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Novel Therapeutic Targets in Melanoma

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

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 32994

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Special Issue Editors

Dr. Stephane Rocchi

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Guest Editor

INSERM U1065, Team 12, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, Nice, France.
Interests: melanoma; targeted therapies; innovative therapies; preclinical research

Dr. Michaël Cerezo

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Co-Guest Editor

INSERM U1065, Team 12, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, Nice, France.
Interests: melanoma; cancer cell homeostasis; anti-cancer novel targets

Special Issue Information

Dear colleagues,

Melanoma is the deadliest form of skin cancer. During the last ten years, melanoma has been a figurehead for targeted therapies and immunotherapy development. Currently, the 5-year overall survival rate for BRAF-mutated patients treated with first-line therapies targeting BRAF^V600E and MEK is only around 30 percent, and for patients treated with immunotherapies, it is around 40 percent for anti-PD1 alone and 50 percent for anti-PD1 plus anti-CTLA4. Unfortunately, even if targeted therapies and immunotherapies have seen huge progress, we have now arrived at a plateau.

In this Special Issue, we want to highlight different new potential strategies regarding the melanoma cells themselves and the tumor microenvironment to bypass resistance and smash this glass ceiling.

Dr. Stephane Rocchi
Dr. Michaël Cerezo
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
resistance
targeted therapies
immunotherapy
anti-cancer novel targets

Published Papers (12 papers)

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Editorial

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3 pages, 201 KiB

Open AccessEditorial

Novel Therapeutic Targets in Melanoma

by Michaël Cerezo and Stéphane Rocchi

Cancers 2023, 15(3), 747; https://doi.org/10.3390/cancers15030747 - 25 Jan 2023

Viewed by 956

Abstract

Melanoma is the most aggressive skin cancer type and ranks amongst the deadliest cancers due to its ability to develop resistance to current therapies [...] Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

Research

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12 pages, 950 KiB

Open AccessArticle

Implementation and Effectiveness of Novel Therapeutic Substances for Advanced Malignant Melanoma in Saxony, Germany, 2010–2020—Cohort Study Based on Administrative Data

by Thomas Datzmann, Jochen Schmitt, Saskia Fuhrmann, Martin Roessler, Friedegund Meier and Olaf Schoffer

Cancers 2021, 13(24), 6150; https://doi.org/10.3390/cancers13246150 - 07 Dec 2021

Cited by 3 | Viewed by 1919

Abstract

(1) Background: Targeted (TT) and immune checkpoint inhibitor (ICI) therapies have become available in the routine care of metastatic melanoma in recent years. (2) Objective: We compared mortality in patients with metastatic melanoma and different systemic therapies. (3) Methods: A retrospective cohort study, based on pseudonymized health insurance data of about two million individuals from Saxony, Germany, was conducted for the years 2010 to 2020. Only patients with an advanced stage, i.e., distant metastases were considered for the main analysis. Relative survival since metastasis and predicted survivor curves derived from a Cox model were used to assess potential differences in mortality. (4) Results: Relative survival was highest in the subgroup with sequential use of ICI and TT. All treatments except interferon had significant hazard ratios (HR) in the Cox model with time-dependent effects indicating a protective effect after treatment initiation (HR 0.01–0.146) but decreasing over time (HR 1.351–2.310). The predicted survivor curves revealed best survival under ICI-TT treatment and worst survival under TT treatment alone. (5) Conclusions: We found real-world evidence for survival benefits of patients with metastatic melanoma who received sequential ICI and TT treatment. It is conceivable that the observed high survival differences were overestimated due to bias, such as confounding by indication. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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19 pages, 19181 KiB

Open AccessArticle

The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

by Lawrence David Mason, Suresh Chava, Kiran Kumar Reddi and Romi Gupta

Cancers 2021, 13(21), 5516; https://doi.org/10.3390/cancers13215516 - 03 Nov 2021

Cited by 16 | Viewed by 2822

Abstract

Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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22 pages, 16240 KiB

Open AccessArticle

Claisened Hexafluoro Inhibits Metastatic Spreading of Amoeboid Melanoma Cells

by Angela Leo, Erica Pranzini, Laura Pietrovito, Elisa Pardella, Matteo Parri, Paolo Cirri, Gennaro Bruno, Maura Calvani, Silvia Peppicelli, Eugenio Torre, Maiko Sasaki, Lily Yang, Lei Zhu, Paola Chiarugi, Giovanni Raugei, Jack L. Arbiser and Maria Letizia Taddei

Cancers 2021, 13(14), 3551; https://doi.org/10.3390/cancers13143551 - 15 Jul 2021

Cited by 2 | Viewed by 2035

Abstract

Metastatic melanoma is characterized by poor prognosis and a low free-survival rate. Thanks to their high plasticity, melanoma cells are able to migrate exploiting different cell motility strategies, such as the rounded/amoeboid-type motility and the elongated/mesenchymal-type motility. In particular, the amoeboid motility strongly contributes to the dissemination of highly invasive melanoma cells and no treatment targeting this process is currently available for clinical application. Here, we tested Claisened Hexafluoro as a novel inhibitor of the amoeboid motility. Reported data demonstrate that Claisened Hexafluoro specifically inhibits melanoma cells moving through amoeboid motility by deregulating mitochondrial activity and activating the AMPK signaling. Moreover, Claisened Hexafluoro is able to interfere with the adhesion abilities and the stemness features of melanoma cells, thus decreasing the in vivo metastatic process. This evidence may contribute to pave the way for future possible therapeutic applications of Claisened Hexafluoro to counteract metastatic melanoma dissemination. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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Review

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19 pages, 1921 KiB

Open AccessReview

Emerging Role of Deubiquitinating Enzymes (DUBs) in Melanoma Pathogenesis

by Mickael Ohanna, Pierric Biber and Marcel Deckert

Cancers 2022, 14(14), 3371; https://doi.org/10.3390/cancers14143371 - 11 Jul 2022

Cited by 4 | Viewed by 2048

Abstract

Metastatic melanoma is the leading cause of death from skin cancer. Therapies targeting the BRAF oncogenic pathway and immunotherapies show remarkable clinical efficacy. However, these treatments are limited to subgroups of patients and relapse is common. Overall, the majority of patients require additional treatments, justifying the development of new therapeutic strategies. Non-genetic and genetic alterations are considered to be important drivers of cellular adaptation mechanisms to current therapies and disease relapse. Importantly, modification of the overall proteome in response to non-genetic and genetic events supports major cellular changes that are required for the survival, proliferation, and migration of melanoma cells. However, the mechanisms underlying these adaptive responses remain to be investigated. The major contributor to proteome remodeling involves the ubiquitin pathway, ubiquitinating enzymes, and ubiquitin-specific proteases also known as DeUBiquitinases (DUBs). In this review, we summarize the current knowledge regarding the nature and roles of the DUBs recently identified in melanoma progression and therapeutic resistance and discuss their potential as novel sources of vulnerability for melanoma therapy. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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0 pages, 1167 KiB

Open AccessReview

Leveraging STING, Batf3 Dendritic Cells, CXCR3 Ligands, and Other Components Related to Innate Immunity to Induce a “Hot” Tumor Microenvironment That Is Responsive to Immunotherapy

by Robin Reschke and Daniel J. Olson

Cancers 2022, 14(10), 2458; https://doi.org/10.3390/cancers14102458 - 16 May 2022

Cited by 11 | Viewed by 4093 | Correction

Abstract

In a T-cell-inflamed phenotype, tumor eradication works best and is potentiated by immunotherapy such as checkpoint blockade. However, a majority of patients die despite receiving immunotherapy. One reason is insufficient T cell priming and infiltration in the tumor. Nature provides us with innate immune mechanisms in T-cell-inflamed tumors that we can adopt for more personalized immunotherapy strategies. Tumor sensing through innate signaling pathways and efficient antigen-presenting possess a significant role in bridging innate and adaptive immunity and generating a T-cell-inflamed tumor. One approach to strengthen these innate immune mechanisms is to deliver innate immune factors such as STING or activated DCs into the tumor microenvironment, in particular in patients resistant to checkpoint blockade. The low number of DCs in the tumor bed could potentially be increased with the growth factor FMS-like tyrosine kinase 3 ligand (Flt3L). CD103+ DCs are integral for three phases of anti-tumor immunity: priming, recruiting, and re-invigoration of effector T cells. Re-activation of dysfunctional T cells is achieved via co-stimulatory molecules such as the 4-1BB ligand. The presence of myeloid-cell-derived CXCL9 and CXCL10 in the tumor microenvironment can predict response to immunotherapy. We outline recent preclinical and clinical approaches to deliver these crucial components bridging innate and adaptive immunity into the tumor microenvironment. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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15 pages, 676 KiB

Open AccessReview

The Genetic Basis of Dormancy and Awakening in Cutaneous Metastatic Melanoma

by Agata Janowska, Michela Iannone, Cristian Fidanzi, Marco Romanelli, Luca Filippi, Marzia Del Re, Manuella Martins and Valentina Dini

Cancers 2022, 14(9), 2104; https://doi.org/10.3390/cancers14092104 - 23 Apr 2022

Cited by 8 | Viewed by 2077

Abstract

Immune dysregulation, in combination with genetic and epigenetic alterations, induces an excessive proliferation of uncontrolled melanoma cells followed by dissemination of the tumor cells to distant sites, invading organs and creating metastasis. Although immunotherapy, checkpoint inhibitors and molecular targeted therapies have been developed as treatment options for advanced melanoma, there are specific mechanisms by which cancer cells can escape treatment. One of the main factors associated with reduced response to therapy is the ability of residual tumor cells to persist in a dormant state, without proliferation. This comprehensive review aimed at understanding the genetic basis of dormancy/awakening phenomenon in metastatic melanoma will help identify the possible therapeutical strategies that might eliminate melanoma circulating tumor cells (CTCs) or keep them in the dormant state forever, thereby repressing tumor relapse and metastatic spread. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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39 pages, 1229 KiB

Open AccessReview

Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma

by Jérémy H. Raymond, Zackie Aktary, Lionel Larue and Véronique Delmas

Cancers 2022, 14(3), 706; https://doi.org/10.3390/cancers14030706 - 29 Jan 2022

Cited by 8 | Viewed by 4300

Abstract

G-protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G-proteins, which induce cellular signaling through various pathways. Such signaling modulates numerous essential cellular processes that occur during melanomagenesis, including proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden melanoma treatment options in the future. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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24 pages, 1848 KiB

Open AccessReview

Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

by Francesca Comito, Rachele Pagani, Giada Grilli, Francesca Sperandi, Andrea Ardizzoni and Barbara Melotti

Cancers 2022, 14(2), 271; https://doi.org/10.3390/cancers14020271 - 06 Jan 2022

Cited by 18 | Viewed by 4033

Abstract

The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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22 pages, 1045 KiB

Open AccessReview

Enhancing Therapeutic Approaches for Melanoma Patients Targeting Epigenetic Modifiers

by Maria Gracia-Hernandez, Zuleima Munoz and Alejandro Villagra

Cancers 2021, 13(24), 6180; https://doi.org/10.3390/cancers13246180 - 08 Dec 2021

Cited by 9 | Viewed by 3451

Abstract

Melanoma is the least common but deadliest type of skin cancer. Melanomagenesis is driven by a series of mutations and epigenetic alterations in oncogenes and tumor suppressor genes that allow melanomas to grow, evolve, and metastasize. Epigenetic alterations can also lead to immune evasion and development of resistance to therapies. Although the standard of care for melanoma patients includes surgery, targeted therapies, and immune checkpoint blockade, other therapeutic approaches like radiation therapy, chemotherapy, and immune cell-based therapies are used for patients with advanced disease or unresponsive to the conventional first-line therapies. Targeted therapies such as the use of BRAF and MEK inhibitors and immune checkpoint inhibitors such as anti-PD-1 and anti-CTLA4 only improve the survival of a small subset of patients. Thus, there is an urgent need to identify alternative standalone or combinatorial therapies. Epigenetic modifiers have gained attention as therapeutic targets as they modulate multiple cellular and immune-related processes. Due to melanoma’s susceptibility to extrinsic factors and reversible nature, epigenetic drugs are investigated as a therapeutic avenue and as adjuvants for targeted therapies and immune checkpoint inhibitors, as they can sensitize and/or reverse resistance to these therapies, thus enhancing their therapeutic efficacy. This review gives an overview of the role of epigenetic changes in melanoma progression and resistance. In addition, we evaluate the latest advances in preclinical and clinical research studying combinatorial therapies and discuss the use of epigenetic drugs such as HDAC and DNMT inhibitors as potential adjuvants for melanoma patients. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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9 pages, 512 KiB

Open AccessReview

Gp-100 as a Novel Therapeutic Target in Uveal Melanoma

by Daniel Martinez-Perez, David Viñal, Isabel Solares, Enrique Espinosa and Jaime Feliu

Cancers 2021, 13(23), 5968; https://doi.org/10.3390/cancers13235968 - 27 Nov 2021

Cited by 17 | Viewed by 3344

Abstract

Uveal melanoma is a rare neoplasm with poor prognosis in the metastatic setting. Unlike cutaneous melanoma, treatment with kinase inhibitors or immune checkpoint inhibitors is not effective. Glycoprotein 100 (Gp-100) is a protein highly expressed in melanocytes and melanoma that has recently been effectively targeted by tebentafusp, a first-in-class bispecific protein of the immune-mobilizing monoclonal T cell receptors against cancer (ImmTACs) family. Tebentafusp targets tumor cells that express a peptide of Gp-100 presented by HLA*A0201, creating an immune synapse that kills targeted tumor cells. Recently, a randomized phase III trial reported an overall survival benefit for tebentafusp in patients with untreated metastatic uveal melanoma. The aim of this comprehensive review is to summarize evidence of Gp-100 as a therapeutic target in melanoma, and the preclinical and clinical development of tebentafusp as a novel therapeutic strategy for patients with uveal melanoma. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets in Melanoma)

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