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Advances in Melanoma and Skin Cancers

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (15 May 2024) | Viewed by 17525

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Dr. Domenico Mallardo

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Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Institute Nazionale Tumori IRCCS Fondazione "G. Pascale", Via Mariano Semmola, 80131 Naples, Italy
Interests: oncology; translational research of skin cancers; identification of prognostic or predictive biomarkers for immunotherapy treatment; study of gene expression profile in patients with skin cancer; analysis of resistance mechanisms of immunotherapy treatment; biochemical and immunological monitoring; study of immunotherapy treatments in solid tumors; combination strategies with I-O
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Dr. Debora Basile

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Department of Oncology, San Bortolo General Hospital, ULSS 8 Berica-Vicenza, 36100 Vicenza, Italy
Interests: cancer; Immunotherapy; melanoma
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Dr. Maria Grazia Vitale

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Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, National Cancer Institute IRCCS Fondazione “G. Pascale”, Via Mariano Semmola, 80131 Naples, Italy.
Interests: skin cancers; immunotherapy; melanoma; solid tumors; immune mechanisms from Sars-CoV-2 infection in cancer patients
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Malignant melanoma is the most aggressive skin cancer, with a high potential for relapse and metastasization. Treatment with classic chemotherapy drugs has a response rate of 10% and short survival. The availability of immune checkpoint inhibitors (ICI) has radically changed the prognosis not only in melanoma but also in the majority of skin cancers. Indeed, immunotherapy is currently considered the standard of care as adjuvant therapy in high-risk resected stage III or IV melanoma, and it is also demonstrating excellent results in other skin cancers. Despite these important advances, a large subgroup of patients does not respond to treatment, or relapse due to the onset of primary or acquired resistance, resulting in treatment failure in approximately 50% of patients. Therefore, it is necessary to identify specific biomarkers capable of predicting the clinical benefit of immunotherapy in melanoma and skin cancer patients.

The purpose of this Special Issue is to report the resistance mechanisms and prognostic/predictive molecular markers of immunotherapy treatment in patients with skin cancers. Original research, reviews, and short communication articles mainly focused on the molecular basis of and advances in skin cancer immunotherapy are welcome.

Dr. Domenico Mallardo
Dr. Debora Basile
Dr. Maria Grazia Vitale
Guest Editors

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Keywords

melanoma
immunotherapy
biomarkers
translational research
drug repurposing
prognostic markers
predictive markers
combination immunotherapy

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Published Papers (8 papers)

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14 pages, 6601 KiB

Open AccessArticle

A Combined Proteomic and Transcriptomic Signature Is Predictive of Response to Anti-PD-1 Treatment: A Retrospective Study in Metastatic Melanoma Patients

by Domenico Mallardo, Mario Fordellone, Andrew White, Jakob Vowinckel, Michael Bailey, Francesca Sparano, Antonio Sorrentino, Mario Mallardo, Bianca Arianna Facchini, Rosaria De Filippi, Gerardo Ferrara, Vito Vanella, Kristina Beeler, Paolo Chiodini, Alessandra Cesano, Sarah Warren and Paolo A. Ascierto

Int. J. Mol. Sci. 2024, 25(17), 9345; https://doi.org/10.3390/ijms25179345 - 28 Aug 2024

Viewed by 1014

Abstract

Resistance biomarkers are needed to identify patients with advanced melanoma obtaining a response to ICI treatment and developing resistance later. We searched a combination of molecular signatures of response to ICIs in patients with metastatic melanoma. In a retrospective study on patients with metastatic melanoma treated with an anti-PD-1 agent carried out at Istituto Nazionale Tumori—IRCCS—Fondazione “G. Pascale”, Naples, Italy. We integrated a whole proteome profiling of metastatic tissue with targeted transcriptomics. To assess the prognosis of patients according to groups of low and high risk, we used PFS and OS as outcomes. To identify the proteins and mRNAs gene signatures associated with the patient’s response groups, the discriminant analysis for sparse data performed via partial least squares procedure was performed. Tissue samples from 22 patients were analyzed. A combined protein and gene signature associated with poorer response to ICI immunotherapy in terms of PFS and OS was identified. The PFS and OS Kaplan–Meier curves were significantly better for patients with high expression of the protein signature compared to patients with low expression of the protein signature and who were high-risk (Protein: HR = 0.023, 95% CI: 0.003–0.213; p < 0.0001. Gene: HR = 0.053, 95% CI: 0.011–0.260; p < 0.0001). The Kaplan–Meier curves showed that patients with low-risk gene signatures had better PFS (HR = 0 0.221, 95% CI: 0.071–0.68; p = 0.007) and OS (HR = 0.186, 95% CI: 0.05–0.695; p = 0.005). The proteomic and transcriptomic combined analysis was significantly associated with the outcomes of the anti-PD-1 treatment with a better predictive value compared to a single signature. All the patients with low expression of protein and gene signatures had progression within 6 months of treatment (median PFS = 3 months, 95% CI: 2–3), with a significant difference vs. the low-risk group (median PFS = not reached; p < 0.0001), and significantly poorer survival (OS = 9 months, 95% CI: 5–9) compared to patients with high expression of protein and gene signatures (median OS = not reached; p < 0.0001). We propose a combined proteomic and transcriptomic signature, including genes involved in pro-tumorigenic pathways, thereby identifying patients with reduced probability of response to immunotherapy with ICIs for metastatic melanoma. Full article

(This article belongs to the Special Issue Advances in Melanoma and Skin Cancers)

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24 pages, 7945 KiB

Open AccessArticle

Anti-Melanoma Effects of Miconazole: Investigating the Mitochondria Involvement

by Francesca Scatozza, Maria Miriam Giardina, Carola Valente, Virginia Vigiano Benedetti and Antonio Facchiano

Int. J. Mol. Sci. 2024, 25(7), 3589; https://doi.org/10.3390/ijms25073589 - 22 Mar 2024

Viewed by 2178

Abstract

Miconazole is an antimycotic drug showing anti-cancer effects in several cancers. However, little is known on its effects in melanoma. A375 and SK-MEL-28 human melanoma cell lines were exposed to miconazole and clotrimazole (up to 100 mM). Proliferation, viability with MTT assay and vascular mimicry were assayed at 24 h treatment. Molecular effects were measured at 6 h, namely, ATP-, ROS-release and mitochondria-related cytofluorescence. A metabolomic profile was also investigated at 6 h treatment. Carnitine was one of the most affected metabolites; therefore, the expression of 29 genes involved in carnitine metabolism was investigated in the public platform GEPIA2 on 461 melanoma patients and 558 controls. After 24 h treatments, miconazole and clotrimazole strongly and significantly inhibited proliferation in the presence of 10% serum on either melanoma cell lines; they also strongly reduced viability and vascular mimicry. After 6 h treatment, ATP reduction and ROS increase were observed, as well as a significant reduction in mitochondria-related fluorescence. Further, in A375, miconazole strongly and significantly altered expression of several metabolites including carnitines, phosphatidyl-cholines, all amino acids and several other small molecules, mostly metabolized in mitochondria. The expression of 12 genes involved in carnitine metabolism was found significantly modified in melanoma patients, 6 showing a significant impact on patients’ survival. Finally, miconazole antiproliferation activity on A375 was found completely abrogated in the presence of carnitine, supporting a specific role of carnitine in melanoma protection toward miconazole effect, and was significantly reversed in the presence of caspases inhibitors such as ZVAD-FMK and Ac-DEVD-CHO, and a clear pro-apoptotic effect was observed in miconazole-treated cells, by FACS analysis of Annexin V-FITC stained cells. Miconazole strongly affects proliferation and other biological features in two human melanoma cell lines, as well as mitochondria-related functions such as ATP- and ROS-release, and the expression of several metabolites is largely dependent on mitochondria function. Miconazole, likely acting via carnitine and mitochondria-dependent apoptosis, is therefore suggested as a candidate for further investigations in melanoma treatments. Full article

(This article belongs to the Special Issue Advances in Melanoma and Skin Cancers)

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21 pages, 2973 KiB

Open AccessArticle

Effective Targeting of Melanoma Cells by Combination of Mcl-1 and Bcl-2/Bcl-x_L/Bcl-w Inhibitors

by Zhe Peng, Bernhard Gillissen, Antje Richter, Tobias Sinnberg, Max S. Schlaak and Jürgen Eberle

Int. J. Mol. Sci. 2024, 25(6), 3453; https://doi.org/10.3390/ijms25063453 - 19 Mar 2024

Cited by 2 | Viewed by 1675

Abstract

Recent advances in melanoma therapy have significantly improved the prognosis of metastasized melanoma. However, large therapeutic gaps remain that need to be closed by new strategies. Antiapoptotic Bcl-2 proteins critically contribute to apoptosis deficiency and therapy resistance. They can be targeted by BH3 mimetics, small molecule antagonists that mimic the Bcl-2 homology domain 3 (BH3) of proapoptotic BH3-only proteins. By applying in vitro experiments, we aimed to obtain an overview of the possible suitability of BH3 mimetics for future melanoma therapy. Thus, we investigated the effects of ABT-737 and ABT-263, which target Bcl-2, Bcl-x_L and Bcl-w as well as the Bcl-2-selective ABT-199 and the Mcl-1-selective S63845, in a panel of four BRAF-mutated and BRAF-WT melanoma cell lines. None of the inhibitors showed significant effectiveness when used alone; however, combination of S63845 with each one of the three ABTs almost completely abolished melanoma cell survival and induced apoptosis in up to 50–90% of the cells. Special emphasis was placed here on the understanding of the downstream pathways involved, which may allow improved applications of these strategies. Thus, cell death induction was correlated with caspase activation, loss of mitochondrial membrane potential, phosphorylation of histone H2AX, and ROS production. Caspase dependency was demonstrated by a caspase inhibitor, which blocked all effects. Upregulation of Mcl-1, induced by S63845 itself, as reported previously, was blocked by the combinations. Indeed, Mcl-1, as well as XIAP (X-linked inhibitor of apoptosis), were strongly downregulated by combination treatments. These findings demonstrate that melanoma cells can be efficiently targeted by BH3 mimetics, but the right combinations have to be selected. The observed pronounced activation of apoptosis pathways demonstrates the decisive role of apoptosis in the loss of cell viability by BH3 mimetics. Full article

(This article belongs to the Special Issue Advances in Melanoma and Skin Cancers)

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12 pages, 3567 KiB

Open AccessArticle

In Vitro Experiments on the Effects of GP-2250 on BRAF-Mutated Melanoma Cell Lines and Benign Melanocytes

by Thilo Gambichler, Friederike Harnischfeger, Marina Skrygan, Britta Majchrzak-Stiller, Marie Buchholz, Thomas Müller and Chris Braumann

Int. J. Mol. Sci. 2023, 24(20), 15336; https://doi.org/10.3390/ijms242015336 - 19 Oct 2023

Cited by 1 | Viewed by 1735

Abstract

Enhanced glycolysis (Warburg effect) driven by the BRAF oncogene, dysregulated GAPDH expression, and activation of the PI3K/AKT/mTOR signaling pathway may significantly contribute to the resistance-targeted therapy of BRAF-mutated melanomas. Therefore, we aimed to study for the first time the anti-tumor activity of the GAPDH inhibitor GP-2250 in BRAF-mutated melanoma cell lines and benign melanocytes. We employed three melanoma cell lines and one primary melanocyte cell line (Ma-Mel-61a, Ma-Mel-86a, SH-4 and ATCC-PCS-200-013, respectively), which were exposed to different GP-2250 doses. GP-2250’s effects on cell proliferation and viability were evaluated by means of the BrdU and MTT assays, respectively. The RealTime-Glo Annexin V Apoptosis and Necrosis Assay was performed for the evaluation of apoptosis and necrosis induction. RT-PCR and western blotting were implemented for the determination of AKT and STAT3 gene and protein expression analyses, respectively. The melanoma cell lines showed a dose-dependent response to GP-2250 during BrDU and MTT testing. The RealTime-Glo Annexin V assay revealed the heterogenous impact of GP-2250 on apoptosis as well as necrosis. With respect to the melanoma cell lines Ma-Mel-86a and SH-4, the responses and dosages were comparable to those used for the MTT viability assay. Using the same dose range of GP-2250 administered to melanoma cells, however, we observed neither the noteworthy apoptosis nor necrosis of GP-2250-treated benign melanocytes. The gene expression profiles in the melanoma cell lines for AKT and STAT3 were heterogenous, whereby AKT as well as STAT3 gene expression were most effectively downregulated using the highest GP-2250 doses. Immunoblotting revealed that there was a time-dependent decrease in protein expression at the highest GP-2250 dose used, whereas a time- as well as dose-dependent AKT decrease was predominantly observed in Ma-Mel-61a. The STAT3 protein expression of Ma-Mel-86a and SH-4 was reduced in a time-dependent pattern at lower and moderate doses. STAT3 expression in Ma-Me-61a was barely altered by GP-2250. In conclusion, GP-2250 has anti-neoplastic effects in BRAF-mutated melanoma cell lines regarding tumor cell viability, proliferation, and apoptosis/necrosis. GP-2250 is able to downregulate the gene and protein expression of aberrant tumorigenic pathways in melanoma cell lines. Since GP-2250 is a GAPDH inhibitor, the substance may be a promising combination therapy for tumors presenting the Warburg effect, such as melanoma. Full article

(This article belongs to the Special Issue Advances in Melanoma and Skin Cancers)

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Review

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13 pages, 879 KiB

Open AccessReview

Programmed Cell Death Ligand 1 Immunohistochemical Expression and Cutaneous Melanoma: A Controversial Relationship

by Vincenzo Fiorentino, Cristina Pizzimenti, Mariausilia Franchina, Ludovica Pepe, Fernanda Russotto, Pietro Tralongo, Marina Gloria Micali, Gaetano Basilio Militi and Maria Lentini

Int. J. Mol. Sci. 2024, 25(1), 676; https://doi.org/10.3390/ijms25010676 - 4 Jan 2024

Cited by 2 | Viewed by 2975

Abstract

Cutaneous melanoma (CM) is traditionally considered one of the most “immunogenic” tumors, eliciting a high immune response. However, despite the presence of tumor-infiltrating lymphocytes (TILs), melanoma cells use strategies to suppress antitumor immunity and avoid being eliminated by immune surveillance. The PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) axis is a well-known immune escape system adopted by neoplastic cells. Therefore, immunotherapy with PD-1 and PD-L1 inhibitors is quickly becoming the main treatment approach for metastatic melanoma patients. However, the clinical utility of PD-L1 expression assessment in CM is controversial, and the interpretation of PD-L1 scores in clinical practice is still a matter of debate. Nonetheless, the recent literature data show that by adopting specific PD-L1 assessment methods in melanoma samples, a correlation between the expression of such a biomarker and a positive response to PD-1-based immunotherapy can be seen. Our review aims to describe the state-of-the-art knowledge regarding the prognostic and predictive role of PD-L1 expression in CM while also referring to possible biological explanations for the variability in its expressions and related treatment responses. Full article

(This article belongs to the Special Issue Advances in Melanoma and Skin Cancers)

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26 pages, 1374 KiB

Open AccessReview

Current Status and Molecular Mechanisms of Resistance to Immunotherapy in Oral Malignant Melanoma

by Sena Zeynep Usta, Toshihiro Uchihashi, Shingo Kodama, Kyoko Kurioka, Toshihiro Inubushi, Takuya Shimooka, Akinari Sugauchi, Soju Seki and Susumu Tanaka

Int. J. Mol. Sci. 2023, 24(24), 17282; https://doi.org/10.3390/ijms242417282 - 8 Dec 2023

Cited by 2 | Viewed by 2216

Abstract

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) antibodies, have initiated a new era in the treatment of malignant melanoma. ICIs can be used in various settings, including first-line, adjuvant, and neo-adjuvant therapy. In the scope of this review, we examined clinical studies utilizing ICIs in the context of treating oral mucosal melanoma, a rare disease, albeit with an extremely poor prognosis, with a specific focus on unraveling the intricate web of resistance mechanisms. The absence of a comprehensive review focusing on ICIs in oral mucosal melanoma is notable. Therefore, this review seeks to address this deficiency by offering a novel and thorough analysis of the current status, potential resistance mechanisms, and future prospects of applying ICIs specifically to oral malignant melanoma. Clarifying and thoroughly understanding these mechanisms will facilitate the advancement of effective therapeutic approaches and enhance the prospects for patients suffering from oral mucosal melanoma. Full article

(This article belongs to the Special Issue Advances in Melanoma and Skin Cancers)

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13 pages, 294 KiB

Open AccessReview

Efficacy of Pembrolizumab in Advanced Melanoma: A Narrative Review

by Giulio Rizzetto, Edoardo De Simoni, Elisa Molinelli, Annamaria Offidani and Oriana Simonetti

Int. J. Mol. Sci. 2023, 24(15), 12383; https://doi.org/10.3390/ijms241512383 - 3 Aug 2023

Cited by 4 | Viewed by 3178

Abstract

Pembrolizumab has been shown to increase survival in patients with metastatic melanoma. Considering the numerous oncoming studies, we decided to conduct a narrative review of the latest efficacy evidence regarding the use of pembrolizumab, alone or in combination, in patients with metastatic melanoma. A search was conducted in PubMed using “pembrolizumab,” and “metastatic melanoma” as keywords, considering studies from 2022 onward. We reviewed pembrolizumab and associations, cost-effectiveness, virus, advanced acral melanoma, long-term outcomes, real-life data, biomarkers, obesity, and vaccines. In conclusion, pembrolizumab is a fundamental option in the therapy of metastatic melanoma. However, a certain group of patients do not respond and, therefore, new combination options need to be evaluated. In particular, the use of vaccines tailored to tumor epitopes could represent a breakthrough in the treatment of resistant forms. Further studies with larger sample numbers are needed to confirm the preliminary results. Full article

(This article belongs to the Special Issue Advances in Melanoma and Skin Cancers)

Other

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9 pages, 3078 KiB

Open AccessBrief Report

Pentoxifylline and Norcantharidin Modify p62 Expression in 2D and 3D Cultures of B16F1 Cells

by José Luis González-Quiroz, Juan Moisés Ocampo-Godínez, Victoria Noemi Hernández-González, Ruth Angélica Lezama, Elba Reyes-Maldonado, Armando Vega-López and María Lilia Domínguez-López

Int. J. Mol. Sci. 2024, 25(10), 5140; https://doi.org/10.3390/ijms25105140 - 9 May 2024

Viewed by 1076

Abstract

Three-dimensional cell cultures have improved the evaluation of drugs for cancer therapy, due to their high similarity to solid tumors. In melanoma, autophagy appears to show a dual role depending on the progression of the disease. p62 protein has been proposed for the evaluation of autophagic flux since its expression is an indicator of the state of autophagy. Pentoxifylline (PTX) and Norcantharidin (NCTD) are drugs that have been shown to possess anticancer effects. In this work, we used B16F1 mouse melanoma cells in two-dimensional (2D) monolayer cultures and three-dimensional (3D) spheroids to test the effect of PTX and NCTD over the p62 expression. We analyzed the effect on p62 expression through Western blot and immunofluorescence assays. Our results indicate that PTX decreases p62 expression in both cell culture models, while Norcantharidin increases its expression in 3D cultures at 24 h. Therefore, these drugs could have a potential therapeutic use for the regulation of autophagy in melanoma, depending on the state of evolution of the disease. Full article

(This article belongs to the Special Issue Advances in Melanoma and Skin Cancers)

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