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Cancers
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Emerging Therapeutics in Advanced Melanoma
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Emerging Therapeutics in Advanced Melanoma

A topical collection in Cancers (ISSN 2072-6694). This collection belongs to the section "Cancer Therapy".

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Editors

Dr. Jeremy S. Bordeaux

E-Mail Website
Guest Editor
Department of Dermatology, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
Interests: melanoma; mohs surgery; immunotherapy; health disparities; clinical practice guidelines
Dr. Luke D. Rothermel

E-Mail Website
Guest Editor
Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
Interests: melanoma; soft tissue malignancies; T cell immunotherapies; cancer metabolism; chemotherapy resistance

Topical Collection Information

Dear Colleagues,

Treatment options for advanced melanoma have evolved rapidly over the past decade. Survival for patients with stage 4 disease has improved remarkably with the introduction of immune and targeted therapies. Our understanding of the immune system and its interaction with melanoma continues to evolve; gene therapies are becoming more refined; tumor and host metabolisms provide intriguing targets to overcome therapeutic resistance. Many efforts have led to current clinical trials, but nascent research that will define the next wave of melanoma therapies may yet be underappreciated.

This collection focuses on Emerging Therapeutics in Advanced Melanoma and seeks expert reviews as well as original research articles to highlight the most promising research in melanoma. We are seeking publications from research specialists in the melanoma microenvironment including immune subsets (i.e. T cells, macrophages, dendritic cells, etc.), stromal components (i.e. fibroblasts, endothelial cells, pericytes, etc.), and the nutrient microenvironment with its metabolic implications. Additional contributions will include emerging targets for drug therapies, improved uses of old treatments (i.e. chemotherapy, radiation, etc.), the evolution of oncolytic virotherapies, and novel approaches like gene or stem cell therapies. This work will ask experts to identify what they see as the most promising lines of investigation, and will provide a glimpse into the future of melanoma treatment.

We look forward to receiving your contributions.

Dr. Jeremy S. Bordeaux
Dr. Luke D. Rothermel
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 collection 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
  • tumor microenvironment
  • cancer metabolism
  • immunotherapy
  • targeted therapy
  • oncolytic virotherapy
  • chemotherapy resistance
  • gene
  • therapy
  • stem cell therapy
  • cancer vaccine

Published Papers (10 papers)

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2023

Jump to: 2022

15 pages, 1033 KiB  
Review
New Approaches to Targeted Therapy in Melanoma
by Manuel Felipe Fernandez, Jacob Choi and Jeffrey Sosman
Cancers 2023, 15(12), 3224; https://doi.org/10.3390/cancers15123224 - 17 Jun 2023
Cited by 7 | Viewed by 2301
Abstract
It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, [...] Read more.
It was just slightly more than a decade ago when metastatic melanoma carried a dismal prognosis with few, if any, effective therapies. Since then, the evolution of cancer immunotherapy has led to new and effective treatment approaches for melanoma. However, despite these advances, a sizable portion of patients with advanced melanoma have de novo or acquired resistance to immune checkpoint inhibitors. At the same time, therapies (BRAF plus MEK inhibitors) targeting the BRAFV600 mutations found in 40–50% of cutaneous melanomas have also been critical for optimizing management and improving patient outcomes. Even though immunotherapy has been established as the initial therapy in most patients with cutaneous melanoma, subsequent effective therapy is limited to BRAFV600 melanoma. For all other melanoma patients, driver mutations have not been effectively targeted. Numerous efforts are underway to target melanomas with NRAS mutations, NF-1 LOF mutations, and other genetic alterations leading to activation of the MAP kinase pathway. In this era of personalized medicine, we will review the current genetic landscape, molecular classifications, emerging drug targets, and the potential for combination therapies for non-BRAFV600 melanoma. Full article
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10 pages, 1170 KiB  
Article
Effects of the Introduction of Modern Immunotherapy on the Outcome of Isolated Limb Perfusion for Melanoma In-Transit Metastases
by Carl-Jacob Holmberg, Jan Mattsson and Roger Olofsson Bagge
Cancers 2023, 15(2), 472; https://doi.org/10.3390/cancers15020472 - 12 Jan 2023
Cited by 3 | Viewed by 1479
Abstract
Isolated limb perfusion (ILP) is an effective locoregional treatment for melanoma in-transit metastasis, but the advent of modern effective immunotherapy, such as ICI (immune checkpoint inhibitors), has changed the treatment landscape. The primary aims of this study were to compare the characteristics of [...] Read more.
Isolated limb perfusion (ILP) is an effective locoregional treatment for melanoma in-transit metastasis, but the advent of modern effective immunotherapy, such as ICI (immune checkpoint inhibitors), has changed the treatment landscape. The primary aims of this study were to compare the characteristics of the patient population receiving ILP before and after the introduction of modern systemic treatments and to assess if outcomes after ILP were influenced by previous immunotherapy treatment. A single-centre analysis of patients that underwent ILP for melanoma in-transit metastasis between 2010 and 2021 was conducted, with patients grouped and compared by treatment time period: pre-ICI era (2010–2014) and ICI era (2017–2021). 218 patients were included. Patients undergoing ILP in the ICI era were slightly older (median age 73 vs. 68 years) compared to the pre-ICI era, with no other difference found. The overall response rate (ORR) was 83% vs. 84% and the complete response (CR) rate was 52% vs. 47% for the pre-ICI era and the ICI era, respectively. For patients that had received and failed immunotherapy prior to ILP (n = 20), the ORR was 75% and the CR rate was 50%. Melanoma-specific survival has improved, with a 3-year survival rate of 54% in the pre-ICI era vs. 86% in the ICI era. The patient population undergoing ILP for in-transit melanoma is largely unchanged in the current era of effective systemic treatments. Response rates have not decreased, and prior ICI treatment did not affect response rates, making ILP still a valid treatment option for this patient group. Full article
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2022

Jump to: 2023

18 pages, 2946 KiB  
Article
YO2 Induces Melanoma Cell Apoptosis through p53-Mediated LRP1 Downregulation
by Yousef Salama, Satoshi Takahashi, Yuko Tsuda, Yoshio Okada, Koichi Hattori and Beate Heissig
Cancers 2023, 15(1), 288; https://doi.org/10.3390/cancers15010288 - 31 Dec 2022
Cited by 4 | Viewed by 1717
Abstract
The multifunctional endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1) has been implicated in melanoma growth. However, the mechanism of LRP1 expression in melanoma cells remains only partially understood. In most melanomas, the TP53 tumor suppressor is retained as a non-mutated, inactive form [...] Read more.
The multifunctional endocytic receptor low-density lipoprotein receptor-related protein 1 (LRP1) has been implicated in melanoma growth. However, the mechanism of LRP1 expression in melanoma cells remains only partially understood. In most melanomas, the TP53 tumor suppressor is retained as a non-mutated, inactive form that fails to suppress tumors. We identify TP53 as a regulator of LRP1-mediated tumor growth. TP53 enhances the expression of miRNA miR-103/107. These miRNAs target LRP1 expression on melanoma cells. TP53 overexpression in human and murine melanoma cells was achieved using lentivirus or treatment with the small molecule YO-2, a plasmin inhibitor known to induce apoptosis in various cancer cell lines. TP53 restoration enhanced the expression of the tumor suppressor miR-103/107, resulting in the downregulation of LRP1 and suppression of tumor growth in vivo and in vitro. Furthermore, LRP1 overexpression or p53 downregulation prevented YO-2-mediated melanoma growth inhibition. We identified YO-2 as a novel p53 inducer in melanoma cells. Cotreatment of YO-2 with doxorubicin blocked tumor growth in vivo and in a murine melanoma model, suggesting that YO-2 exerts anti-melanoma effects alone or in combination with conventional myelosuppressive drugs. Full article
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11 pages, 280 KiB  
Article
Tumor Burden and Health-Related Quality of Life in Patients with Melanoma In-Transit Metastases
by Hanna Wesslau, Anders Carlander, Lars Ny, Fredrik Wärnberg, Roger Olofsson Bagge and Ann-Sophie Lindqvist Bagge
Cancers 2023, 15(1), 161; https://doi.org/10.3390/cancers15010161 - 27 Dec 2022
Cited by 1 | Viewed by 1243
Abstract
Background: Few studies have investigated the health-related quality of life (HRQOL) in patients with melanoma in-transit metastases (ITM). The aim was to investigate the association between tumor burden and HRQOL, including disparities pertaining to sex and age, in treatment-naïve patients with ITM. Methods: [...] Read more.
Background: Few studies have investigated the health-related quality of life (HRQOL) in patients with melanoma in-transit metastases (ITM). The aim was to investigate the association between tumor burden and HRQOL, including disparities pertaining to sex and age, in treatment-naïve patients with ITM. Methods: Functional Assessment of Cancer Therapy-Melanoma (FACT-M) questionnaire was used to assess HRQOL Pairwise comparisons using t-tests between clinical cutoffs are presented and multiple linear regression analysis showing the unique associations of gender, age, number of tumors, tumor size, presence of lymph node metastases, and tumor localization. Results: A total of 95 patients, 47% females and 53% males (median age 72 years) were included between 2012 and 2021. Women scored significantly lower on emotional well-being (p = 0.038) and lower on FACT-M (p = 0.058). Patients who had ≥10 tumors scored significantly lower on FACT-M (p = 0.015), emotional- and functional well-being (p = 0.04, p = 0.004, respectively), melanoma scale (p = 0.005), and FACT-G (p = 0.027). There was no significant difference in HRQOL depending on age, size of tumors, localization, or presence of lymph node metastases. Conclusion: For patients with melanoma ITMs, the female sex and higher tumor burden (i.e., number of tumors) were significantly correlated with lower HRQOL. However, these findings do not fully explain HRQOL for this patient population, and future research should consider the possibility that there are specific questions for patients with ITM where current instruments might fail to measure their discomfort to the full extent. Full article
20 pages, 4879 KiB  
Article
BG34-200 Immunotherapy of Advanced Melanoma
by Veronique Roche, Victor Sandoval, Zachary Senders, Joshua Lyons, Claire Wolford and Mei Zhang
Cancers 2022, 14(23), 5911; https://doi.org/10.3390/cancers14235911 - 30 Nov 2022
Cited by 1 | Viewed by 1380
Abstract
High levels of myeloid-derived cells are characteristic of the tumor microenvironment (TME) of advanced melanoma. These cells interact with tumor cells to suppress the development of antitumor immune responses, regulate tumor metastasis, and drive cancer’s resistance to virtually all types of therapy. Therefore, [...] Read more.
High levels of myeloid-derived cells are characteristic of the tumor microenvironment (TME) of advanced melanoma. These cells interact with tumor cells to suppress the development of antitumor immune responses, regulate tumor metastasis, and drive cancer’s resistance to virtually all types of therapy. Therefore, methods to disrupt tumor-associated myeloid cell function are actively being sought to find a cure. Our team has recently developed a plant-derived carbohydrate molecule, BG34-200, that modulates tumor-associated myeloid cells by targeting the cell surface receptor CD11b. In this study, we found that BG34-200 IV administration could significantly inhibit tumor growth and improve survival in B16F10 mice with advanced melanoma. Our data supported a model that the entry of BG34-200 into circulating melanoma tumor-associated inflammatory monocytes (TAIMs) could trigger a sequential immune activation: the BG34-200+ TAIM subsets migrated to tumor and differentiated into monocyte-derived dendritic cells (mo-DCs); then, the BG34-200+ mo-DCs migrated to tumor draining lymph nodes, where they triggered the generation of tumor-antigen-specific T cells. Based upon these results, we combined BG34-200 treatment with adoptive transfer of TdLN-derived T cells to treat advanced melanoma, which significantly improved animal survival and helped tumor-free survivors be resistant to a second tumor-cell challenge. The scientific findings from this study will allow us to develop new technology and apply BG34-200-based immunotherapy to patients with advanced melanoma who have not responded to current standard of care therapies with and without immunotherapy. Full article
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16 pages, 321 KiB  
Review
Triple Combination of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives
by Michèle Welti, Florentia Dimitriou, Ralf Gutzmer and Reinhard Dummer
Cancers 2022, 14(22), 5489; https://doi.org/10.3390/cancers14225489 - 08 Nov 2022
Cited by 6 | Viewed by 1601
Abstract
Immune checkpoint inhibitors (ICIs), namely programmed cell death 1 (PD-1) or cytotoxic t-lymphocyte antigen 4 (CTLA-4) inhibitors, are currently the standard of care for the treatment of advanced melanoma, with robust and durable responses in a subset of patients. For BRAFV600-mutant melanoma, treatment [...] Read more.
Immune checkpoint inhibitors (ICIs), namely programmed cell death 1 (PD-1) or cytotoxic t-lymphocyte antigen 4 (CTLA-4) inhibitors, are currently the standard of care for the treatment of advanced melanoma, with robust and durable responses in a subset of patients. For BRAFV600-mutant melanoma, treatment with BRAF and MEK inhibitors has resulted in high objective response rates, but most responses are short-lived. Preclinical data suggest that BRAF and MEK inhibitors result in immunomodulatory changes in the tumor microenvironment; early data in murine models further suggest that these changes could enhance sensitivity to ICIs. Subsequently, the notion of combining the two therapy modalities for a more effective response was further evolved in early phase clinical trials. In this review, we analyzed the results of recent phase 2 and 3 clinical trials investigating the combination of ICIs with targeted therapy in BRAFV600-mutated advanced melanoma. Furthermore, we evaluated the results of recent studies investigating the first-line treatment sequencing of ipilimumab/nivolumab and BRAF/MEK inhibitors in these patients. We discussed the study limitations and interpreted how these recent advances could be incorporated into the treatment landscape of advanced BRAFV600-mutant melanoma. Full article
16 pages, 1886 KiB  
Review
Trends in Melanoma Phase 3 Clinical Trials since 2010: Is there Hope for Advanced Melanoma Therapies beyond Approved Treatment Mechanisms?
by Hanna H. Kakish, Fasih Ali Ahmed, Mohamedraed Elshami, Alexander W. Loftus, Richard S. Hoehn, John B. Ammori, Lee M. Ocuin, Jordan M. Winter, Jeremy S. Bordeaux, Ankit Mangla and Luke D. Rothermel
Cancers 2022, 14(21), 5184; https://doi.org/10.3390/cancers14215184 - 22 Oct 2022
Cited by 7 | Viewed by 1812
Abstract
Background: Several drugs and treatment modalities are under investigation to improve current melanoma therapy options. This review profiles the trends in clinical trial investment in late-stage melanoma, and anticipates what changes are expected in melanoma treatment, with a focus on exploratory drug mechanisms. [...] Read more.
Background: Several drugs and treatment modalities are under investigation to improve current melanoma therapy options. This review profiles the trends in clinical trial investment in late-stage melanoma, and anticipates what changes are expected in melanoma treatment, with a focus on exploratory drug mechanisms. Methods: We reviewed nine international clinical trial databases for registered, interventional, and phase 3 cutaneous melanoma clinical trials since 2010. Results: 73 trials studied drug therapies in late-stage (stage III and IV) melanoma. Exploratory mechanisms were investigated in 32% (23/73) of the late-stage melanoma drug therapy trials. Most exploratory drug trials include immunotherapy drug mechanisms (15/23 trials). Two exploratory mechanisms showed promise: the anti-LAG3 antibody, relatlimab, and the hapten modified vaccine, MVax. Many (52%) trials of exploratory mechanisms are ongoing including the use of adoptive cell transfer immunotherapies, dendritic cell vaccine therapy, and histone deacetylase (HDAC) inhibitors, among others. Conclusions: Since most clinical trials focus on previously approved drug mechanisms, it is likely that paradigm-changing treatments will involve these therapies being used in new treatment contexts or combinations. Only 2 exploratory drug mechanisms studied since 2010 have achieved promising results in the phase 3 setting, though many other trials are ongoing at this time. Full article
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17 pages, 26790 KiB  
Article
Role of the Hedgehog Pathway and CAXII in Controlling Melanoma Cell Migration and Invasion in Hypoxia
by Gaia Giuntini, Federica Coppola, Alessandro Falsini, Irene Filippi, Sara Monaci, Antonella Naldini and Fabio Carraro
Cancers 2022, 14(19), 4776; https://doi.org/10.3390/cancers14194776 - 29 Sep 2022
Cited by 3 | Viewed by 1426
Abstract
Background: Malignant melanoma is the leading cause of death among skin cancer patients due to its tendency to metastasize. Alterations at the molecular level are often evident, which is why melanoma biology has garnered increasing interest. The hedgehog (Hh) pathway, which is essential [...] Read more.
Background: Malignant melanoma is the leading cause of death among skin cancer patients due to its tendency to metastasize. Alterations at the molecular level are often evident, which is why melanoma biology has garnered increasing interest. The hedgehog (Hh) pathway, which is essential for embryonic development, is aberrantly re-activated in melanoma and may represent a promising therapeutic target. In addition, carbonic anhydrase XII (CAXII) represents a poor prognostic target for hypoxic tumors, such as melanoma, and is involved in cell migration. Thus, we decided to investigate whether and how the Hh pathway and CAXII may control melanoma cell migration and invasiveness. Methods: The migratory and invasive capabilities of SK-MEL-28 and A375 cell lines, either un-transfected or transiently transfected with Smoothened (SMO), GLI1, or CAXII siRNA, were studied under normoxic or hypoxic conditions. Results: For the first time, we showed that SMO and GLI1 silencing resulted in the downregulation of CAXII expression in both moderately and highly invasive melanoma cells under hypoxia. The Hh pathway as well as CAXII inhibition by siRNA resulted in impaired malignant melanoma migration and invasion. Conclusion: Our results suggest that CAXII and the Hh pathway are relevant in melanoma invasion and may be novel and promising therapeutical targets for melanoma clinical management. Full article
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45 pages, 2778 KiB  
Systematic Review
Exogenous Hormone Factors in Relation to the Risk of Malignant Melanoma in Women: A Systematic Review and Meta-Analysis
by Manuela Chiavarini, Giulia Naldini, Irene Giacchetta and Roberto Fabiani
Cancers 2022, 14(13), 3192; https://doi.org/10.3390/cancers14133192 - 29 Jun 2022
Cited by 5 | Viewed by 1727
Abstract
The influence of exogenous female hormones on the risk of developing malignant melanoma in women remains controversial. The aim of our review and meta-analysis is to summarize the evidence and derive a more accurate estimation of the association between oral contraceptives (OCs) or [...] Read more.
The influence of exogenous female hormones on the risk of developing malignant melanoma in women remains controversial. The aim of our review and meta-analysis is to summarize the evidence and derive a more accurate estimation of the association between oral contraceptives (OCs) or menopausal hormone therapy (MHT) and the risk of developing malignant melanoma in women. PubMed, Web of Science, and Scopus database were searched for studies published up until October 2021. The PRISMA statement and MOOSE guidelines were followed. Studies were pooled using a random effects model. Heterogeneity was explored with the chi-square-based Cochran’s Q statistic and the I2 statistic. Publication bias was assessed with Begg’s test and Egger’s test. Forty-six studies met the eligibility criteria. The pooled analysis (26 studies) on OC use and the risk of developing cutaneous malignant melanoma (CMM) showed no significant association, but demonstrated significant association for cohort studies (OR 1.08, 95% CI 1.01–1.16; I2 = 0.00%, p = 0.544). The pooled analysis (16 studies) showed a significantly increased risk of CMM in association with MHT (OR 1.15, 95% CI 1.08–1.23; I2 = 25.32%, p = 0.169). Stratifying the results by study design showed that a significant increased risk of CMM was associated with MHT in the cohort studies (OR 1.12; 95% CI 1.04–1.19; I2 = 0%, p = 0.467). No significant publication bias could be detected. Further studies are needed to investigate the potential association with formulation, duration of use, and dosage of use, and to better understand the role of possible confounders. Full article
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24 pages, 1037 KiB  
Review
The Mycobiome: Cancer Pathogenesis, Diagnosis, and Therapy
by Ahmed Gamal, Mohammed Elshaer, Mayyadah Alabdely, Ahmed Kadry, Thomas S. McCormick and Mahmoud Ghannoum
Cancers 2022, 14(12), 2875; https://doi.org/10.3390/cancers14122875 - 10 Jun 2022
Cited by 13 | Viewed by 3621
Abstract
Cancer is among the leading causes of death globally. Despite advances in cancer research, a full understanding of the exact cause has not been established. Recent data have shown that the microbiome has an important relationship with cancer on various levels, including cancer [...] Read more.
Cancer is among the leading causes of death globally. Despite advances in cancer research, a full understanding of the exact cause has not been established. Recent data have shown that the microbiome has an important relationship with cancer on various levels, including cancer pathogenesis, diagnosis and prognosis, and treatment. Since most studies have focused only on the role of bacteria in this process, in this article we review the role of fungi—another important group of the microbiome, the totality of which is referred to as the “mycobiome”—in the development of cancer and how it can impact responses to anticancer medications. Furthermore, we provide recent evidence that shows how the different microbial communities interact and affect each other at gastrointestinal and non-gastrointestinal sites, including the skin, thereby emphasizing the importance of investigating the microbiome beyond bacteria. Full article
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