Treatment of uveal melanoma: where are we now?

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Abstract

Uveal melanoma, a rare subset of melanoma, is the most common primary intraocular malignancy in adults. Despite effective primary therapy, nearly 50% of patients will develop metastatic disease. Outcomes for those with metastatic disease remain dismal due to a lack of effective therapies. The unique biology and immunology of uveal melanoma necessitates the development of dedicated management and treatment approaches. Ongoing efforts seek to optimize the efficacy of targeted therapy and immunotherapy in both the adjuvant and metastatic setting. This review provides a comprehensive, updated overview of disease biology and risk stratification, the management of primary disease, options for adjuvant therapy, and the current status of treatment strategies for metastatic disease.

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Mutations in GNA11 in uveal melanoma.

Catherine D. Van Raamsdonk, Klaus G. Griewank, Michelle Crosby … (2010)

Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi. We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway. Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.).

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Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry.

Xiaodong Feng, Maria Degese, Ramiro Iglesias-Bartolomé … (2014)

Mutually exclusive activating mutations in the GNAQ and GNA11 oncogenes, encoding heterotrimeric Gαq family members, have been identified in ∼ 83% and ∼ 6% of uveal and skin melanomas, respectively. However, the molecular events underlying these GNAQ-driven malignancies are not yet defined, thus limiting the ability to develop cancer-targeted therapies. Here, we focused on the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway that controls organ size. We found that Gαq stimulates YAP through a Trio-Rho/Rac signaling circuitry promoting actin polymerization, independently of phospholipase Cβ and the canonical Hippo pathway. Furthermore, we show that Gαq promotes the YAP-dependent growth of uveal melanoma cells, thereby identifying YAP as a suitable therapeutic target in uveal melanoma, a GNAQ/GNA11-initiated human malignancy. Copyright © 2014 Elsevier Inc. All rights reserved.

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Metastatic disease from uveal melanoma: treatment options and future prospects

Richard D Carvajal, Gary K. Schwartz, Tongalp H. Tezel … (2016)

Uveal melanoma represents ∼85% of all ocular melanomas and up to 50% of patients develop metastatic disease. Metastases are most frequently localised to the liver and, as few patients are candidates for potentially curative surgery, this is associated with a poor prognosis. There is currently little published evidence for the optimal management and treatment of metastatic uveal melanoma and the lack of effective therapies in this setting has led to the widespread use of systemic treatments for patients with cutaneous melanoma. Uveal and cutaneous melanomas are intrinsically different diseases and so dedicated management strategies and therapies for uveal melanoma are much needed. This review explores the biology of uveal melanoma and how this relates to ongoing trials of targeted therapies in the metastatic disease setting. In addition, we consider the options to optimise patient management and care.

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Author and article information

Contributors

Jessica Yang

Daniel K. Manson

Brian P. Marr

Richard D. Carvajal

Journal

Journal ID (nlm-ta): Ther Adv Med Oncol

Journal ID (iso-abbrev): Ther Adv Med Oncol

Journal ID (publisher-id): TAM

Journal ID (hwp): sptam

Title: Therapeutic Advances in Medical Oncology

Publisher: SAGE Publications (Sage UK: London, England )

ISSN (Print): 1758-8340

ISSN (Electronic): 1758-8359

Publication date (Electronic): 21 February 2018

Publication date Collection: 2018

Volume: 10

Electronic Location Identifier: 1758834018757175

Affiliations

[1-1758834018757175]Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA

[2-1758834018757175]Division of Hematology/Oncology, Columbia University Medical Center, New York, NY, USA

[3-1758834018757175]Department of Ophthalmology, Columbia University Medical Center, New York, NY, USA

[4-1758834018757175]Assistant Professor of Medicine, Director of Experimental Therapeutics and Melanoma Services, Division of Hematology/Oncology, Columbia University Medical Center, 177 Fort Washington Avenue, MHB 6GN-435, New York, NY 10032, USA

[5-1758834018757175]Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA

Author notes

[*] rdc2150@ 123456cumc.columbia.edu

Article

Publisher ID: 10.1177_1758834018757175

DOI: 10.1177/1758834018757175

PMC ID: 5824910

PubMed ID: 29497459

SO-VID: e100099d-e356-4323-ae43-3c6c6053f6fc

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This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

History

Date received : 18 October 2017

Date accepted : 12 January 2018

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cover-date January-December 2018

Keywords: adjuvant therapy,immunotherapy,liver-directed therapy,targeted therapy,uveal melanoma

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Keywords: adjuvant therapy, immunotherapy, liver-directed therapy, targeted therapy, uveal melanoma

Treatment of uveal melanoma: where are we now?

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Cancer Immunotherapy

Most cited references 73

Mutations in GNA11 in uveal melanoma.

Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry.

Metastatic disease from uveal melanoma: treatment options and future prospects

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