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Cancers
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Therapies of Uveal Melanoma
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Therapies of Uveal Melanoma

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

Deadline for manuscript submissions: closed (30 May 2023) | Viewed by 11774

Special Issue Editors

Dr. Manuel Rodrigues

E-Mail Website
Guest Editor
Department of Medical Oncology, Institut Curie, Paris Science & Lettres Research University, 75005 Paris, France
Institut Curie, Institut national de la santé et de la recherche médicale (INSERM), PSL Research University, U830, 75005 Paris, France
Interests: gynecological and ocular cancer
Dr. Sergio Roman-Roman

E-Mail Website
Guest Editor
Translational Research Department, Institut Curie, Paris, France
Interests: antitumor; uveal melanoma; tumor models

Special Issue Information

Dear Colleagues,

Uveal melanoma (UM) is the most common intraocular malignant tumor in adults. Primary tumors are treated with conservative strategies, such as brachytherapy or proton-beam therapy but sometimes require enucleation. Even if local treatment is very efficient, up to 50% of patients will eventually suffer metastatic recurrence. Risk of metastatic recurrence can be estimated with TNM staging, as well as transcriptomic or genomic signatures. When metastatic, UM is associated with poor prognosis. Until recently with the positive results of two clinical trials with tebentafusp, no treatment had previously shown clinical efficiency on metastatic UMs. Various inhibitors have been tested in clinical trials to target GNAQ/GNA11-activating mutations, including MAPK and PKC, with limited, if any, clinical benefit. Cytotoxic drugs and immune checkpoint inhibitors are associated with limited activity, although some exceptional responder patients have been reported.

This Special Issue will focus on the treatment of primary, as well as metastatic, UM patients. We will not only accept papers on the different, current and future therapeutic options, but also on the development of new targets and new models, as well as on the supportive and psychological care of our patients.

Examples of eligible themes:
Diagnosis and Prognosis
     Ophthalmology
     Pathology including Molecular Pathology
Prognostication and psychological consequences
Patient advocacy
Local treatment approaches
     Surgery
     Radiotherapy / Protontherapy
     Consequences including radio-induced retinopathies and psychological consequences
Follow-up of UM patients after local treatment
     Imaging
     Circulating biomarkers
Treatment of metastatic disease
     Surgery
     Liver-directed therapies including chemoembolization
     Radiotherapy
     Chemotherapy
Immunotherapy
     Targeted therapies
Supportive care including palliative and psychological care

Best regards,

Dr. Manuel Rodrigues
Dr. Sergio Roman-Roman
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 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

  • Uveal melanoma (UM)
  • Ophthalmology
  • Pathology
  • Surgery
  • Diagnosis and prognosis
  • Psychological consequences
  • Local treatment approaches
  • Treatment of metastatic disease
  • Immunotherapy
  • Supportive care

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Published Papers (4 papers)

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Research

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13 pages, 2007 KiB  
Article
FAK Inhibitor-Based Combinations with MEK or PKC Inhibitors Trigger Synergistic Antitumor Effects in Uveal Melanoma
by Malcy Tarin, Fariba Némati, Didier Decaudin, Christine Canbezdi, Benjamin Marande, Lisseth Silva, Héloïse Derrien, Aart G. Jochemsen, Sophie Gardrat, Sophie Piperno-Neumann, Manuel Rodrigues, Pascale Mariani, Nathalie Cassoux, Marc-Henri Stern, Sergio Roman-Roman and Samar Alsafadi
Cancers 2023, 15(8), 2280; https://doi.org/10.3390/cancers15082280 - 13 Apr 2023
Cited by 5 | Viewed by 2230
Abstract
Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Even if radiation or surgery permit an efficient control of the primary tumor, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment of UM metastases [...] Read more.
Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Even if radiation or surgery permit an efficient control of the primary tumor, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment of UM metastases is challenging and the patient survival is very poor. The most recurrent event in UM is the activation of Gαq signaling induced by mutations in GNAQ/11. These mutations activate downstream effectors including protein kinase C (PKC) and mitogen-activated protein kinases (MAPK). Clinical trials with inhibitors of these targets have not demonstrated a survival benefit for patients with UM metastasis. Recently, it has been shown that GNAQ promotes YAP activation through the focal adhesion kinase (FAK). Pharmacological inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in UM both in vitro and in vivo. In this study, we have evaluated the synergy of the FAK inhibitor with a series of inhibitors targeting recognized UM deregulated pathways in a panel of cell lines. The combined inhibition of FAK and MEK or PKC had highly synergistic effects by reducing cell viability and inducing apoptosis. Furthermore, we demonstrated that these combinations exert a remarkable in vivo activity in UM patient-derived xenografts. Our study confirms the previously described synergy of the dual inhibition of FAK and MEK and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM. Full article
(This article belongs to the Special Issue Therapies of Uveal Melanoma)
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18 pages, 1599 KiB  
Article
Cerivastatin Synergizes with Trametinib and Enhances Its Efficacy in the Therapy of Uveal Melanoma
by Adriana Agnese Amaro, Rosaria Gangemi, Laura Emionite, Patrizio Castagnola, Gilberto Filaci, Martine J. Jager, Enrica Teresa Tanda, Francesco Spagnolo, Matteo Mascherini, Ulrich Pfeffer and Michela Croce
Cancers 2023, 15(3), 886; https://doi.org/10.3390/cancers15030886 - 31 Jan 2023
Cited by 6 | Viewed by 2028
Abstract
Background: Metastatic uveal melanoma (MUM) is a highly aggressive, therapy-resistant disease. Driver mutations in Gα-proteins GNAQ and GNA11 activate MAP-kinase and YAP/TAZ pathways of oncogenic signalling. MAP-kinase and MEK-inhibitors do not significantly block MUM progression, likely due to persisting YAP/TAZ signalling. Statins inhibit [...] Read more.
Background: Metastatic uveal melanoma (MUM) is a highly aggressive, therapy-resistant disease. Driver mutations in Gα-proteins GNAQ and GNA11 activate MAP-kinase and YAP/TAZ pathways of oncogenic signalling. MAP-kinase and MEK-inhibitors do not significantly block MUM progression, likely due to persisting YAP/TAZ signalling. Statins inhibit YAP/TAZ activation by blocking the mevalonate pathway, geranyl-geranylation, and subcellular localisation of the Rho-GTPase. We investigated drugs that affect the YAP/TAZ pathway, valproic acid, verteporfin and statins, in combination with MEK-inhibitor trametinib. Methods: We established IC50 values of the individual drugs and monitored the effects of their combinations in terms of proliferation. We selected trametinib and cerivastatin for evaluation of cell cycle and apoptosis. Synergism was detected using isobologram and Chou–Talalay analyses. The most synergistic combination was tested in vivo. Results: Synergistic concentrations of trametinib and cerivastatin induced a massive arrest of proliferation and cell cycle and enhanced apoptosis, particularly in the monosomic, BAP1-mutated UPMM3 cell line. The combined treatment reduced ERK and AKT phosphorylation, increased the inactive, cytoplasmatic form of YAP and significantly impaired the growth of UM cells with monosomy of chromosome 3 in NSG mice. Conclusion: Statins can potentiate the efficacy of MEK inhibitors in the therapy of UM. Full article
(This article belongs to the Special Issue Therapies of Uveal Melanoma)
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Review

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16 pages, 336 KiB  
Review
Ocular Complications of Radiotherapy in Uveal Melanoma
by Mihail Zemba, Otilia-Maria Dumitrescu, Alina Gabriela Gheorghe, Madalina Radu, Mihai Alexandru Ionescu, Andrei Vatafu and Valentin Dinu
Cancers 2023, 15(2), 333; https://doi.org/10.3390/cancers15020333 - 4 Jan 2023
Cited by 15 | Viewed by 2678
Abstract
Uveal melanoma is the most common primary malignant intraocular tumor in adults. Radiation therapy has replaced enucleation and is now the preferred treatment in most cases. Nonetheless, around 70% of patients develop radiation-related complications, some of which are vision-threatening. The objective of this [...] Read more.
Uveal melanoma is the most common primary malignant intraocular tumor in adults. Radiation therapy has replaced enucleation and is now the preferred treatment in most cases. Nonetheless, around 70% of patients develop radiation-related complications, some of which are vision-threatening. The objective of this review is to present the most important complications associated with radiotherapy in the treatment of uveal melanoma and their pathogenesis, incidence, risk factors, and available preventive and therapeutic measures. The most common complications are cataracts, with a reported incidence ranging from 4% to 69%, and radiation retinopathy, reported in 5–68% of cases. Radiation-related complications are responsible for approximately half of secondary enucleations, the leading cause being neovascular glaucoma. A poor visual outcome is mainly associated with the presence of radiation retinopathy and radiation optic neuropathy. Therapeutic options are available for the majority of complications with the notable exception of optic neuropathy. However, many studies report a final visual acuity of less than 20/200 in more than 60% of treated eyes. Reducing complication rates can be achieved by lowering the dose of radiation, with the use of eccentric, customized plaques and careful planning of the irradiation delivery in order to protect structures vital to vision and by associating radiation therapy with other methods with the aim of reducing tumor volume. Full article
(This article belongs to the Special Issue Therapies of Uveal Melanoma)
21 pages, 1756 KiB  
Review
New Perspectives for Eye-Sparing Treatment Strategies in Primary Uveal Melanoma
by Krzysztof Bilmin, Kamil J. Synoradzki, Anna M. Czarnecka, Mateusz J. Spałek, Tamara Kujawska, Małgorzata Solnik, Piotr Merks, Mario Damiano Toro, Robert Rejdak and Michał Fiedorowicz
Cancers 2022, 14(1), 134; https://doi.org/10.3390/cancers14010134 - 28 Dec 2021
Cited by 14 | Viewed by 3899
Abstract
Uveal melanoma is the most common intraocular malignancy and arises from melanocytes in the choroid, ciliary body, or iris. The current eye-sparing treatment options include surgical treatment, plaque brachytherapy, proton beam radiotherapy, stereotactic photon radiotherapy, or photodynamic therapy. However, the efficacy of these [...] Read more.
Uveal melanoma is the most common intraocular malignancy and arises from melanocytes in the choroid, ciliary body, or iris. The current eye-sparing treatment options include surgical treatment, plaque brachytherapy, proton beam radiotherapy, stereotactic photon radiotherapy, or photodynamic therapy. However, the efficacy of these methods is still unsatisfactory. This article reviews several possible new treatment options and their potential advantages in treating localized uveal melanoma. These methods may be based on the physical destruction of the cancerous cells by applying ultrasounds. Two examples of such an approach are High-Intensity Focused Ultrasound (HIFU)—a promising technology of thermal destruction of solid tumors located deep under the skin and sonodynamic therapy (SDT) that induces reactive oxygen species. Another approach may be based on improving the penetration of anti-cancer agents into UM cells. The most promising technologies from this group are based on enhancing drug delivery by applying electric current. One such approach is called transcorneal iontophoresis and has already been shown to increase the local concentration of several different therapeutics. Another technique, electrically enhanced chemotherapy, may promote drug delivery from the intercellular space to cells. Finally, new advanced nanoparticles are developed to combine diagnostic imaging and therapy (i.e., theranostics). However, these methods are mostly at an early stage of development. More advanced and targeted preclinical studies and clinical trials would be needed to introduce some of these techniques to routine clinical practice. Full article
(This article belongs to the Special Issue Therapies of Uveal Melanoma)
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