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.

An experimental strategy to probe Gq contribution to signal transduction in living cells

“…Thereby, FR and YM lock their cognate Gαβγ heterotrimers in the inactive GDP-bound form. Thus far, both depsipeptides are considered potent and highly selective for Gq over all other Gα families ( 24 , 25 , 26 , 27 , 28 ), explaining their widespread use to explore the biological consequences arising from specific Gq inhibition in vitro , ex vivo , and in vivo ( 14 , 22 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ).…”

“…Moreover, phospholipase C (PLC) β2 and β3 isoforms are synergistically activated by Gαq and Gβγ, the latter originating from Gi/o heterotrimers ( 68 , 69 , 70 , 71 , 72 ). For the above reasons, clarification of the purported nonselective pharmacology of FR and YM is important for basic science where both inhibitors are used to probe the function of Gq/11 ( 14 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ), as well as for translational science where both are explored as therapeutic leads in asthma ( 52 ), ocular melanoma ( 53 , 54 , 57 , 58 , 59 ), and cardiovascular diseases ( 22 , 55 , 56 , 60 ).…”

The Microenvironment Combining with Immune Infiltration of Uveal Melanoma

“…The bioinformatic method was performed to further clari ed the pathways that DEGs involved, including gene annotation, pathway enrichment and proteinnetwork construction. The role of mutations in the occurrence and development of UM was analyzed, and the correlation between mutations and gene expression was discussed [22]. Consequently, we analyzed the immune in ltration condition of UM.…”

Construction and Validation of a Novel Immunosignature for Overall Survival in Uveal Melanoma

“…Uveal melanoma (UM), arising from melanocytes in the uvea, is the most common primary intraocular malignancy in adults ( Li et al, 2020 ). More than 90% of UM cases have choroidal involvement, and the remaining 10% are confined to the ciliary body or the iris ( Shields et al, 2012 ).…”

“…The pathogenetic mechanisms and markers that influence the prognosis of UM patients have been extensively investigated in the past few decades ( Li et al, 2020 ). Accumulating evidence reveals that chromosomal abnormalities in UM, including chromosome 3 monosomy (monosomy 3), gains of chromosomal arm 8q, and loss of chromosomal arm 1p, are closely related to an increased risk of metastasis ( Aalto et al, 2001 ; Trolet et al, 2009 ; Damato et al, 2010 ), while gain of chromosomal arm 6p is associated with longer metastasis-free survival (MFS; Aalto et al, 2001 ).…”