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15 pages, 620 KiB

Open AccessArticle

Anti-PD-1 Monotherapy in Advanced Melanoma—Real-World Data from a 77-Month-Long Retrospective Observational Study

by Daniella Kuzmanovszki, Norbert Kiss, Béla Tóth, Tünde Kerner, Veronika Tóth, József Szakonyi, Kende Lőrincz, Judit Hársing, Eleonóra Imrédi, Alexa Pfund, Ákos Szabó, Valentin Brodszky, Fanni Rencz and Péter Holló

Biomedicines 2022, 10(7), 1737; https://doi.org/10.3390/biomedicines10071737 - 19 Jul 2022

Cited by 12 | Viewed by 2528

Abstract

Real-world evidence plays an important role in the assessment of efficacy and safety of novel therapies. The increasing use of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma has led to notably improved clinical outcomes, while they are also associated with immune-related [...] Read more.

Real-world evidence plays an important role in the assessment of efficacy and safety of novel therapies. The increasing use of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma has led to notably improved clinical outcomes, while they are also associated with immune-related adverse events (irAEs). The majority of the available data are based on clinical trials, where the investigated subjects often do not adequately represent the general patient population of the everyday practice. Although there is a niche of objective biomarkers for the future treatment response of ICIs, certain studies suggest that irAEs may be predictive. The aim of this study was to carry out a retrospective analysis of treatment data from patients with advanced melanoma, treated with a single anti-PD-1 agent (pembrolizumab or nivolumab) during a 77-month-long period. Treatment efficacy and occurrence of adverse events were analyzed to identify potential predictive markers. Primary and secondary endpoints were the overall survival (OS) and progression-free survival (PFS). In our cohort, we demonstrated that the occurrence of more than one irAE showed a correlation with response to PD-1 ICI therapy and improved the OS and PFS. Our study suggests, that the grade of toxicity of the irAE may affect the survival rate. Full article

(This article belongs to the Special Issue Diagnostics and Therapeutics of Melanoma)

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11 pages, 1476 KiB

Open AccessArticle

Melanoma Cell State-Specific Responses to TNFα

by Su Yin Lim, Sara Alavi, Zizhen Ming, Elena Shklovskaya, Carina Fung, Ashleigh Stewart and Helen Rizos

Biomedicines 2021, 9(6), 605; https://doi.org/10.3390/biomedicines9060605 - 26 May 2021

Cited by 3 | Viewed by 3049

Abstract

Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD1) pathway have revolutionized the treatment of patients with advanced metastatic melanoma. PD1 inhibitors reinvigorate exhausted tumor-reactive T cells, thus restoring anti-tumor immunity. Tumor necrosis factor alpha (TNFα) is abundantly expressed as [...] Read more.

Immune checkpoint inhibitors that target the programmed cell death protein 1 (PD1) pathway have revolutionized the treatment of patients with advanced metastatic melanoma. PD1 inhibitors reinvigorate exhausted tumor-reactive T cells, thus restoring anti-tumor immunity. Tumor necrosis factor alpha (TNFα) is abundantly expressed as a consequence of T cell activation and can have pleiotropic effects on melanoma response and resistance to PD1 inhibitors. In this study, we examined the influence of TNFα on markers of melanoma dedifferentiation, antigen presentation and immune inhibition in a panel of 40 melanoma cell lines. We report that TNFα signaling is retained in all melanomas but the downstream impact of TNFα was dependent on the differentiation status of melanoma cells. We show that TNFα is a poor inducer of antigen presentation molecules HLA-ABC and HLA-DR but readily induces the PD-L2 immune checkpoint in melanoma cells. Our results suggest that TNFα promotes dynamic changes in melanoma cells that may favor immunotherapy resistance. Full article

(This article belongs to the Special Issue Diagnostics and Therapeutics of Melanoma)

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18 pages, 2887 KiB

Open AccessArticle

Cell Proliferation Is Strongly Associated with the Treatment Conditions of an ER Stress Inducer New Anti-Melanoma Drug in Melanoma Cell Lines

by István Szász, Viktória Koroknai, Vikas Patel, Tibor Hajdú, Tímea Kiss, Róza Ádány and Margit Balázs

Biomedicines 2021, 9(2), 96; https://doi.org/10.3390/biomedicines9020096 - 20 Jan 2021

Cited by 5 | Viewed by 3990

Abstract

HA15 is a new anti-melanoma drug that triggers endoplasmic reticulum (ER) stress and causes deleterious effects on melanoma cell viability due to autophagy and apoptosis, regardless of driver mutations or drug resistance. In this study, we investigated the effect of HA15 on the [...] Read more.

HA15 is a new anti-melanoma drug that triggers endoplasmic reticulum (ER) stress and causes deleterious effects on melanoma cell viability due to autophagy and apoptosis, regardless of driver mutations or drug resistance. In this study, we investigated the effect of HA15 on the viability/proliferation of BRAFV600E-mutant melanoma cells using different culture conditions. In contrast to the published data, we did not detect significant melanoma cell death under normal culture conditions using HA15 treatment. Indeed, only cells that were cultured under long-term starvation conditions were sensitive to the drug. Quantitative measurements of ER stress and autophagy markers showed that the compound HA15 does not trigger stress alone but synergistically enhances ER stress under starvation conditions. Importantly, we observed that the viability of normal melanocytes decreased significantly with treatment, even at low HA15 concentrations. Finally yet importantly, we were able to generate HA15-resistant cell lines, which failed by Cerezo et al. In summary, HA15 only influences the viability of cells that are starved for several hours before and during treatment. However, this in vitro setting is far from the in vivo conditions. In addition, our data clearly show that melanoma cells can acquire HA15 resistance. Further studies are needed to prove that HA15 is an effective anti-cancer agent. Full article

(This article belongs to the Special Issue Diagnostics and Therapeutics of Melanoma)

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16 pages, 3330 KiB

Open AccessArticle

Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1 Immunotherapy

by Silvia M. Bacot, Taylor A. Harper, Rebecca L. Matthews, Christie Jane Fennell, Adovi Akue, Mark A. KuKuruga, Shiowjen Lee, Tao Wang and Gerald M. Feldman

Int. J. Mol. Sci. 2020, 21(23), 9023; https://doi.org/10.3390/ijms21239023 - 27 Nov 2020

Cited by 18 | Viewed by 4891

Abstract

The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell [...] Read more.

The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the primary mechanism of action of anti-PD-1 therapy. In this study, we established a model system to test T cell functions modulated by Nivolumab using anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs), and characterized T cell functions primarily based on the knowledge gained from retrospective observations of patients treated with anti-PD-1 immunotherapy. During a comprehensive cytokine profile assessment to identify potential biomarkers, we found that Nivolumab increases expression of T helper type 1 (Th1) associated cytokines such as interferon-γ (IFN-γ) and interleukin-2 (IL-2) in a subset of donors. Furthermore, Nivolumab increases production of Th2, Th9, and Th17 associated cytokines, as well as many proinflammatory cytokines such as IL-6 in a subset of donors. Conversely, Nivolumab treatment has no impact on T cell proliferation, expression of CD25, CD69, or Granzyme B, and only modestly increases in the expansion of regulatory T cells. Our results suggest that assessment of cytokine production using a simple PBMC-based T cell functional assay could be used as a potential predictive marker for anti-PD-1 immunotherapy. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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28 pages, 11591 KiB

Open AccessArticle

Knockout of ACTB and ACTG1 with CRISPR/Cas9(D10A) Technique Shows that Non-Muscle β and γ Actin Are Not Equal in Relation to Human Melanoma Cells’ Motility and Focal Adhesion Formation

by Natalia Malek, Ewa Mrówczyńska, Aleksandra Michrowska, Ewa Mazurkiewicz, Iuliia Pavlyk and Antonina Joanna Mazur

Int. J. Mol. Sci. 2020, 21(8), 2746; https://doi.org/10.3390/ijms21082746 - 15 Apr 2020

Cited by 20 | Viewed by 6018

Abstract

Non-muscle actins have been studied for many decades; however, the reason for the existence of both isoforms is still unclear. Here we show, for the first time, a successful inactivation of the ACTB (CRISPR clones with inactivated ACTB, CR-ACTB) and [...] Read more.

Non-muscle actins have been studied for many decades; however, the reason for the existence of both isoforms is still unclear. Here we show, for the first time, a successful inactivation of the ACTB (CRISPR clones with inactivated ACTB, CR-ACTB) and ACTG1 (CRISPR clones with inactivated ACTG1, CR-ACTG1) genes in human melanoma cells (A375) via the RNA-guided D10A mutated Cas9 nuclease gene editing [CRISPR/Cas9(D10A)] technique. This approach allowed us to evaluate how melanoma cell motility was impacted by the lack of either β actin coded by ACTB or γ actin coded by ACTG1. First, we observed different distributions of β and γ actin in the cells, and the absence of one actin isoform was compensated for via increased expression of the other isoform. Moreover, we noted that γ actin knockout had more severe consequences on cell migration and invasion than β actin knockout. Next, we observed that the formation rate of bundled stress fibers in CR-ACTG1 cells was increased, but lamellipodial activity in these cells was impaired, compared to controls. Finally, we discovered that the formation rate of focal adhesions (FAs) and, subsequently, FA-dependent signaling were altered in both the CR-ACTB and CR-ACTG1 clones; however, a more detrimental effect was observed for γ actin-deficient cells. Our research shows that both non-muscle actins play distinctive roles in melanoma cells’ FA formation and motility. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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31 pages, 5937 KiB

Open AccessArticle

Human Melanoma-Cell Metabolic Profiling: Identification of Novel Biomarkers Indicating Metastasis

by Mariangela Kosmopoulou, Aikaterini F. Giannopoulou, Aikaterini Iliou, Dimitra Benaki, Aristeidis Panagiotakis, Athanassios D. Velentzas, Eumorphia G. Konstantakou, Issidora S. Papassideri, Emmanuel Mikros, Dimitrios J. Stravopodis and Evagelos Gikas

Int. J. Mol. Sci. 2020, 21(7), 2436; https://doi.org/10.3390/ijms21072436 - 31 Mar 2020

Cited by 20 | Viewed by 4555

Abstract

Melanoma is the most aggressive type of skin cancer, leading to metabolic rewiring and enhancement of metastatic transformation. Efforts to improve its early and accurate diagnosis are largely based on preclinical models and especially cell lines. Hence, we herein present a combinational Nuclear [...] Read more.

Melanoma is the most aggressive type of skin cancer, leading to metabolic rewiring and enhancement of metastatic transformation. Efforts to improve its early and accurate diagnosis are largely based on preclinical models and especially cell lines. Hence, we herein present a combinational Nuclear Magnetic Resonance (NMR)- and Ultra High Performance Liquid Chromatography-High-Resolution Tandem Mass Spectrometry (UHPLC-HRMS/MS)-mediated untargeted metabolomic profiling of melanoma cells, to landscape metabolic alterations likely controlling metastasis. The cell lines WM115 and WM2664, which belong to the same patient, were examined, with WM115 being derived from a primary, pre-metastatic, tumor and WM2664 clonally expanded from lymph-node metastases. Metabolite samples were analyzed using NMR and UHPLC-HRMS. Multivariate statistical analysis of high resolution NMR and MS (positive and negative ionization) results was performed by Principal Component Analysis (PCA), Partial Least Squares-Discriminant Analysis (PLS-DA) and Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA), while metastasis-related biomarkers were determined on the basis of VIP lists, S-plots and Student’s t-tests. Receiver Operating Characteristic (ROC) curves of NMR and MS data revealed significantly differentiated metabolite profiles for each cell line, with WM115 being mainly characterized by upregulated levels of phosphocholine, choline, guanosine and inosine. Interestingly, WM2664 showed notably increased contents of hypoxanthine, myo-inositol, glutamic acid, organic acids, purines, pyrimidines, AMP, ADP, ATP and UDP(s), thus indicating the critical roles of purine, pyrimidine and amino acid metabolism during human melanoma metastasis. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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15 pages, 3574 KiB

Open AccessArticle

The Antitumor Effect of Lipophilic Bisphosphonate BPH1222 in Melanoma Models: The Role of the PI3K/Akt Pathway and the Small G Protein Rheb

by Dominika Rittler, Marcell Baranyi, Eszter Molnár, Tamás Garay, István Jalsovszky, Imre Károly Varga, Luca Hegedűs, Clemens Aigner, József Tóvári, József Tímár and Balázs Hegedűs

Int. J. Mol. Sci. 2019, 20(19), 4917; https://doi.org/10.3390/ijms20194917 - 3 Oct 2019

Cited by 13 | Viewed by 3280

Abstract

Malignant melanoma is one of the most metastatic cancer types, and despite recent success with novel treatment strategies, there is still a group of patients who do not respond to any therapies. Earlier, the prenylation inhibitor hydrophilic bisphosphonate zoledronic acid (ZA) was found [...] Read more.

Malignant melanoma is one of the most metastatic cancer types, and despite recent success with novel treatment strategies, there is still a group of patients who do not respond to any therapies. Earlier, the prenylation inhibitor hydrophilic bisphosphonate zoledronic acid (ZA) was found to inhibit melanoma growth in vitro, but only a weaker effect was observed in vivo due to its hydrophilic properties. Recently, lipophilic bisphosphonates (such as BPH1222) were developed. Accordingly, for the first time, we compared the effect of BPH1222 to ZA in eight melanoma lines using viability, cell-cycle, clonogenic and spheroid assays, videomicroscopy, immunoblot, and xenograft experiments. Based on 2D and spheroid assays, the majority of cell lines were more sensitive to BPH. The activation of Akt and S6 proteins, but not Erk, was inhibited by BPH. Additionally, BPH had a stronger apoptotic effect than ZA, and the changes of Rheb showed a correlation with apoptosis. In vitro, only M24met cells were more sensitive to ZA than to BPH; however, in vivo growth of M24met was inhibited more strongly by BPH. Here, we present that lipophilic BPH is more effective on melanoma cells than ZA and identify the PI3K pathway, particularly Rheb as an important mediator of growth inhibition. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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13 pages, 1667 KiB

Open AccessArticle

Long-Term Vemurafenib Exposure Induced Alterations of Cell Phenotypes in Melanoma: Increased Cell Migration and Its Association with EGFR Expression

by Eszter Molnár, Tamás Garay, Marco Donia, Marcell Baranyi, Dominika Rittler, Walter Berger, József Tímár, Michael Grusch and Balázs Hegedűs

Int. J. Mol. Sci. 2019, 20(18), 4484; https://doi.org/10.3390/ijms20184484 - 11 Sep 2019

Cited by 22 | Viewed by 3490

Abstract

Acquired resistance during BRAF inhibitor therapy remains a major challenge for melanoma treatment. Accordingly, we evaluated the phenotypical and molecular changes of isogeneic human V600E BRAF-mutant melanoma cell line pairs pre- and post-treatment with vemurafenib. Three treatment naïve lines were subjected to in [...] Read more.

Acquired resistance during BRAF inhibitor therapy remains a major challenge for melanoma treatment. Accordingly, we evaluated the phenotypical and molecular changes of isogeneic human V600E BRAF-mutant melanoma cell line pairs pre- and post-treatment with vemurafenib. Three treatment naïve lines were subjected to in vitro long-term vemurafenib treatment while three pairs were pre- and post-treatment patient-derived lines. Molecular and phenotypical changes were assessed by Sulforhodamine-B (SRB) assay, quantitative RT-PCR (q-RT-PCR), immunoblot, and time-lapse microscopy. We found that five out of six post-treatment cells had higher migration activity than pretreatment cells. However, no unequivocal correlation between increased migration and classic epithelial–mesenchymal transition (EMT) markers could be identified. In fast migrating cells, the microphthalmia-associated transcription factor (MITF) and epidermal growth factor receptor (EGFR) mRNA levels were considerably lower and significantly higher, respectively. Interestingly, high EGFR expression was associated with elevated migration but not with proliferation. Cells with high EGFR expression showed significantly decreased sensitivity to vemurafenib treatment, and had higher Erk activation and FRA-1 expression. Importantly, melanoma cells with higher EGFR expression were more resistant to the EGFR inhibitor erlotinib treatment than cells with lower expression, with respect to both proliferation and migration inhibition. Finally, EGFR-high melanoma cells were characterized by higher PD-L1 expression, which might in turn indicate that immunotherapy may be an effective approach in these cases. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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20 pages, 3993 KiB

Open AccessArticle

Physiologically Relevant Oxygen Concentration (6% O₂) as an Important Component of the Microenvironment Impacting Melanoma Phenotype and Melanoma Response to Targeted Therapeutics In Vitro

by Marta Osrodek, Mariusz L. Hartman and Malgorzata Czyz

Int. J. Mol. Sci. 2019, 20(17), 4203; https://doi.org/10.3390/ijms20174203 - 27 Aug 2019

Cited by 19 | Viewed by 4204

Abstract

Cancer cell phenotype largely depends on oxygen availability. The atmospheric oxygen concentration (21%) used in in vitro studies is much higher than in any human tissue. Using well-characterized patient-derived melanoma cell lines, we compared: (i) activities of several signaling pathways, and (ii) the [...] Read more.

Cancer cell phenotype largely depends on oxygen availability. The atmospheric oxygen concentration (21%) used in in vitro studies is much higher than in any human tissue. Using well-characterized patient-derived melanoma cell lines, we compared: (i) activities of several signaling pathways, and (ii) the effects of vemurafenib and trametinib in hyperoxia (21% O₂), normoxia (6% O₂) and hypoxia (1% O₂). A high plasticity of melanoma cells in response to changes in oxygen supplementation and drug treatment was observed, and the transcriptional reprograming and phenotypic changes varied between cell lines. Normoxia enhanced the expression of vascular endothelial growth factor (VEGF), glucose metabolism/transport-related genes, and changed percentages of NGFR- and MITF-positive cells in cell line-dependent manner. Increased protein stability might be responsible for high PGC1α level in MITF^low melanoma cells. Vemurafenib and trametinib while targeting the activity of MAPK/ERK pathway irrespective of oxygen concentration, were less effective in normoxia than hyperoxia in reducing levels of VEGF, PGC1α, SLC7A11 and Ki-67-positive cells in cell line-dependent manner. In conclusion, in vitro studies performed in atmospheric oxygen concentration provide different information on melanoma cell phenotype and response to drugs than performed in normoxia, which might partially explain the discrepancies between results obtained in vitro and in clinical settings. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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34 pages, 27533 KiB

Open AccessArticle

Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients

by Aikaterini F. Giannopoulou, Eumorphia G. Konstantakou, Athanassios D. Velentzas, Socratis N. Avgeris, Margaritis Avgeris, Nikos C. Papandreou, Ilianna Zoi, Vicky Filippa, Stamatia Katarachia, Antonis D. Lampidonis, Anastasia Prombona, Popi Syntichaki, Christina Piperi, Efthimia K. Basdra, Vassiliki Iconomidou, Evangelia Papadavid, Ema Anastasiadou, Issidora S. Papassideri, Athanasios G. Papavassiliou, Gerassimos E. Voutsinas, Andreas Scorilas and Dimitrios J. Stravopodis Show full author list Hide full author list

Int. J. Mol. Sci. 2019, 20(4), 937; https://doi.org/10.3390/ijms20040937 - 21 Feb 2019

Cited by 9 | Viewed by 4834

Abstract

Background: Skin cancer represents the most common human malignancy, and it includes BCC, SCC, and melanoma. Since melanoma is one of the most aggressive types of cancer, we have herein attempted to develop a gene-specific intron retention signature that can distinguish BCC and [...] Read more.

Background: Skin cancer represents the most common human malignancy, and it includes BCC, SCC, and melanoma. Since melanoma is one of the most aggressive types of cancer, we have herein attempted to develop a gene-specific intron retention signature that can distinguish BCC and SCC from melanoma biopsy tumors. Methods: Intron retention events were examined through RT-sqPCR protocols, using total RNA preparations derived from BCC, SCC, and melanoma Greek biopsy specimens. Intron-hosted miRNA species and their target transcripts were predicted via the miRbase and miRDB bioinformatics platforms, respectively. Ιntronic ORFs were recognized through the ORF Finder application. Generation and visualization of protein interactomes were achieved by the IntAct and Cytoscape softwares, while tertiary protein structures were produced by using the I-TASSER online server. Results: c-MYC and Sestrin-1 genes proved to undergo intron retention specifically in melanoma. Interaction maps of proteins encoded by genes being potentially targeted by retained intron-accommodated miRNAs were generated and SRPX2 was additionally delivered to our melanoma-specific signature. Novel ORFs were identified in MCT4 and Sestrin-1 introns, with potentially critical roles in melanoma development. Conclusions: The property of c-MYC, Sestrin-1, and SRPX2 genes to retain specific introns could be clinically used to molecularly differentiate non-melanoma from melanoma tumors. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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Review

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21 pages, 5262 KiB

Open AccessReview

Anorectal and Genital Mucosal Melanoma: Diagnostic Challenges, Current Knowledge and Therapeutic Opportunities of Rare Melanomas

by Margaret Ottaviano, Emilio Francesco Giunta, Laura Marandino, Marianna Tortora, Laura Attademo, Davide Bosso, Cinzia Cardalesi, Antonietta Fabbrocini, Mario Rosanova, Antonia Silvestri, Liliana Montella, Pasquale Tammaro, Ester Marra, Claudia Trojaniello, Maria Grazia Vitale, Ester Simeone, Teresa Troiani, Bruno Daniele and Paolo Antonio Ascierto

Biomedicines 2022, 10(1), 150; https://doi.org/10.3390/biomedicines10010150 - 11 Jan 2022

Cited by 15 | Viewed by 4323

Abstract

Mucosal melanomas (MM) are rare tumors, being less than 2% of all diagnosed melanomas, comprising a variegated group of malignancies arising from melanocytes in virtually all mucosal epithelia, even if more frequently found in oral and sino-nasal cavities, ano-rectum and female genitalia (vulva [...] Read more.

Mucosal melanomas (MM) are rare tumors, being less than 2% of all diagnosed melanomas, comprising a variegated group of malignancies arising from melanocytes in virtually all mucosal epithelia, even if more frequently found in oral and sino-nasal cavities, ano-rectum and female genitalia (vulva and vagina). To date, there is no consensus about the optimal management strategy of MM. Furthermore, the clinical rationale of molecular tumor characterization regarding BRAF, KIT or NRAS, as well as the therapeutic value of immunotherapy, chemotherapy and targeted therapy, has not yet been deeply explored and clearly established in MM. In this overview, focused on anorectal and genital MM as models of rare melanomas deserving of a multidisciplinary approach, we highlight the need of referring these patients to centers with experts in melanoma, anorectal and uro-genital cancers treatments. Taking into account the rarity, the poor outcomes and the lack of effective treatment options for MM, tailored research needs to be promptly promoted. Full article

(This article belongs to the Special Issue Diagnostics and Therapeutics of Melanoma)

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31 pages, 1856 KiB

Open AccessReview

Antibody-Based Immunotherapy: Alternative Approaches for the Treatment of Metastatic Melanoma

by Fleury Augustin Nsole Biteghe, Nyangone Ekome Toung Chalomie, Neelakshi Mungra, Guillaume Vignaux, Nan Gao, Aurelia Vergeade, Ambrose Okem, Krupa Naran, Jean De La Croix Ndong and Stefan Barth

Biomedicines 2020, 8(9), 327; https://doi.org/10.3390/biomedicines8090327 - 3 Sep 2020

Cited by 11 | Viewed by 5453

Abstract

Melanoma is the least common form of skin cancer and is associated with the highest mortality. Where melanoma is mostly unresponsive to conventional therapies (e.g., chemotherapy), BRAF inhibitor treatment has shown improved therapeutic outcomes. Photodynamic therapy (PDT) relies on a light-activated compound to [...] Read more.

Melanoma is the least common form of skin cancer and is associated with the highest mortality. Where melanoma is mostly unresponsive to conventional therapies (e.g., chemotherapy), BRAF inhibitor treatment has shown improved therapeutic outcomes. Photodynamic therapy (PDT) relies on a light-activated compound to produce death-inducing amounts of reactive oxygen species (ROS). Their capacity to selectively accumulate in tumor cells has been confirmed in melanoma treatment with some encouraging results. However, this treatment approach has not reached clinical fruition for melanoma due to major limitations associated with the development of resistance and subsequent side effects. These adverse effects might be bypassed by immunotherapy in the form of antibody–drug conjugates (ADCs) relying on the ability of monoclonal antibodies (mAbs) to target specific tumor-associated antigens (TAAs) and to be used as carriers to specifically deliver cytotoxic warheads into corresponding tumor cells. Of late, the continued refinement of ADC therapeutic efficacy has given rise to photoimmunotherapy (PIT) (a light-sensitive compound conjugated to mAbs), which by virtue of requiring light activation only exerts its toxic effect on light-irradiated cells. As such, this review aims to highlight the potential clinical benefits of various armed antibody-based immunotherapies, including PDT, as alternative approaches for the treatment of metastatic melanoma. Full article

(This article belongs to the Special Issue Diagnostics and Therapeutics of Melanoma)

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27 pages, 1200 KiB

Open AccessReview

Current Molecular Markers of Melanoma and Treatment Targets

by Kevin Yang, Allen S.W. Oak, Radomir M. Slominski, Anna A. Brożyna and Andrzej T. Slominski

Int. J. Mol. Sci. 2020, 21(10), 3535; https://doi.org/10.3390/ijms21103535 - 16 May 2020

Cited by 51 | Viewed by 7009

Abstract

Melanoma is a deadly skin cancer that becomes especially difficult to treat after it metastasizes. Timely identification of melanoma is critical for effective therapy, but histopathologic diagnosis can frequently pose a significant challenge to this goal. Therefore, auxiliary diagnostic tools are imperative to [...] Read more.

Melanoma is a deadly skin cancer that becomes especially difficult to treat after it metastasizes. Timely identification of melanoma is critical for effective therapy, but histopathologic diagnosis can frequently pose a significant challenge to this goal. Therefore, auxiliary diagnostic tools are imperative to facilitating prompt recognition of malignant lesions. Melanoma develops as result of a number of genetic mutations, with UV radiation often acting as a mutagenic risk factor. Novel methods of genetic testing have improved detection of these molecular alterations, which subsequently revealed important information for diagnosis and prognosis. Rapid detection of genetic alterations is also significant for choosing appropriate treatment and developing targeted therapies for melanoma. This review will delve into the understanding of various mutations and the implications they may pose for clinical decision making. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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28 pages, 1467 KiB

Open AccessReview

The miRNAs Role in Melanoma and in Its Resistance to Therapy

by Francesca Varrone and Emilia Caputo

Int. J. Mol. Sci. 2020, 21(3), 878; https://doi.org/10.3390/ijms21030878 - 29 Jan 2020

Cited by 59 | Viewed by 6532

Abstract

Melanoma is the less common but the most malignant skin cancer. Since the survival rate of melanoma metastasis is about 10–15%, many different studies have been carried out in order to find a more effective treatment. Although the development of target-based therapies and [...] Read more.

Melanoma is the less common but the most malignant skin cancer. Since the survival rate of melanoma metastasis is about 10–15%, many different studies have been carried out in order to find a more effective treatment. Although the development of target-based therapies and immunotherapeutic strategies has improved chances for patient survival, melanoma treatment still remains a big challenge for oncologists. Here, we collect recent data about the emerging role of melanoma-associated microRNAs (miRNAs) currently available treatments, and their involvement in drug resistance. We also reviewed miRNAs as prognostic factors, because of their chemical stability and resistance to RNase activity, in melanoma progression. Moreover, despite miRNAs being considered small conserved regulators with the limitation of target specificity, we outline the dual role of melanoma-associated miRNAs, as oncogenic and/or tumor suppressive factors, compared to other tumors. Full article

(This article belongs to the Special Issue Molecular Biology of Melanoma)

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