression identified IL-1b, IL-6, IP-10, PDGF-BB, and RANTES differently expressed in melanoma (p < 0.05). Expression of IL-8, GM-CSF, MCP-1, and TNF-α was found to be significantly correlated with Breslow thickness. Eotaxin and MCP-1 were found differentially expressed in male vs. female patients. Tissue expression analysis identified very effective marker/predictor genes, namely, IL-1Ra, IL-7, MIP-1a, and MIP-1b, with individual AUC values of 0.88, 0.86, 0.93, 0.87, respectively. SVM analysis of the tissue expression data identified the combination of these four molecules as the most effective signature to discriminate melanoma patients (AUC = 0.98). Validation, using the GEPIA2 database on an additional 1019 independent samples, fully confirmed these observations. The present study demonstrates, for the first time, that the IL-1Ra, IL-7, MIP-1a, and MIP-1b gene signature discriminates melanoma from control tissues with extremely high efficacy. We therefore propose this 4-molecule combination as an effective melanoma marker. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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21 pages, 2614 KiB  
Article
Cancer Stem Cells and the Slow Cycling Phenotype: How to Cut the Gordian Knot Driving Resistance to Therapy in Melanoma
by Luigi Fattore, Rita Mancini and Gennaro Ciliberto
Cancers 2020, 12(11), 3368; https://doi.org/10.3390/cancers12113368 - 13 Nov 2020
Cited by 17 | Viewed by 2502
Abstract
Cancer 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 [...] Read more.
Cancer 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. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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23 pages, 3523 KiB  
Article
ShcD Binds DOCK4, Promotes Ameboid Motility and Metastasis Dissemination, Predicting Poor Prognosis in Melanoma
by Ewa Aladowicz, Letizia Granieri, Federica Marocchi, Simona Punzi, Giuseppina Giardina, Pier Francesco Ferrucci, Giovanni Mazzarol, Maria Capra, Giuseppe Viale, Stefano Confalonieri, Sara Gandini, Fiorenza Lotti and Luisa Lanfrancone
Cancers 2020, 12(11), 3366; https://doi.org/10.3390/cancers12113366 - 13 Nov 2020
Cited by 5 | Viewed by 2281
Abstract
Metastases are the primary cause of cancer-related deaths. The underlying molecular and biological mechanisms remain, however, elusive, thus preventing the design of specific therapies. In melanomas, the metastatic process is influenced by the acquisition of metastasis-associated mutational and epigenetic traits and the activation [...] Read more.
Metastases are the primary cause of cancer-related deaths. The underlying molecular and biological mechanisms remain, however, elusive, thus preventing the design of specific therapies. In melanomas, the metastatic process is influenced by the acquisition of metastasis-associated mutational and epigenetic traits and the activation of metastatic-specific signaling pathways in the primary melanoma. In the current study, we investigated the role of an adaptor protein of the Shc family (ShcD) in the acquisition of metastatic properties by melanoma cells, exploiting our cohort of patient-derived xenografts (PDXs). We provide evidence that the depletion of ShcD expression increases a spread cell shape and the capability of melanoma cells to attach to the extracellular matrix while its overexpression switches their morphology from elongated to rounded on 3D matrices, enhances cells’ invasive phenotype, as observed on collagen gel, and favors metastasis formation in vivo. ShcD overexpression sustains amoeboid movement in melanoma cells, by suppressing the Rac1 signaling pathway through the confinement of DOCK4 in the cytoplasm. Inactivation of the ShcD signaling pathway makes melanoma cells more sensitive to therapeutic treatments. Consistently, ShcD expression predicts poor outcome in a cohort of 183 primary melanoma patients. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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15 pages, 1067 KiB  
Article
Multimodal Treatment of Advanced Mucosal Melanoma in the Era of Modern Immunotherapy
by Pawel Teterycz, Anna M. Czarnecka, Alice Indini, Mateusz J. Spałek, Alice Labianca, Pawel Rogala, Bożena Cybulska-Stopa, Pietro Quaglino, Umberto Ricardi, Serena Badellino, Anna Szumera-Ciećkiewicz, Slawomir Falkowski, Mario Mandala and Piotr Rutkowski
Cancers 2020, 12(11), 3131; https://doi.org/10.3390/cancers12113131 - 26 Oct 2020
Cited by 14 | Viewed by 2625
Abstract
Mucosal melanoma is a rare disease epidemiologically and molecularly distinct from cutaneous melanoma developing from melanocytes located in mucosal membranes. Little is known about its therapy. In this paper, we aimed to evaluate the results of immunotherapy and radiotherapy in a group of [...] Read more.
Mucosal melanoma is a rare disease epidemiologically and molecularly distinct from cutaneous melanoma developing from melanocytes located in mucosal membranes. Little is known about its therapy. In this paper, we aimed to evaluate the results of immunotherapy and radiotherapy in a group of patients with advanced mucosal melanoma, based on the experience of five high-volume centers in Poland and Italy. There were 82 patients (53 female, 29 male) included in this retrospective study. The median age in this group was 67.5 (IQR: 57.25–75.75). All patients received anti-PD1 or anti-CTLA4 antibodies in the first or second line of treatment. Twenty-three patients received radiotherapy during anti-PD1 treatment. In the first-line treatment, the median progression-free survival (PFS) reached six months in the anti-PD1 group, which was statistically better than 3.1 months in the other modalities group (p = 0.004). The median overall survival (OS) was 16.3 months (CI: 12.1–22.3) in the whole cohort. Patients who received radiotherapy (RT) during the anti-PD1 treatment had a median PFS of 8.9 months (CI: 7.4–NA), whereas patients treated with single-modality anti-PD1 therapy had a median PFS of 4.2 months (CI: 3.0–7.8); this difference was statistically significant (p = 0.047). Anti-PD1 antibodies are an effective treatment option in advanced mucosal melanoma (MM). The addition of RT may have been beneficial in the selected subgroup of mucosal melanoma patients. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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15 pages, 1790 KiB  
Article
Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII
by Gaia Giuntini, Sara Monaci, Ylenia Cau, Mattia Mori, Antonella Naldini and Fabio Carraro
Cancers 2020, 12(10), 3018; https://doi.org/10.3390/cancers12103018 - 17 Oct 2020
Cited by 13 | Viewed by 2609
Abstract
Background: Intratumoral hypoxia contributes to cancer progression and poor prognosis. Carbonic anhydrases IX (CAIX) and XII (CAXII) play pivotal roles in tumor cell adaptation and survival, as aberrant Hedgehog (Hh) pathway does. In malignant melanoma both features have been investigated for years, but [...] Read more.
Background: Intratumoral hypoxia contributes to cancer progression and poor prognosis. Carbonic anhydrases IX (CAIX) and XII (CAXII) play pivotal roles in tumor cell adaptation and survival, as aberrant Hedgehog (Hh) pathway does. In malignant melanoma both features have been investigated for years, but they have not been correlated before and/or identified as a potential pharmacological target. Here, for the first time, we demonstrated that malignant melanoma cell motility was impaired by targeting CAXII via either CAs inhibitors or through the inhibition of the Hh pathway. Methods: We tested cell motility in three melanoma cell lines (WM-35, SK-MEL28, and A375), with different invasiveness capabilities. To this end we performed a scratch assay in the presence of the smoothened (SMO) antagonist cyclopamine (cyclo) or CAs inhibitors under normoxia or hypoxia. Then, we analyzed the invasiveness potential in the cell lines which were more affected by cyclo and CAs inhibitors (SK-MEL28 and A375). Western blot was employed to assess the expression of the hypoxia inducible factor 1α, CAXII, and FAK phosphorylation. Immunofluorescence staining was performed to verify the blockade of CAXII expression. Results: Hh inhibition reduced melanoma cell migration and CAXII expression under both normoxic and hypoxic conditions. Interestingly, basal CAXII expression was higher in the two more aggressive melanoma cell lines. Finally, a direct CAXII blockade impaired melanoma cell migration and invasion under hypoxia. This was associated with a decrease of FAK phosphorylation and metalloprotease activities. Conclusions: CAXII may be used as a target for melanoma treatment not only through its direct inhibition, but also through Hh blockade. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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15 pages, 856 KiB  
Article
Arthralgia Induced by BRAF Inhibitor Therapy in Melanoma Patients
by Martin Salzmann, Karolina Benesova, Kristina Buder-Bakhaya, Dimitrios Papamichail, Antonia Dimitrakopoulou-Strauss, Hanns-Martin Lorenz, Alexander H. Enk and Jessica C. Hassel
Cancers 2020, 12(10), 3004; https://doi.org/10.3390/cancers12103004 - 16 Oct 2020
Cited by 3 | Viewed by 2007
Abstract
Introduction: BRAF inhibitors (BRAFi), commonly used in BRAF-mutated metastatic melanoma (MM) treatment, frequently cause arthralgia. Although this is one of the most common side effects, it has not been characterized yet. Methods: We retrospectively included all patients treated with BRAFi +/− MEK inhibitors [...] Read more.
Introduction: BRAF inhibitors (BRAFi), commonly used in BRAF-mutated metastatic melanoma (MM) treatment, frequently cause arthralgia. Although this is one of the most common side effects, it has not been characterized yet. Methods: We retrospectively included all patients treated with BRAFi +/− MEK inhibitors (MEKi) for MM at the National Center for Tumor Diseases (Heidelberg) between 2010 and 2018 and reviewed patient charts for the occurrence and management of arthralgia. The evaluation was supplemented by an analysis of frozen sera. Results: We included 154 patients (63% males); 31% (48/154) of them reported arthralgia with a median onset of 21 days after the start of the therapy. Arthralgia mostly affected small joints (27/36, 75%) and less frequently large joints (19/36, 53%). The most commonly affected joints were in fingers (19/36, 53%), wrists (16/36, 44%), and knees (12/36, 33%). In 67% (24/36) of the patients, arthralgia occurred with a symmetrical polyarthritis, mainly of small joints, resembling the pattern typically observed in patients affected by rheumatoid arthritis (RA), for which a role of the MAPK signaling pathway was previously described. Patients were negative for antinuclear antibodies, anti-citrullinated protein antibodies, and rheumatoid factor; arthritis was visible in 10 of 13 available PET–CT scans. The development of arthralgia was linked to better progression-free survival and overall survival. Conclusion: Arthralgia is a common side effect in patients receiving BRAFi +/− MEKi therapy and often presents a clinical pattern similar to that observed in RA patients. Its occurrence was associated with longer-lasting tumor control. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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18 pages, 3528 KiB  
Article
Loss of Two-Pore Channel 2 (TPC2) Expression Increases the Metastatic Traits of Melanoma Cells by a Mechanism Involving the Hippo Signalling Pathway and Store-Operated Calcium Entry
by Antonella D’Amore, Ali Ahmed Hanbashi, Silvia Di Agostino, Fioretta Palombi, Andrea Sacconi, Aniruddha Voruganti, Marilena Taggi, Rita Canipari, Giovanni Blandino, John Parrington and Antonio Filippini
Cancers 2020, 12(9), 2391; https://doi.org/10.3390/cancers12092391 - 24 Aug 2020
Cited by 21 | Viewed by 3583
Abstract
Melanoma is one of the most aggressive and treatment-resistant human cancers. The two-pore channel 2 (TPC2) is located on late endosomes, lysosomes and melanosomes. Here, we characterized how TPC2 knockout (KO) affected human melanoma cells derived from a metastatic site. TPC2 KO increased [...] Read more.
Melanoma is one of the most aggressive and treatment-resistant human cancers. The two-pore channel 2 (TPC2) is located on late endosomes, lysosomes and melanosomes. Here, we characterized how TPC2 knockout (KO) affected human melanoma cells derived from a metastatic site. TPC2 KO increased these cells’ ability to invade the extracelullar matrix and was associated with the increased expression of mesenchymal markers ZEB-1, Vimentin and N-Cadherin, and the enhanced secretion of MMP9. TPC2 KO also activated genes regulated by YAP/TAZ, which are key regulators of tumourigenesis and metastasis. Expression levels of ORAI1, a component of store-operated Ca2+ entry (SOCE), and PKC-βII, part of the HIPPO pathway that negatively regulates YAP/TAZ activity, were reduced by TPC2 KO and RNA interference knockdown. We propose a cellular mechanism mediated by ORAI1/Ca2+/PKC-βII to explain these findings. Highlighting their potential clinical significance, patients with metastatic tumours showed a reduction in TPC2 expression. Our research indicates a novel role of TPC2 in melanoma. While TPC2 loss may not activate YAP/TAZ target genes in primary melanoma, in metastatic melanoma it could activate such genes and increase cancer aggressiveness. These findings aid the understanding of tumourigenesis mechanisms and could provide new diagnostic and treatment strategies for skin cancer and other metastatic cancers. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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23 pages, 2956 KiB  
Article
Plasmacytoid Dendritic Cell Impairment in Metastatic Melanoma by Lactic Acidosis
by Matilde Monti, Raffaella Vescovi, Francesca Consoli, Davide Farina, Daniele Moratto, Alfredo Berruti, Claudia Specchia and William Vermi
Cancers 2020, 12(8), 2085; https://doi.org/10.3390/cancers12082085 - 28 Jul 2020
Cited by 17 | Viewed by 2087
Abstract
The introduction of targeted therapies and immunotherapies has significantly improved the outcome of metastatic melanoma (MM) patients. These approaches rely on immune functions for their anti-melanoma response. Plasmacytoid dendritic cells (pDCs) exhibit anti-tumor function by production of effector molecules, type I interferons (I-IFNs), [...] Read more.
The introduction of targeted therapies and immunotherapies has significantly improved the outcome of metastatic melanoma (MM) patients. These approaches rely on immune functions for their anti-melanoma response. Plasmacytoid dendritic cells (pDCs) exhibit anti-tumor function by production of effector molecules, type I interferons (I-IFNs), and cytokines. Tissue and blood pDCs result compromised in MM, although these findings are still partially conflicting. This study reports that blood pDCs were dramatically depleted in MM, particularly in patients with high lactate dehydrogenase (LDH) and high tumor burden; the reduced pDC frequency was associated with poor overall survival. Circulating pDCs resulted also in significant impairment in interferon alpha (IFN-α) and C-X-C motif chemokine 10 (CXCL10) production in response to toll-like receptor (TLR)-7/8 agonists; on the contrary, the response to TLR-9 agonist remained intact. In the BRAFV600+ subgroup, no recovery of pDC frequency could be obtained by BRAF and MEK inhibitors (BRAFi; MEKi), whereas their function was partially rescued. Mechanistically, in vitro exposure to lactic acidosis impaired both pDC viability and function. In conclusion, pDCs from MM patients were found to be severely impaired, with a potential role for lactic acidosis. Short-term responses to treatments were not associated with pDC recovery, suggesting long-lasting effects on their compartment. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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16 pages, 1235 KiB  
Article
WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion
by Purusottam Mohapatra, Vikas Yadav, Maren Toftdahl and Tommy Andersson
Cancers 2020, 12(2), 346; https://doi.org/10.3390/cancers12020346 - 04 Feb 2020
Cited by 17 | Viewed by 3210
Abstract
WNT5A is a well-known mediator of melanoma cell invasion and metastasis via its ability to activate protein kinase C (PKC), which is monitored by phosphorylation of the endogenous PKC substrate myristoylated alanine-rich c-kinase substrate (MARCKS). However, a possible direct contribution of MARCKS in [...] Read more.
WNT5A is a well-known mediator of melanoma cell invasion and metastasis via its ability to activate protein kinase C (PKC), which is monitored by phosphorylation of the endogenous PKC substrate myristoylated alanine-rich c-kinase substrate (MARCKS). However, a possible direct contribution of MARCKS in WNT5A-mediated melanoma cell invasion has not been investigated. Analyses of melanoma patient databases suggested that similar to WNT5A expression, MARCKS expression appears to be associated with increased metastasis. A relationship between the two is suggested by the findings that recombinant WNT5A (rWNT5A) induces both increased expression and phosphorylation of MARCKS, whereas WNT5A silencing does the opposite. Moreover, WNT5A-induced invasion of melanoma cells was blocked by siRNA targeting MARCKS, indicating a crucial role of MARCKS expression and/or its phosphorylation. Next, we employed a peptide inhibitor of MARCKS phosphorylation that did not affect MARCKS expression and found that it abolished WNT5A-induced melanoma cell invasion. Similarly, rWNT5A induced the accumulation of phosphorylated MARCKS in membrane protrusions at the leading edge of melanoma cells. Our results demonstrate that WNT5A-induced phosphorylation of MARCKS is not only an indicator of PKC activity but also a crucial regulator of the metastatic behavior of melanoma and therefore an attractive future antimetastatic target in melanoma patients. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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Review

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23 pages, 719 KiB  
Review
Molecular and Immune Biomarkers for Cutaneous Melanoma: Current Status and Future Prospects
by Lorenzo Pilla, Andrea Alberti, Pierluigi Di Mauro, Maria Gemelli, Viola Cogliati, Marina Elena Cazzaniga, Paolo Bidoli and Cristina Maccalli
Cancers 2020, 12(11), 3456; https://doi.org/10.3390/cancers12113456 - 20 Nov 2020
Cited by 11 | Viewed by 3023
Abstract
Advances in the genomic, molecular and immunological make-up of melanoma allowed the development of novel targeted therapy and of immunotherapy, leading to changes in the paradigm of therapeutic interventions and improvement of patients’ overall survival. Nevertheless, the mechanisms regulating either the responsiveness or [...] Read more.
Advances in the genomic, molecular and immunological make-up of melanoma allowed the development of novel targeted therapy and of immunotherapy, leading to changes in the paradigm of therapeutic interventions and improvement of patients’ overall survival. Nevertheless, the mechanisms regulating either the responsiveness or the resistance of melanoma patients to therapies are still mostly unknown. The development of either the combinations or of the sequential treatment of different agents has been investigated but without a strongly molecularly motivated rationale. The need for robust biomarkers to predict patients’ responsiveness to defined therapies and for their stratification is still unmet. Progress in immunological assays and genomic techniques as long as improvement in designing and performing studies monitoring the expression of these markers along with the evolution of the disease allowed to identify candidate biomarkers. However, none of them achieved a definitive role in predicting patients’ clinical outcomes. Along this line, the cross-talk of melanoma cells with tumor microenvironment plays an important role in the evolution of the disease and needs to be considered in light of the role of predictive biomarkers. The overview of the relationship between the molecular basis of melanoma and targeted therapies is provided in this review, highlighting the benefit for clinical responses and the limitations. Moreover, the role of different candidate biomarkers is described together with the technical approaches for their identification. The provided evidence shows that progress has been achieved in understanding the molecular basis of melanoma and in designing advanced therapeutic strategies. Nevertheless, the molecular determinants of melanoma and their role as biomarkers predicting patients’ responsiveness to therapies warrant further investigation with the vision of developing more effective precision medicine. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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22 pages, 976 KiB  
Review
A Framework of Major Tumor-Promoting Signal Transduction Pathways Implicated in Melanoma-Fibroblast Dialogue
by Barbara Bellei, Emilia Migliano and Mauro Picardo
Cancers 2020, 12(11), 3400; https://doi.org/10.3390/cancers12113400 - 17 Nov 2020
Cited by 14 | Viewed by 2714
Abstract
The development of a modified stromal microenvironment in response to neoplastic onset is a common feature of many tumors including cutaneous melanoma. At all stages, melanoma cells are embedded in a complex tissue composed by extracellular matrix components and several different cell populations. [...] Read more.
The development of a modified stromal microenvironment in response to neoplastic onset is a common feature of many tumors including cutaneous melanoma. At all stages, melanoma cells are embedded in a complex tissue composed by extracellular matrix components and several different cell populations. Thus, melanomagenesis is not only driven by malignant melanocytes, but also by the altered communication between melanocytes and non-malignant cell populations, including fibroblasts, endothelial and immune cells. In particular, cancer-associated fibroblasts (CAFs), also referred as melanoma-associated fibroblasts (MAFs) in the case of melanoma, are the most abundant stromal cells and play a significant contextual role in melanoma initiation, progression and metastasis. As a result of dynamic intercellular molecular dialogue between tumor and the stroma, non-neoplastic cells gain specific phenotypes and functions that are pro-tumorigenic. Targeting MAFs is thus considered a promising avenue to improve melanoma therapy. Growing evidence demonstrates that aberrant regulation of oncogenic signaling is not restricted to transformed cells but also occurs in MAFs. However, in some cases, signaling pathways present opposite regulation in melanoma and surrounding area, suggesting that therapeutic strategies need to carefully consider the tumor–stroma equilibrium. In this novel review, we analyze four major signaling pathways implicated in melanomagenesis, TGF-β, MAPK, Wnt/β-catenin and Hyppo signaling, from the complementary point of view of tumor cells and the microenvironment. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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15 pages, 276 KiB  
Review
Functional Characterization of Cholinergic Receptors in Melanoma Cells
by Anna Maria Lucianò and Ada Maria Tata
Cancers 2020, 12(11), 3141; https://doi.org/10.3390/cancers12113141 - 27 Oct 2020
Cited by 8 | Viewed by 2508
Abstract
In the last two decades, the scientific community has come to terms with the importance of non-neural acetylcholine in light of its multiple biological and pathological functions within and outside the nervous system. Apart from its well-known physiological role both in the central [...] Read more.
In the last two decades, the scientific community has come to terms with the importance of non-neural acetylcholine in light of its multiple biological and pathological functions within and outside the nervous system. Apart from its well-known physiological role both in the central and peripheral nervous systems, in the autonomic nervous system, and in the neuromuscular junction, the expression of the acetylcholine receptors has been detected in different peripheral organs. This evidence has contributed to highlight new roles for acetylcholine in various biological processes, (e.g., cell viability, proliferation, differentiation, migration, secretion). In addition, growing evidence in recent years has also demonstrated new roles for acetylcholine and its receptors in cancer, where they are involved in the modulation of cell proliferation, apoptosis, angiogenesis, and epithelial mesenchymal transition. In this review, we describe the functional characterization of acetylcholine receptors in different tumor types, placing attention on melanoma. The latest set of data accessible through literature, albeit limited, highlights how cholinergic receptors both of muscarinic and nicotinic type can play a relevant role in the migratory processes of melanoma cells, suggesting their possible involvement in invasion and metastasis. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
18 pages, 4666 KiB  
Review
Circulating Tumor DNA Testing Opens New Perspectives in Melanoma Management
by Alessandra Sacco, Laura Forgione, Marianeve Carotenuto, Antonella De Luca, Paolo A. Ascierto, Gerardo Botti and Nicola Normanno
Cancers 2020, 12(10), 2914; https://doi.org/10.3390/cancers12102914 - 10 Oct 2020
Cited by 27 | Viewed by 3052
Abstract
Malignant melanoma accounts for about 1% of all skin cancers, but it causes most of the skin cancer-related deaths. Circulating tumor DNA (ctDNA) testing is emerging as a relevant tool for the diagnosis and monitoring of cancer. The availability of highly sensitive techniques, [...] Read more.
Malignant melanoma accounts for about 1% of all skin cancers, but it causes most of the skin cancer-related deaths. Circulating tumor DNA (ctDNA) testing is emerging as a relevant tool for the diagnosis and monitoring of cancer. The availability of highly sensitive techniques, including next generation sequencing (NGS)-based panels, has increased the fields of application of ctDNA testing. While ctDNA-based tests for the early detection of melanoma are not available yet, perioperative ctDNA analysis in patients with surgically resectable melanoma offers relevant prognostic information: i) the detection of ctDNA before surgery correlates with the extent and the aggressiveness of the disease; ii) ctDNA testing after surgery/adjuvant therapy identifies minimal residual disease; iii) testing ctDNA during the follow-up can detect a tumor recurrence, anticipating clinical/radiological progression. In patients with advanced melanoma, several studies have demonstrated that the analysis of ctDNA can better depict tumor heterogeneity and provides relevant prognostic information. In addition, ctDNA testing during treatment allows assessing the response to systemic therapy and identifying resistance mechanisms. Although validation in prospective clinical trials is needed for most of these approaches, ctDNA testing opens up new scenarios in the management of melanoma patients that could lead to improvements in the diagnosis and therapy of this disease. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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18 pages, 864 KiB  
Review
Advances in Natural or Synthetic Nanoparticles for Metastatic Melanoma Therapy and Diagnosis
by Maria Beatrice Arasi, Francesca Pedini, Sonia Valentini, Nadia Felli and Federica Felicetti
Cancers 2020, 12(10), 2893; https://doi.org/10.3390/cancers12102893 - 09 Oct 2020
Cited by 15 | Viewed by 2602
Abstract
Advanced melanoma is still a major challenge in oncology. In the early stages, melanoma can be treated successfully with surgery and the survival rate is high, nevertheless the survival rate drops drastically after metastasis dissemination. The identification of parameters predictive of the prognosis [...] Read more.
Advanced melanoma is still a major challenge in oncology. In the early stages, melanoma can be treated successfully with surgery and the survival rate is high, nevertheless the survival rate drops drastically after metastasis dissemination. The identification of parameters predictive of the prognosis to support clinical decisions and of new efficacious therapies are important to ensure patients the best possible prognosis. Recent progress in nanotechnology allowed the development of nanoparticles able to protect drugs from degradation and to deliver the drug to the tumor. Modification of the nanoparticle surface by specific molecules improves retention and accumulation in the target tissue. In this review, we describe the potential role of nanoparticles in advanced melanoma treatment and discuss the current efforts of designing polymeric nanoparticles for controlled drug release at the site upon injection. In addition, we highlight the advances as well as the challenges of exosome-based nanocarriers as drug vehicles. We place special focus on the advantages of these natural nanocarriers in delivering various cargoes in advanced melanoma treatment. We also describe the current advances in knowledge of melanoma-related exosomes, including their biogenesis, molecular contents and biological functions, focusing our attention on their utilization for early diagnosis and prognosis in melanoma disease. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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26 pages, 1659 KiB  
Review
Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy
by Italia Falcone, Fabiana Conciatori, Chiara Bazzichetto, Gianluigi Ferretti, Francesco Cognetti, Ludovica Ciuffreda and Michele Milella
Cancers 2020, 12(10), 2870; https://doi.org/10.3390/cancers12102870 - 06 Oct 2020
Cited by 62 | Viewed by 4991
Abstract
Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was [...] Read more.
Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase kinase (MEK), v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immunotherapy. However, despite the progress made in the melanoma treatment, primary and/or acquired drug resistance remains an unresolved problem. The molecular dynamics that promote this phenomenon are very complex but several studies have shown that the tumor microenvironment (TME) plays, certainly, a key role. In this review, we will describe the new melanoma treatment approaches and we will analyze the mechanisms by which TME promotes resistance to targeted therapy and immunotherapy. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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29 pages, 3315 KiB  
Review
Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review
by Ilaria Proietti, Nevena Skroza, Nicoletta Bernardini, Ersilia Tolino, Veronica Balduzzi, Anna Marchesiello, Simone Michelini, Salvatore Volpe, Alessandra Mambrin, Giorgio Mangino, Giovanna Romeo, Patrizia Maddalena, Catherine Rees and Concetta Potenza
Cancers 2020, 12(10), 2801; https://doi.org/10.3390/cancers12102801 - 29 Sep 2020
Cited by 70 | Viewed by 8084
Abstract
This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: [...] Read more.
This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of ‘escape routes’, so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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28 pages, 1149 KiB  
Review
Oncogenic Tyrosine Phosphatases: Novel Therapeutic Targets for Melanoma Treatment
by Elisa Pardella, Erica Pranzini, Angela Leo, Maria Letizia Taddei, Paolo Paoli and Giovanni Raugei
Cancers 2020, 12(10), 2799; https://doi.org/10.3390/cancers12102799 - 29 Sep 2020
Cited by 9 | Viewed by 3547
Abstract
Despite a large number of therapeutic options available, malignant melanoma remains a highly fatal disease, especially in its metastatic forms. The oncogenic role of protein tyrosine phosphatases (PTPs) is becoming increasingly clear, paving the way for novel antitumor treatments based on their inhibition. [...] Read more.
Despite a large number of therapeutic options available, malignant melanoma remains a highly fatal disease, especially in its metastatic forms. The oncogenic role of protein tyrosine phosphatases (PTPs) is becoming increasingly clear, paving the way for novel antitumor treatments based on their inhibition. In this review, we present the oncogenic PTPs contributing to melanoma progression and we provide, where available, a description of new inhibitory strategies designed against these enzymes and possibly useful in melanoma treatment. Considering the relevance of the immune infiltrate in supporting melanoma progression, we also focus on the role of PTPs in modulating immune cell activity, identifying interesting therapeutic options that may support the currently applied immunomodulating approaches. Collectively, this information highlights the value of going further in the development of new strategies targeting oncogenic PTPs to improve the efficacy of melanoma treatment. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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Graphical abstract

28 pages, 781 KiB  
Review
Molecular Insights and Emerging Strategies for Treatment of Metastatic Uveal Melanoma
by Fabiana Mallone, Marta Sacchetti, Alessandro Lambiase and Antonietta Moramarco
Cancers 2020, 12(10), 2761; https://doi.org/10.3390/cancers12102761 - 25 Sep 2020
Cited by 26 | Viewed by 3630
Abstract
Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than [...] Read more.
Uveal melanoma (UM) is the most common intraocular cancer. In recent decades, major advances have been achieved in the diagnosis and prognosis of UM allowing for tailored treatments. However, nearly 50% of patients still develop metastatic disease with survival rates of less than 1 year. There is currently no standard of adjuvant and metastatic treatment in UM, and available therapies are ineffective resulting from cutaneous melanoma protocols. Advances and novel treatment options including liver-directed therapies, immunotherapy, and targeted-therapy have been investigated in UM-dedicated clinical trials on single compounds or combinational therapies, with promising results. Therapies aimed at prolonging or targeting metastatic tumor dormancy provided encouraging results in other cancers, and need to be explored in UM. In this review, the latest progress in the diagnosis, prognosis, and treatment of UM in adjuvant and metastatic settings are discussed. In addition, novel insights into tumor genetics, biology and immunology, and the mechanisms underlying metastatic dormancy are discussed. As evident from the numerous studies discussed in this review, the increasing knowledge of this disease and the promising results from testing of novel individualized therapies could offer future perspectives for translating in clinical use. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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45 pages, 1709 KiB  
Review
Essential Oils and Their Main Chemical Components: The Past 20 Years of Preclinical Studies in Melanoma
by Marta Di Martile, Stefania Garzoli, Rino Ragno and Donatella Del Bufalo
Cancers 2020, 12(9), 2650; https://doi.org/10.3390/cancers12092650 - 16 Sep 2020
Cited by 19 | Viewed by 6535
Abstract
The last two decades have seen the development of effective therapies, which have saved the lives of a large number of melanoma patients. However, therapeutic options are still limited for patients without BRAF mutations or in relapse from current treatments, and severe side [...] Read more.
The last two decades have seen the development of effective therapies, which have saved the lives of a large number of melanoma patients. However, therapeutic options are still limited for patients without BRAF mutations or in relapse from current treatments, and severe side effects often occur during therapy. Thus, additional insights to improve treatment efficacy with the aim to decrease the likelihood of chemoresistance, as well as reducing side effects of current therapies, are required. Natural products offer great opportunities for the discovery of antineoplastic drugs, and still represent a useful source of novel molecules. Among them, essential oils, representing the volatile fraction of aromatic plants, are always being actively investigated by several research groups and show promising biological activities for their use as complementary or alternative medicine for several diseases, including cancer. In this review, we focused on studies reporting the mechanism through which essential oils exert antitumor action in preclinical wild type or mutant BRAF melanoma models. We also discussed the latest use of essential oils in improving cancer patients’ quality of life. As evidenced by the many studies listed in this review, through their effect on apoptosis and tumor progression-associated properties, essential oils can therefore be considered as potential natural pharmaceutical resources for cancer management. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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13 pages, 309 KiB  
Review
BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions
by Ilaria Proietti, Nevena Skroza, Simone Michelini, Alessandra Mambrin, Veronica Balduzzi, Nicoletta Bernardini, Anna Marchesiello, Ersilia Tolino, Salvatore Volpe, Patrizia Maddalena, Marco Di Fraia, Giorgio Mangino, Giovanna Romeo and Concetta Potenza
Cancers 2020, 12(7), 1823; https://doi.org/10.3390/cancers12071823 - 07 Jul 2020
Cited by 80 | Viewed by 5800
Abstract
The BRAF inhibitors vemurafenib, dabrafenib and encorafenib are used in the treatment of patients with BRAF-mutant melanoma. They selectively target BRAF kinase and thus interfere with the mitogen-activated protein kinase (MAPK) signalling pathway that regulates the proliferation and survival of melanoma cells. In [...] Read more.
The BRAF inhibitors vemurafenib, dabrafenib and encorafenib are used in the treatment of patients with BRAF-mutant melanoma. They selectively target BRAF kinase and thus interfere with the mitogen-activated protein kinase (MAPK) signalling pathway that regulates the proliferation and survival of melanoma cells. In addition to their molecularly targeted activity, BRAF inhibitors have immunomodulatory effects. The MAPK pathway is involved in T-cell receptor signalling, and interference in the pathway by BRAF inhibitors has beneficial effects on the tumour microenvironment and anti-tumour immune response in BRAF-mutant melanoma, including increased immune-stimulatory cytokine levels, decreased immunosuppressive cytokine levels, enhanced melanoma differentiation antigen expression and presentation of tumour antigens by HLA 1, and increased intra-tumoral T-cell infiltration and activity. These effects promote recognition of the tumour by the immune system and enhance anti-tumour T-cell responses. Combining BRAF inhibitors with MEK inhibitors provides more complete blockade of the MAPK pathway. The immunomodulatory effects of BRAF inhibition alone or in combination with MEK inhibition provide a rationale for combining these targeted therapies with immune checkpoint inhibitors. Available data support the synergy between these treatment approaches, indicating such combinations provide an additional beneficial effect on the tumour microenvironment and immune response in BRAF-mutant melanoma. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
23 pages, 1721 KiB  
Review
Sex and Gender Disparities in Melanoma
by Maria Bellenghi, Rossella Puglisi, Giada Pontecorvi, Alessandra De Feo, Alessandra Carè and Gianfranco Mattia
Cancers 2020, 12(7), 1819; https://doi.org/10.3390/cancers12071819 - 07 Jul 2020
Cited by 66 | Viewed by 6531
Abstract
Worldwide, the total incidence of cutaneous melanoma is higher in men than in women, with some differences related to ethnicity and age and, above all, sex and gender. Differences exist in respect to the anatomic localization of melanoma, in that it is more [...] Read more.
Worldwide, the total incidence of cutaneous melanoma is higher in men than in women, with some differences related to ethnicity and age and, above all, sex and gender. Differences exist in respect to the anatomic localization of melanoma, in that it is more frequent on the trunk in men and on the lower limbs in women. A debated issue is if—and to what extent—melanoma development can be attributed to gender-specific behaviors or to biologically intrinsic differences. In the search for factors responsible for the divergences, a pivotal role of sex hormones has been observed, although conflicting results indicate the involvement of other mechanisms. The presence on the X chromosome of numerous miRNAs and coding genes playing immunological roles represents another important factor, whose relevance can be even increased by the incomplete X chromosome random inactivation. Considering the known advantages of the female immune system, a different cancer immune surveillance efficacy was suggested to explain some sex disparities. Indeed, the complexity of this picture emerged when the recently developed immunotherapies unexpectedly showed better improvements in men than in women. Altogether, these data support the necessity of further studies, which consider enrolling a balanced number of men and women in clinical trials to better understand the differences and obtain actual gender-equitable healthcare. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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20 pages, 1273 KiB  
Review
Cell-Mediated Release of Nanoparticles as a Preferential Option for Future Treatment of Melanoma
by Anastasia Chillà, Francesca Margheri, Alessio Biagioni, Tommaso Del Rosso, Gabriella Fibbi, Mario Del Rosso and Anna Laurenzana
Cancers 2020, 12(7), 1771; https://doi.org/10.3390/cancers12071771 - 02 Jul 2020
Cited by 6 | Viewed by 2379
Abstract
Targeted and immune therapies have unquestionably improved the prognosis of melanoma patients. However the treatment of this neoplasm still requires approaches with a higher therapeutic index, in order to reduce shortcomings related to toxic effects and aspecific targeting. This means developing therapeutic tools [...] Read more.
Targeted and immune therapies have unquestionably improved the prognosis of melanoma patients. However the treatment of this neoplasm still requires approaches with a higher therapeutic index, in order to reduce shortcomings related to toxic effects and aspecific targeting. This means developing therapeutic tools derived with high affinity molecules for tumor components differentially expressed in melanoma cells with respect to their normal counterpart. Nanomedicine has sought to address this problem owing to the high modulability of nanoparticles. This approach exploits not only the enhanced permeability and retention effect typical of the tumor microenvironment (passive targeting), but also the use of specific “molecular antennas” that recognize some tumor-overexpressed molecules (active targeting). This line of research has given rise to the so-called “smart nanoparticles,” some of which have already passed the preclinical phase and are under clinical trials in melanoma patients. To further improve nanoparticles partition within tumors, for some years now a line of thought is exploiting the molecular systems that regulate the innate tumor-homing activity of platelets, granulocytes, monocytes/macrophages, stem cells, endothelial-colony-forming cells, and red blood cells loaded with nanoparticles. This new vision springs from the results obtained with some of these cells in regenerative medicine, an approach called “cell therapy.” This review takes into consideration the advantages of cell therapy as the only one capable of overcoming the limits of targeting imposed by the increased interstitial pressure of tumors. Full article
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
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