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Pharmaceuticals
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Pharmacological Treatments for Melanoma
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Pharmacological Treatments for Melanoma

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (25 June 2024) | Viewed by 18608

Special Issue Editors

Dr. Astrid Parenti

E-Mail Website
Guest Editor
Department of Health Sciences, Clinical Pharmacology and Oncology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
Interests: nitric oxide; endothelium; melanoma biology; angiogenesis; vascular inflammation; cardiovascular disease
Special Issues, Collections and Topics in MDPI journals
Dr. Anna Laurenzana

E-Mail Website
Guest Editor
Dipartimento di Scienze Biomediche Sperimentali e Cliniche “Mario Serio” Viale Morgagni, 50-50134 Florence, Italy
Interests: acidic-adapted melanoma cells; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cutaneous melanoma is one of the most invasive and metastatic human tumors and accounts for most skin cancer deaths despite comprising less than 5% of all cutaneous malignancies; it has an incidence that grows faster, in both males and females, compared to other malignancies. Treatment strategies for the advanced disease have dramatically changed in recent years, improving the life expectancy of melanoma patients by significantly increasing their overall survival (OS) and progression-free survival (PFS) due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients display resistance, both innate and acquired, to systemic treatments. For these reasons, a lot of studies have been made to understand the molecular mechanisms of de novo and acquired resistance to targeted therapies to eventually treat patients who progress on these treatments.

For this Special Issue, we welcome research articles and reviews that present the latest evidence on melanoma research and new possible therapeutic targets that can contribute to deepening the knowledge on this aggressive and complex tumor and, eventually, overcoming acquired resistance to BRAF/MEK inhibitors.

Dr. Astrid Parenti
Dr. Anna Laurenzana
Guest Editors

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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

  • advanced melanoma
  • immune escape
  • metastasis
  • targeted therapies
  • biomarkers
  • precision medicine
  • tumor microenvironment

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Published Papers (7 papers)

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Research

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19 pages, 5820 KiB  
Article
Unveiling the Role of Tryptophan 2,3-Dioxygenase in the Angiogenic Process
by Marta Cecchi, Cecilia Anceschi, Angela Silvano, Maria Luisa Coniglio, Aurora Chinnici, Lucia Magnelli, Andrea Lapucci, Anna Laurenzana and Astrid Parenti
Pharmaceuticals 2024, 17(5), 558; https://doi.org/10.3390/ph17050558 - 27 Apr 2024
Viewed by 1412
Abstract
Background: Indoleamine 2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO) are the two principals enzymes involved in the catabolization of tryptophan (Trp) into kynurenine (Kyn). Despite their well-established role in the immune escape, their involvement in angiogenesis remains uncertain. We aimed to characterize TDO and IDO1 [...] Read more.
Background: Indoleamine 2,3-dioxygenase (IDO1) and tryptophan-2,3-dioxygenase (TDO) are the two principals enzymes involved in the catabolization of tryptophan (Trp) into kynurenine (Kyn). Despite their well-established role in the immune escape, their involvement in angiogenesis remains uncertain. We aimed to characterize TDO and IDO1 in human umbilical venular endothelial cells (HUVECs) and human endothelial colony-forming cells (ECFCs). Methods: qRT-PCR and immunofluorescence were used for TDO and IDO1 expression while their activity was measured using ELISA assays. Cell proliferation was examined via MTT tests and in in vitro angiogenesis by capillary morphogenesis. Results: HUVECs and ECFCs expressed TDO and IDO1. Treatment with the selective TDO inhibitor 680C91 significantly impaired HUVEC proliferation and 3D-tube formation in response to VEGF-A, while IDO1 inhibition showed no effect. VEGF-induced mTor phosphorylation and Kyn production were hindered by 680C91. ECFC morphogenesis was also inhibited by 680C91. Co-culturing HUVECs with A375 induced TDO up-regulation in both cell types, whose inhibition reduced MMP9 activity and prevented c-Myc and E2f1 upregulation. Conclusions: HUVECs and ECFCs express the key enzymes of the kynurenine pathway. Significantly, TDO emerges as a pivotal player in in vitro proliferation and capillary morphogenesis, suggesting a potential pathophysiological role in angiogenesis beyond its well-known immunomodulatory effects. Full article
(This article belongs to the Special Issue Pharmacological Treatments for Melanoma)
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15 pages, 19731 KiB  
Article
Hedgehog Pathway Inhibition by Novel Small Molecules Impairs Melanoma Cell Migration and Invasion under Hypoxia
by Alessandro Falsini, Gaia Giuntini, Mattia Mori, Francesca Ghirga, Deborah Quaglio, Antonino Cucinotta, Federica Coppola, Irene Filippi, Antonella Naldini, Bruno Botta and Fabio Carraro
Pharmaceuticals 2024, 17(2), 227; https://doi.org/10.3390/ph17020227 - 8 Feb 2024
Cited by 1 | Viewed by 1414
Abstract
Melanoma is the principal cause of death in skin cancer due to its ability to invade and cause metastasis. Hypoxia, which characterises the tumour microenvironment (TME), plays an important role in melanoma development, as cancer cells can adapt and acquire a more aggressive [...] Read more.
Melanoma is the principal cause of death in skin cancer due to its ability to invade and cause metastasis. Hypoxia, which characterises the tumour microenvironment (TME), plays an important role in melanoma development, as cancer cells can adapt and acquire a more aggressive phenotype. Carbonic anhydrases (CA) activity, involved in pH regulation, is related to melanoma cell migration and invasion. Furthermore, the Hedgehog (Hh) pathway, already known for its role in physiological processes, is a pivotal character in cancer cell growth and can represent a promising pharmacological target. In this study, we targeted Hh pathway components with cyclopamine, glabrescione B and C22 in order to observe their effect on carbonic anhydrase XII (CAXII) expression especially under hypoxia. We then performed a migration and invasion assay on two melanoma cell lines (SK-MEL-28 and A375) where Smoothened, the upstream protein involved in Hh regulation, and GLI1, the main transcription factor that determines Hh pathway activation, were chemically inhibited. Data suggest the existence of a relationship between CAXII, hypoxia and the Hedgehog pathway demonstrating that the chemical inhibition of the Hh pathway and CAXII reduction resulted in melanoma migration and invasion impairment especially under hypoxia. As in recent years drug resistance to small molecules has arisen, the development of new chemical compounds is crucial. The multitarget Hh inhibitor C22 proved to be effective without signs of cytotoxicity and, for this reason, it can represent a promising compound for future studies, with the aim to reach a better melanoma disease management. Full article
(This article belongs to the Special Issue Pharmacological Treatments for Melanoma)
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14 pages, 2392 KiB  
Article
A Novel Acetylation-Immune Subtyping for the Identification of a BET Inhibitor-Sensitive Subgroup in Melanoma
by Liuying Wang, Liuchao Zhang, Shuang Li, Lei Cao, Kang Li and Weiwei Zhao
Pharmaceuticals 2023, 16(7), 1037; https://doi.org/10.3390/ph16071037 - 21 Jul 2023
Viewed by 1469
Abstract
Background: There have been significant advancements in melanoma therapies. BET inhibitors (BETis) show promise in impairing melanoma growth. However, identifying BETi-sensitive melanoma subtypes is challenging. Methods and Results: We analyzed 48 melanoma cell lines and 104 patients and identified two acetylation-immune subtypes (ALISs) [...] Read more.
Background: There have been significant advancements in melanoma therapies. BET inhibitors (BETis) show promise in impairing melanoma growth. However, identifying BETi-sensitive melanoma subtypes is challenging. Methods and Results: We analyzed 48 melanoma cell lines and 104 patients and identified two acetylation-immune subtypes (ALISs) in the cell lines and three ALISs in the patients. ALIS I, with high HAT1 and low KAT2A expression, showed a higher sensitivity to the BETi JQ-1 than ALIS II. ALIS III had low HAT1 expression. The TAD2B expression was low in ALIS I and II. KAT2A and HAT1 expressions were negatively correlated with the methylation levels of their CG sites (p = 0.0004 and 0.0003). Immunological gene sets, including B cell metagenes, activated stroma-related genes, fibroblast TGF response signatures (TBRS), and T cell TBRS-related genes, were up-regulated in ALIS I. Furthermore, KAT2A played a key role in regulating BETi sensitivity. Conclusions: The sensitivity of ALIS I to the BETi JQ-1 may be due to the inhibition of BETi resistance pathways and genes by low KAT2A expression and the dysregulation of the immune microenvironment by high HAT1 expression resulting from the absence of immune cells. ALIS I had the worst progression but showed sensitivity to BETi and B-cell-related immunotherapy, despite not responding to BRAF inhibitors. Full article
(This article belongs to the Special Issue Pharmacological Treatments for Melanoma)
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17 pages, 5129 KiB  
Article
Overexpression of Krüppel-Like Factor 9 Enhances the Antitumor Properties of Paclitaxel in Malignant Melanoma-Derived Cell Lines
by Mohammed O. Altonsy, George X. Song-Zhao, Mahmoud M. Mostafa and Paule Régine Mydlarski
Pharmaceuticals 2023, 16(4), 557; https://doi.org/10.3390/ph16040557 - 6 Apr 2023
Viewed by 1606
Abstract
Over the past decade, the treatment of metastatic melanoma has improved significantly due to the development of innovative therapies, such as drugs that target the BRAF/MAPK kinase pathway and the PD-1 pathway. However, these therapies do not work for all patients, highlighting the [...] Read more.
Over the past decade, the treatment of metastatic melanoma has improved significantly due to the development of innovative therapies, such as drugs that target the BRAF/MAPK kinase pathway and the PD-1 pathway. However, these therapies do not work for all patients, highlighting the need for additional research on the pathophysiology of melanoma. Paclitaxel is a chemotherapeutic agent used when first-line treatments are unsuccessful; however, its efficacy is limited. Since Krüppel-like factor 9 (KLF9) (antioxidant repressor) is downregulated in melanoma, we propose that restoring KLF9 levels may sensitize malignant melanoma to chemotherapeutic agents, such as paclitaxel. We used adenovirus overexpression and siRNA technologies to assess the role of KLF9 in mediating the response of malignant melanoma-derived cell lines RPMI-7951 and A375 to paclitaxel treatment. We found that increasing KLF9 levels potentiates the effectiveness of paclitaxel, as shown by apoptotic parameters such as decreased cell viability, pro-caspase-3 activation, increased number of annexin V-positive cells, and reduction in nuclear proliferation marker (KI67). These results suggest that KLF9 may be a potential target for improving chemotherapeutic response in melanoma. Full article
(This article belongs to the Special Issue Pharmacological Treatments for Melanoma)
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13 pages, 2590 KiB  
Article
Adjuvant Anti-PD-1 Immunotherapy versus Conventional Therapy for Stage III Melanoma: A Real-World Retrospective Cohort Study
by Tong Li, Yu Xu, Wei Sun, Wangjun Yan, Chunmeng Wang, Tu Hu, Xiaowei Zhang, Zhiguo Luo, Xin Liu and Yong Chen
Pharmaceuticals 2023, 16(1), 41; https://doi.org/10.3390/ph16010041 - 28 Dec 2022
Cited by 2 | Viewed by 2457
Abstract
The use of adjuvant therapy has provided survival benefits in patients with advanced melanoma. This study aimed to explore the recurrence and prognosis of the PD-1 inhibitor, conventional interferon (IFN), or observation (OBS) on resected stage III acral and cutaneous melanoma patients through [...] Read more.
The use of adjuvant therapy has provided survival benefits in patients with advanced melanoma. This study aimed to explore the recurrence and prognosis of the PD-1 inhibitor, conventional interferon (IFN), or observation (OBS) on resected stage III acral and cutaneous melanoma patients through a retrospective analysis. Patients with resected stage III melanoma at Fudan University Shanghai Cancer Center from 2017 to 2021 were enrolled with all of their clinicopathologic characteristics collected. They were divided into three groups: PD-1 inhibitor, IFN, and OBS. Survival analyses were performed to indicate the significance of different adjuvant therapies. A total of 199 patients were enrolled (PD-1 n = 126; IFN n = 31; and OBS n = 42), with their median follow-up times being 21 months, 24 months, and 49 months, respectively. The PD-1 inhibitor significantly improved relapse-free survival (p = 0.027) and overall survival (p = 0.033) compared with conventional treatment (IFN+OBS). The superiority of the PD-1 inhibitor was witnessed in stage IIIC/D (p = 0.000) acral (p = 0.05) melanoma patients with ulceration (p = 0.011) or lymph node macrometastasis (p = 0.010). The PD-1 inhibitor significantly reduced local recurrence and systemic metastasis compared with conventional therapy (p = 0.002). In conclusion, adjuvant anti-PD-1 immunotherapy can achieve better survival outcomes in acral and cutaneous melanoma patients compared with conventional treatment, without considering adverse events. More clinical benefits were seen in later-stage acral melanoma patients with ulceration or lymph node macrometastasis. Full article
(This article belongs to the Special Issue Pharmacological Treatments for Melanoma)
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17 pages, 4553 KiB  
Article
Mitochondrion-Targeted NIR Therapeutic Agent Suppresses Melanoma by Inducing Apoptosis and Cell Cycle Arrest via E2F/Cyclin/CDK Pathway
by Changzhen Sun, Jianv Wang, Tong Xia, Qin Sun, Yijing He, Hailan Wang, Qizhou He and Li Liu
Pharmaceuticals 2022, 15(12), 1589; https://doi.org/10.3390/ph15121589 - 19 Dec 2022
Cited by 5 | Viewed by 2217
Abstract
Malignant melanoma is the most fatal form of skin cancer worldwide, and earlier diagnosis and more effective therapies are required to improve prognosis. As a possible solution, near-infrared fluorescent heptamethine cyanine dyes have been shown to be useful for tumor diagnosis and treatment. [...] Read more.
Malignant melanoma is the most fatal form of skin cancer worldwide, and earlier diagnosis and more effective therapies are required to improve prognosis. As a possible solution, near-infrared fluorescent heptamethine cyanine dyes have been shown to be useful for tumor diagnosis and treatment. Here, we synthesized a novel theranostic agent, IR-817, a multifunctional bioactive small-molecule that has near-infrared emission, targets mitochondria in cancer cells, and has selective anti-cancer effects. In in vitro experiments, IR-817 preferentially accumulated in melanoma cells through organic anion transporting polypeptide transporters but also selectively inhibited the growth of tumor cells by inducing mitochondrial-dependent intrinsic apoptosis. Mechanistically, IR-817 caused G0/G1 cell cycle arrest by targeting the E2F/Cyclin/CDK pathway. Finally, IR-817 significantly suppressed the growth of xenograft tumors in zebrafish and mice. Immunohistochemical staining and hematoxylin and eosin staining revealed that IR-817 induced apoptosis and inhibited tumor cell proliferation without notable side effects. Therefore, mitochondrial-targeting theranostic agent IR-817 may be promising for accurate tumor diagnosis, real-time monitoring, and safe anti-cancer treatments. Full article
(This article belongs to the Special Issue Pharmacological Treatments for Melanoma)
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Review

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13 pages, 275 KiB  
Review
A Review of Current and Pipeline Drugs for Treatment of Melanoma
by Nicole Natarelli, Sarah J. Aleman, Isabella M. Mark, Jasmine T. Tran, Sean Kwak, Elizabeth Botto, Shaliz Aflatooni, Michael J. Diaz and Shari R. Lipner
Pharmaceuticals 2024, 17(2), 214; https://doi.org/10.3390/ph17020214 - 7 Feb 2024
Cited by 7 | Viewed by 6994
Abstract
Malignant melanoma is the most aggressive form of skin cancer. Standard treatment options include surgery, radiation therapy, systemic chemotherapy, targeted therapy, and immunotherapy. Combining these modalities often yields better responses. Surgery is suitable for localized cases, sometimes involving lymph node dissection and biopsy, [...] Read more.
Malignant melanoma is the most aggressive form of skin cancer. Standard treatment options include surgery, radiation therapy, systemic chemotherapy, targeted therapy, and immunotherapy. Combining these modalities often yields better responses. Surgery is suitable for localized cases, sometimes involving lymph node dissection and biopsy, to assess the spread of the disease. Radiation therapy may be sometimes used as a standalone treatment or following surgical excision. Systemic chemotherapy, while having low response rates, is utilized as part of combination treatments or when other methods fail. The development of resistance to systemic chemotherapies and associated side effects have prompted further research and clinical trials for novel approaches. In the case of advanced-stage melanoma, a comprehensive approach may be necessary, incorporating targeted therapies and immunotherapies that demonstrate significant antitumor activity. Targeted therapies, including inhibitors targeting BRAF, MEK, c-KIT, and NRAS, are designed to block the specific molecules responsible for tumor growth. These therapies show promise, particularly in patients with corresponding mutations. Combination therapy, including BRAF and MEK inhibitors, has been evidenced to improve progression-free survival; however, concerns about resistance and cutaneous toxicities highlight the need for close monitoring. Immunotherapies, leveraging tumor-infiltrating lymphocytes and CAR T cells, enhance immune responses. Lifileucel, an FDA-approved tumor-infiltrating lymphocyte therapy, has demonstrated improved response rates in advanced-stage melanoma. Ongoing trials continue to explore the efficacy of CAR T-cell therapy for advanced melanoma. Checkpoint inhibitors targeting CTLA-4 and PD-1 have enhanced outcomes. Emerging IL-2 therapies boost dendritic cells, enhancing anticancer immunity. Oncolytic virus therapy, approved for advanced melanoma, augments treatment efficacy in combination approaches. While immunotherapy has significantly advanced melanoma treatment, its success varies, prompting research into new drugs and factors influencing outcomes. This review provides insights into current melanoma treatments and recent therapeutic advances. Full article
(This article belongs to the Special Issue Pharmacological Treatments for Melanoma)
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