Uveal melanoma: progress in molecular biology and therapeutics

Abstract

Uveal melanoma (UM) is the most common intraocular malignancy in adults. So far, no systemic therapy or standard treatment exists to reduce the risk of metastasis and improve overall survival of patients. With the increased knowledge regarding the molecular pathways that underlie the oncogenesis of UM, it is expected that novel therapeutic approaches will be available to conquer this disease. This review provides a summary of the current knowledge of, and progress made in understanding, the pathogenesis, genetic mutations, epigenetics, and immunology of UM. With the advent of the omics era, multi-dimensional big data are publicly available, providing an innovation platform to develop effective targeted and personalized therapeutics for UM patients. Indeed, recently, a great number of therapies have been reported specifically for UM caused by oncogenic mutations, as well as other etiologies. In this review, special attention is directed to advancements in targeted therapies. In particular, we discuss the possibilities of targeting: GNAQ/GNA11, PLCβ, and CYSLTR2 mutants; regulators of G-protein signaling; the secondary messenger adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6); downstream pathways, such as those involving mitogen-activated protein kinase/MEK/extracellular signal-related kinase, protein kinase C (PKC), phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR), Trio/Rho/Rac/Yes-associated protein, and inactivated BAP1; and immune-checkpoint proteins cytotoxic T-lymphocyte antigen 4 and programmed cell-death protein 1/programmed cell-death ligand 1. Furthermore, we conducted a survey of completed and ongoing clinical trials applying targeted and immune therapies for UM. Although drug combination therapy based on the signaling pathways involved in UM has made great progress, targeted therapy is still an unmet medical need.

Keywords: GNAQ/GNA11 mutation; UM clinical trials; UM signaling pathway; UM-targeted therapy; uveal melanoma.

Figure 1.

Clinical manifestation and imaging examinations of typical UM patients. (a) A patient has a rounded neoplasm at the posterior pole of his left eye, involving the choroid, which is black and raised via retinal camera and ultrasonography examination. (b) A patient has multicenter neoplasms with a wide base involving the posterior pole and equator choroid of his left eye. Images were taken from two UM patients referred to Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine. Written informed consent for publication of their images was obtained from the patient. UM, uveal melanoma.

Figure 2.

Schematic representation of G-protein movement and the Gα subunit inhibition by YM‑254890 and FR900359. The Gα subunit can bind to GTP or GDP. The GDP-bound state connects with β and γ subunits to form a trimer. When GDP is exchanged into GTP upon agonist stimulating GPCR, the Gα subunit becomes activated, dissociates from the receptor and Gβγ subunits and triggers the downstream signaling cascades. With the help of the GTPase domain in Gα subunit, GTP is hydrolyzed into GDP and the signal is terminated. GDP releasing and the guanine-nucleotide-free state of Gα subunit is necessary for GTP binding, when the α-helical domain (purple) is separated from the Ras-like domain (green). YM-254890 or FR900359 (blue) binds to the hinge region of Gα_q/11, preventing the separation of the domains necessary for GDP release. GDP, guanosine diphosphate; GPCR, G-protein-coupled receptor; GTP, guanosine triphosphate.

Figure 3.

Gα_q/11 signaling pathways. The main downstream signaling pathways of GNAQ/GNA11 include PKC/MAPK/MEK/ERK, Trio/Rho/Rac/YAP, PI3K/Akt/mTOR, and ARF6/GEP100. The important nodes have been identified as druggable targets (labeled with red). ARF6, adenosine diphosphate ribosylation factor 6; GEP, guanine-nucleotide exchange factor; ERK, extracellular signal-related kinase; GNAQ, guanine-nucleotide-binding protein G(q); GNA11, guanine-nucleotide-binding protein G(11) subunit alpha; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; YAP, Yes-associated protein.