Submit to Special Issue Submit Abstract to Special Issue Review for Cancers Propose a Special Issue

Journal Menu

Journal Browser

► Journal Browser

Advances in Uveal Melanoma

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

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

Deadline for manuscript submissions: 30 April 2026 | Viewed by 18672

Share This Special Issue

Special Issue Editors

Prof. Dr. Takami Sato

E-Mail Website
Guest Editor

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1015 Walnut Street, 1024 Curtis Building, Philadelphia, PA 19107, USA
Interests: uveal melanoma; cancer immunology; immunotherapy; liver-directed treatment; tumor microenvironment; mouse models
Special Issues, Collections and Topics in MDPI journals

Dr. Mizue Terai

E-Mail Website
Guest Editor

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, 1015 Walnut Street, 1015 Curtis Building, Philadelphia, PA 19107, USA
Interests: uveal melanoma; cancer immunology; immunotherapy; tumor microenvironment; mouse models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Uveal melanoma (UM) is a rare form of melanoma, accounting for approximately 5% of all melanoma cases in the United States. Despite successful treatments of primary UM, up to 50% of UM patients subsequently develop systemic metastases, which spread predominantly to the liver.

Over the last decade, major discoveries have been made in the field of UM, including the identification of Gα_q/11 mutations as driver mutations and BAP1 and SF3B1 mutations as epigenetic determinants. Advances in technology also resulted in two treatments being approved by the US FDA, namely T-cell engager, tebemtafusp-tebn (Kimmtrak™), and percutaneous hepatic perfusion with HEPZATO KIT™ (melphalan for injection/hepatic delivery system). These approaches totally changed the landscape of treatment for metastatic uveal melanoma (MUM).

In this Special Issue, we aim to envision the current status of our understanding of UM and discuss the future directions of translational research projects. We hope that this Special Issue will guide researchers in the field of UM to identify a curative approach for MUM patients.

Prof. Dr. Takami Sato
Dr. Mizue Terai
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 communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

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

uveal melanoma
eye cancer
liver metastasis
Gαq/11 mutations
BAP1
SF3B1
PRAME
dormancy
liver-directed treatment
T-cell engager

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
Reprint: MDPI Books provides the opportunity to republish successful Special Issues in book format, both online and in print.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (10 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

17 pages, 2021 KB

Open AccessArticle

Clinicopathological Characteristics and BAP1 Expression in an Enucleation-Based Uveal Melanoma Cohort: A Single-Center Croatian Experience with Long-Term Follow-Up

by Domagoj Vlašić, Mira Knežić Zagorec, Antonia Jakovčević, Dina Lešin Gaćina, Marijana Ćorić and Tomislav Jukić

Cancers 2026, 18(8), 1211; https://doi.org/10.3390/cancers18081211 - 10 Apr 2026

Viewed by 163

Abstract

Background/Objectives: Loss of nuclear BAP1 (BRCA1-associated protein 1) expression is a well-established adverse prognostic marker in uveal melanoma (UM). However, data from Central and Southeastern European populations are limited. This descriptive study aimed to evaluate BAP1 immunohistochemical expression in a Croatian enucleation-based UM cohort, characterize its associations with clinicopathological parameters, and contextualize the findings within the published literature. Methods: Formalin-fixed, paraffin-embedded tumor tissue from 58 consecutive patients with primary choroidal and ciliary body melanoma treated with enucleation at University Hospital Centre Zagreb (2006–2016) was analyzed immunohistochemically for BAP1 nuclear expression. Associations with clinicopathological parameters were assessed using chi-square and Fisher’s exact tests. Survival analysis was performed using Kaplan–Meier estimation, log-rank tests, and Cox proportional hazards regression with a median follow-up of 11.2 years. Results: Loss of nuclear BAP1 expression was observed in 53/58 (91.4%) specimens, resulting in a severely imbalanced distribution (53 versus 5 patients) precluding meaningful comparative survival analysis. Five-year and 10-year overall survival rates were 72.4% and 51.7%, respectively, with a median overall survival of 14.5 years. BAP1 loss was associated with longer disease-free survival (log-rank p = 0.020); however, this finding likely reflects a statistical artifact attributable to the extremely small BAP1-retained group (n = 5) harboring concurrent adverse features and should not be interpreted biologically. The study was underpowered to draw prognostic inferences regarding BAP1 status. Exploratory survival analyses are presented for transparency but should not be interpreted inferentially. Conclusions: The exceptionally high prevalence of BAP1 loss reflects the selection bias inherent in enucleation-based cohorts, which are enriched for large, molecularly high-risk tumors. This study provides the first comprehensive BAP1 immunohistochemical data from Croatia, contributing to the growing evidence that enucleation cohorts represent a distinct, biologically high-risk subgroup in which BAP1 immunohistochemistry offers limited discriminatory value. The extended follow-up of 11.2 years confirms the prolonged natural history of UM. Future multi-center studies incorporating molecular validation and diverse treatment modalities are needed to establish the prognostic utility of BAP1 across the full spectrum of UM disease. Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Figure 1

13 pages, 5306 KB

Open AccessArticle

Cancer Vaccine Targeting Mutated GNAQ-Expressing Uveal Melanoma

by Vitali Alexeev, Mizue Terai, Sergei Koshkin, Olga Igoucheva and Takami Sato

Cancers 2026, 18(3), 480; https://doi.org/10.3390/cancers18030480 - 31 Jan 2026

Viewed by 629

Abstract

Background/Objectives: Uveal melanoma (UM) is the most common intraocular malignancy in adults. Although brachytherapy of the primary tumor provides an approximate 80% five-year survival, with time, nearly half of patients experience predominant liver metastases. It was proposed that malignant cells migrate early and stay dormant as they adapt to the liver microenvironment. We propose that cancer vaccine-mediated activation of UM-targeted immunity in primary UM patients could prevent progression of metastatic disease from dormant cells or malignant seeds. Thus, this study explored DNA vaccination as a measure to educate the immune system to recognize the most common UM-associated Q209L tumor driver mutation in GNAQ and GNA11 G-alpha proteins. Methods: Several DNA constructs encoding mutated GNAQ were developed and tested for activation of UM-reactive T cells in HLA-A2/Hd transgenic mice and human T cells ex vivo. Results: Constructs containing immune-enhancing PADRE and VP22-derived epitopes boosted T cell responses against mutant GNAQ, which correlated with reduced experimental lung metastases. Ex vivo dendritic cell-mediated T cell activation with vaccine constructs containing optimized structure produced cytolytic T cells that secreted IFN gamma and killed mutated GNAQ-expressing UM cells in vitro. Conclusions: These findings propose the utility of the fusion DNA vaccines in eliciting T cell immunity against UM cells bearing the Q209L mutation in GNAQ/GNA11 protein to prevent the establishment and progression of metastatic disease. Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Figure 1

19 pages, 2902 KB

Open AccessCommunication

Unraveling Resistance Mechanisms to Gαq Pathway Inhibition in Uveal Melanoma: Insights from Signaling-Activation Library Screening

by Simone Lubrano, Rodolfo Daniel Cervantes-Villagrana, Nadia Arang, Elena Sofia Cardenas-Alcoser, Kuniaki Sato, Gabriela Cuesta-Margolles, Justine S. Paradis, Monica Acosta and J. Silvio Gutkind

Cancers 2026, 18(1), 74; https://doi.org/10.3390/cancers18010074 - 25 Dec 2025

Cited by 1 | Viewed by 725

Abstract

Background/Objectives: Uveal melanoma (UVM), the leading primary intraocular cancer in adults, is driven by GNAQ/GNA11 mutations, encoding the active forms of Gαq proteins. While local treatments like surgery or radiation can control primary tumors, nearly half of patients die from metastasis. Our aim was identifying potential pathways involved in resistance to targeted therapy in UVM. Methods: Here, we screened 100 pathway-activating mutant complementary DNAs by lentiviral overexpression to identify those that enhance the survival of cancer cells in the presence of clinically relevant targeted therapies, using BAP1 wild-type UVM cells and validated the most significant results in BAP1-mutant cells. Results: This revealed JAK/STAT activation, overexpression of anti-apoptotic BCL2/BCL-XL, and dysregulated PI3K/mTOR or Hippo pathways as escape routes under MEK-ERK or FAK inhibition. Bioinformatic analysis of UVM transcriptome in TCGA further showed that high expression of the hallmark PI3K/AKT/mTOR pathway and IL6/JAK/STAT signaling correlates with poor prognosis. A similar correlation was shown by YAP and anti-apoptotic signatures. The analysis of individual representative genes from these signatures revealed that MTOR, BCL2L1 (BCL-XL), and TEAD4 gene expression are linked to poorer survival, underscoring the potential clinical impact of these adaptive pathways. Proliferation and apoptosis assay demonstrated that aberrant activation of AKT and YAP promotes resistance to FAK and MEK inhibitors. Conclusions: These findings support the adaptability of UVM lesions and suggest rational combination therapies targeting both primary GNAQ/GNA11-driven oncogenic signals and their compensatory networks as a more effective, personalized treatment approach for advanced UVM. Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Figure 1

14 pages, 546 KB

Open AccessArticle

Survival Outcome After Percutaneous Hepatic Perfusion with High-Dose Melphalan for Liver-Dominant Metastatic Uveal Melanoma: A 10-Year Single-Center Experience

by Carolin M. Reiner, Martin A. Schneider, Hauke Weilert, Klara Welcker, Jochen Hoedtke, Andreas H. Mahnken, Axel Stang and Roland Brüning

Cancers 2025, 17(23), 3834; https://doi.org/10.3390/cancers17233834 - 29 Nov 2025

Viewed by 1347

Abstract

Background/Objectives: Melphalan-based percutaneous hepatic perfusion (M-PHP) became approved in 2023 for treatment of liver-dominant metastatic uveal melanoma (mUM). Patients with liver-dominant mUM have a poor overall survival (OS) ≤ 12 months; however, the reported OS benefit from M-PHP varies in clinical trials from 9.6 to 27.4 months and remains uncertain. Here, we report the OS outcome after 10 years’ experience with M-PHP treatment of patients with liver-dominant mUM. Methods: A total of 38 consecutive patients (19 women, median age 57.7 years) with liver-dominant mUM underwent 99 M-PHP procedures (median: 2.6 M-PHP/patient) between April 2014 and March 2024 at our institution. OS outcomes were retrospectively analyzed using Kaplan–Meier methods and Cox proportional hazard models. Results: Median OS was 29.1 months after first M-PHP treatment (median follow-up: 25.8 months). The estimated percentage of patients surviving at 1, 2, and 3 years was 79.5%, 53.2%, and 28.5%, respectively. Each additional M-PHP cycle was associated with about 40% reduction in the risk of death (hazard ratio = 0.414). Median OS was numerically improved by 8.4 months with ≥3 versus ≤2 cycles of M-PHP administered (29.8 versus 21.4 months, p = 0.058). No treatment-related deaths occurred. Conclusions: This study found a clinically meaningful OS benefit in M-PHP-treated patients with liver-dominant mUM, reaching nearly 2.5-year median OS with ≥3 M-PHP cycles administered. This finding supports the need to account for the institutional volume and experience with the M-PHP procedure in both clinical practice and research, and may provide an OS reference for estimating OS gains in the evolving therapeutic landscape for mUM patients. Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Figure 1

15 pages, 554 KB

Open AccessArticle

Long-Term Clinical Outcomes for Adolescent and Young-Adult Uveal Melanoma Patients Treated with Dedicated Particle-Beam Radiation

by Carly Zako, Arina Nisanova, Vivian Weinberg, Jessica Scholey, Carisa Swason, Armin R. Afshar, Jeanne Quivey, Inder K. Daftari, Tony Tsai, Susanna S. Park, Michael Seider, Robert N. Johnson, Devron H. Char and Kavita K. Mishra

Cancers 2025, 17(12), 2042; https://doi.org/10.3390/cancers17122042 - 19 Jun 2025

Viewed by 1452

Abstract

Uveal melanoma (UM) is a rare tumor and a challenging diagnosis for adolescent and young-adult (AYA) patients, as it can threaten vision, quality of life, and life expectancy [...] Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Figure 1

18 pages, 1819 KB

Open AccessArticle

Microdissection of Distinct Morphological Regions Within Uveal Melanomas Identifies Novel Drug Targets

by Elsa Toumi, Luke B. Hesson, Vivian Lin, Dale Wright, Elektra Hajdu, Li-Anne S. Lim, Michael Giblin, Fanfan Zhou, Alexandra Hoffmeister, Farida Zabih, Adrian T. Fung, R. Max Conway and Svetlana Cherepanoff

Cancers 2024, 16(24), 4152; https://doi.org/10.3390/cancers16244152 - 13 Dec 2024

Cited by 1 | Viewed by 2086

Abstract

Background/Objectives: Uveal melanomas (UMs) are rare but often deadly malignancies that urgently require viable treatment options. UMs often exhibit tumour heterogeneity, with macroscopic and microscopic differences in morphology between different regions of the same tumour. However, to date, the clinical significance of this and how it may help guide personalised therapy have not been realised. Methods: Using targeted DNA and RNA sequencing of a small case series of large, high-risk primary UMs, we explored whether morphologically distinct regions of the same tumour were associated with distinct molecular profiles. Results: In four of the seven tumours analysed, we detected different sets of genetic variants following the separate analysis of microdissected melanotic and amelanotic regions of the same tumour. These included a MET exon 14 skipping RNA transcript that predicts sensitivity to crizotinib and variants in other genes that are important in active clinical trials for patients with UM and advanced solid tumours. The integration of TCGA data also identified recurrent mutational events in genes that were not previously implicated in UM development (FANCA, SLX4, BRCA2, and ATRX). Conclusions: Our findings show that the molecular analysis of spatially separated and morphologically distinct regions of the same tumour may yield additional, therapeutically relevant genetic variants in uveal melanomas and have implications for the future molecular testing of UMs to identify targeted therapies. Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Figure 1

11 pages, 2287 KB

Open AccessArticle

Survival Benefit of Primary Tumor Treatment in Uveal Melanoma: A Re-Analysis of the Collaborative Ocular Melanoma Study (COMS) and Natural History Study (NHS) Cohorts

by Hans Witzenhausen and Gustav Stalhammar

Cancers 2024, 16(22), 3839; https://doi.org/10.3390/cancers16223839 - 15 Nov 2024

Cited by 3 | Viewed by 1602

Abstract

Objective: To evaluate whether primary tumor treatment provides a survival benefit in uveal melanoma by comparing patients who declined treatment (Natural History Study, NHS) with those who received treatment in the Collaborative Ocular Melanoma Study (COMS) for medium-sized choroidal melanomas. Methods: Individual-level survival data were reverse-engineered from cumulative all-cause mortality curves in the original COMS and NHS publications. Censoring patterns were estimated from numbers at risk and descriptive statistics. A Bonferroni-corrected significance level of 0.017 was applied. Additionally, to ensure a conservative approach, NHS cohort data were iteratively adjusted by reducing the 8-year cumulative mortality by one percentage point if the Cox regression hazard ratio for all-cause mortality, the unadjusted risk ratio for death, and the 95% confidence intervals (CIs) of the Kaplan–Meier curves did not show a smaller survival difference than originally reported. Results: Kaplan–Meier analysis revealed significantly higher cumulative mortality in the NHS cohort compared to the COMS cohort (log–rank p = 0.012). When restricting the analysis to the first 8 years to account for unclear censoring patterns beyond this period, the NHS cohort still demonstrated worse survival (p = 0.008). A sensitivity analysis, varying censoring times by ±25% over 1000 iterations, confirmed worse survival in the NHS cohort in 100% of cases. Conclusions: In this re-evaluation, patients who declined treatment for medium-sized choroidal melanomas had significantly worse survival, suggesting a potential survival benefit of primary tumor treatment. Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Figure 1

19 pages, 2530 KB

Open AccessArticle

The Phenotypical Characterization of Dual-Nature Hybrid Cells in Uveal Melanoma

by Emily Marcotte, Alicia Goyeneche, Mohamed Abdouh, Julia Valdemarin Burnier and Miguel Noel Burnier, Jr.

Cancers 2024, 16(18), 3231; https://doi.org/10.3390/cancers16183231 - 22 Sep 2024

Cited by 1 | Viewed by 2349

Abstract

Background: Metastasis, occurring years after primary diagnosis, represents a poor prognosis in uveal melanoma (UM)-affected individuals. The nature of cells involved in this process is under debate. Circulating hybrid cells that have combined tumor and immune cell features found in blood were predictive of metastasis and may correspond to dual-nature cells (DNC) in the primary tumor. Herein, we sought to determine the presence of DNCs in primary UM tumors, the cell types involved in their genesis, and their ability to be formed in vitro. Methods: UM lesions (n = 38) were immunolabeled with HMB45 in combination with immune-cell-specific antibodies. In parallel, we co-cultured UM cells and peripheral blood mononuclear cells (PBMCs) to analyze DNC formation. Results: HMB45⁺/CD45⁺ DNCs were present in 90% (26/29) of the tumors, HMB45⁺/CD8⁺ DNCs were present in 93% (26/28), and HMB45⁺/CD68⁺ DNCs were present in 71% (17/24). DNCs formed with CD8⁺ and CD68⁺ cells were positively correlated to the infiltration of their respective immune cells. Notably, UM cells were prone to hybridize with PBMCs in vitro. Conclusions: This phenotypical characterization of DNCs in UM demonstrates that CD8⁺ T-cells and macrophages are capable of DNC formation, and they are important for better understanding metastatic dissemination, thus paving the path towards novel therapeutic avenues. Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Figure 1

Review

Jump to: Research

18 pages, 1346 KB

Open AccessReview

Understanding and Exacerbating the Biological Response of Uveal Melanoma to Proton Beam Therapy

by Laura Hawkins, Helen Kalirai, Karen Aughton, Rumana N. Hussain, Sarah E. Coupland and Jason L. Parsons

Cancers 2025, 17(19), 3104; https://doi.org/10.3390/cancers17193104 - 24 Sep 2025

Viewed by 1129

Abstract

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, associated with a high tendency for metastasis to the liver. Proton beam therapy (PBT) is the preferred external radiotherapy treatment for primary UM of certain sizes and locations in the eye, due to its efficacy and good local tumour control, as well as its precision to spare surrounding ocular structures. PBT is an effective alternative to surgical enucleation and other non-precision-targeted radiotherapies. Despite this, the radiobiology of UM in response to PBT is still not fully understood. This enhanced knowledge would help to further optimise UM treatment and improve patient outcomes through reducing radiation dosage to ocular structures, treating larger tumours that would otherwise require enucleation, or even offering a treatment strategy for the otherwise fatal liver metastases. In this review, we explore current knowledge of the treatment of UM with PBT, evaluating the biological responses to the therapy. Molecular factors, such as tumour size, oxygen tension levels, DNA damage proficiency, and autophagy, are known to influence the cellular response to radiotherapy, and these will be discussed. Furthermore, we examine innovative strategies to enhance radiotherapy outcomes, such as combination therapies with DNA damage repair and autophagy modulators, as well as advancements in PBT planning and delivery. By integrating current research and emerging technologies, we aim to provide opportunities to improve the therapeutic effectiveness of PBT in UM management. Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Graphical abstract

20 pages, 1030 KB

Open AccessReview

by Justyna Pilch, Jakub Mizera, Maciej Tota and Piotr Donizy

Cancers 2024, 16(21), 3672; https://doi.org/10.3390/cancers16213672 - 30 Oct 2024

Cited by 5 | Viewed by 5958

Abstract

Uveal melanoma (UM), recognized as the most prevalent primary intraocular malignancy in adults, is primarily driven by mutations in the GNAQ and GNA11 genes. These genetic alterations are also implicated in other conditions, which exhibit distinct morphological characteristics. In this article, we investigate the role of GNAQ and GNA11 mutations across varied disorders (e.g., UM, skin blue nevi, and hemangiomas), emphasizing the shared pathogenic mechanisms that connect them despite their differing clinical manifestations. By investigating the molecular pathways affected by these mutations, we provide insights into the potential for targeted therapies that could address not only UM but also other disorders associated with GNAQ/GNA11 mutations. Moreover, we discuss the role of SOX10-positive perivascular cells that may be implicated in the complex pathophysiology of GNAQ/GNA11-related entities. Understanding the common molecular foundation of these conditions opens new ways for research and treatment opportunities, potentially leading to more effective, personalized therapeutic strategies. Full article

(This article belongs to the Special Issue Advances in Uveal Melanoma)

► Show Figures

Journal Menu

Journal Browser

Advances in Uveal Melanoma

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI