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Synoradzki, K.J.; Paduszyńska, N.; Solnik, M.; Toro, M.D.; Bilmin, K.; Bylina, E.; Rutkowski, P.; Yousef, Y.A.; Bucolo, C.; Zweifel, S.A.; et al. Molecular Biology of Uveal Melanoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/55256 (accessed on 14 April 2024).
Synoradzki KJ, Paduszyńska N, Solnik M, Toro MD, Bilmin K, Bylina E, et al. Molecular Biology of Uveal Melanoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/55256. Accessed April 14, 2024.
Synoradzki, Kamil J., Natalia Paduszyńska, Malgorzata Solnik, Mario Damiano Toro, Krzysztof Bilmin, Elżbieta Bylina, Piotr Rutkowski, Yacoub A. Yousef, Claudio Bucolo, Sandrine Anne Zweifel, et al. "Molecular Biology of Uveal Melanoma" Encyclopedia, https://encyclopedia.pub/entry/55256 (accessed April 14, 2024).
Synoradzki, K.J., Paduszyńska, N., Solnik, M., Toro, M.D., Bilmin, K., Bylina, E., Rutkowski, P., Yousef, Y.A., Bucolo, C., Zweifel, S.A., Reibaldi, M., Fiedorowicz, M., & Czarnecka, A.M. (2024, February 21). Molecular Biology of Uveal Melanoma. In Encyclopedia. https://encyclopedia.pub/entry/55256
Synoradzki, Kamil J., et al. "Molecular Biology of Uveal Melanoma." Encyclopedia. Web. 21 February, 2024.
Molecular Biology of Uveal Melanoma
Edit

Uveal melanoma arises from the pigment-producing cells in the iris, ciliary body, and choroid. Its annual incidence is estimated to be around 5–6 cases per million people, but is the most common primary intraocular malignancy in adults. 

biomarkers immunotherapy theranostics nanomedicine

1. Introduction

Uveal melanoma arises from the pigment-producing cells in the iris, ciliary body, and choroid. Its annual incidence is estimated to be around 5–6 cases per million people, but is the most common primary intraocular malignancy in adults. The average age at diagnosis is around 55 years old. The frequency of its occurrence varies depending on race and geographical latitude. The incidence is highest among the Caucasian race (98% of all cases) and at higher latitudes. In Mediterranean countries, there are 2 new cases per 1 million inhabitants per year, while in Scandinavian countries, it is 8–11 per 1 million inhabitants. In the United States, an average of 4.3 new cases per year per 1 million people occur [1][2][3][4]. Over the past few decades, mortality rates have remained stagnant, exceeding 40% for patients who develop systemic diseases and succumb within a decade of diagnosis. Upon metastasis of the disease, life expectancy diminishes to less than one year [4][5][6].

2. Biology of Uveal Melanoma

The development of uveal melanoma is primarily correlated with specific genetic aberrations including chromosome 3 complete monosomy, 6 disomy, and 8q gain or 8p loss, as well as the expression of the human melanoma black 45 (HMB45) antigen, the S-100 protein, Melan-A (also known as the melanoma antigen recognized by T cells 1/MART-1), melanocyte-inducing transcription factors (MITFs), tyrosinase, vimentin, and sex-determining region Y-Box 10 (SOX10), which were detected in immunohistochemistry [7][8]. The predominant mutation occurs at the Q209 position, with 45% of mutations involving GNAQ and 32% involving GNA11. Less commonly, mutations impact the R183 position, with 3% in GNAQ and 2% in GNA11. These mutations lead to a modification in amino acids and do not occur simultaneously [9]. The GNAQ and GNA11 genes are responsible for encoding heterotrimeric Gq-proteins, which play a role in connecting transmembrane receptors to intracellular pathways. The activation of these genes is viewed as an initial signal in the carcinogenesis of uveal melanoma [10]. Other events in UM development include mutations in BAP-1 and SF3B1 genes. Loss or point mutations in BAP1 occur in more than 80% of metastatic uveal melanoma cases. These events are linked to reduced rates of disease-free survival (DFS) and overall survival (OS). Mutations in the BAP1 gene most often result in the early termination of the BAP1 protein and may affect its ubiquitin carboxyl-terminal hydrolase domain, thereby modifying its deubiquitinase activity. Because BAP1 has interactions with multiple proteins and signaling pathways, including the tumor suppressor BRCA1 gene, it plays a vital role in preserving genome stability and DNA damage response [11][12][13]. Around 10–20% of uveal melanoma cases display mutations in the splicing factor 3B subunit 1 (SF3B1) gene. Situated on chromosome 2q33, the SF3B1 gene is responsible for coding a subunit of the spliceosome, a sizable complex engaged in the processing of precursor mRNA. SF3B1 holds a vital function in ensuring accurate splicing by retaining pre-mRNA and determining the splicing site. The X-linked eukaryotic translation initiation factor 1A protein (EIF1AX) is mutated in about 15% of UM cases. This gene locus is found on chromosome 10. The X-linked eukaryotic translation initiation factor 1A protein is a key player in overseeing the initiation of protein translation. Mutations in EIF1AX can cause the mis-selection of start sites, resulting in the inhibited translation of canonical transcripts or potentially elevating the expression of oncogenes [8][13][14][15][16][17]. Again, BAP1, SF3B1, and EIF1AX mutations are mutually exclusive. Mutations in genes including GNAQ, GNA11, SF3B1, EIF1AX, BAP-1, and PRAME are important in assessing prognoses. Epigenetic mechanisms regulated by non-coding RNAs (ncRNA) including microRNAs and long non-coding RNAs are also deregulated in UM, including miR-513a-5p, miR-182, miR-211, miR-137, miR-20a, and miR-27a [7][8][13][18].
Investigations of tumor-driving cell cycle and epigenetic pathways involving the above-mentioned genes have led to novel targeted therapies. Compounds like monoclonal antibodies or small molecules affect the downstream signaling of activated Gαq/11, targeting the factors crucial for UM pathways: the protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) or phosphatidylinositol-3 kinase (PI3K)/mTOR/AKT and the IGF-1/IGF-1R pathway, which inhibit proteins like YAP (yes-associated protein), focal adhesion kinase (FAK), PARP, bromodomain and extra-terminal (BET), Brahma-associated factor complexes (BAF), or HDAC inhibitors. Preclinical or clinical trials are currently being undertaken to evaluate compounds that target mentioned proteins and pathways [19].
Extending diagnostics with genetic abnormalities in UM cells significantly increases the scope of information, precision, and accuracy of diagnosis and generates further challenges for the effective use of obtained data. Currently, the role of genetic mutations and circulating miRNAs in uveal melanoma is being investigated in the NCT05179174 trial run by the Ophthalmology Clinic of the “Policlinico-Vittorio Emanuele” University Hospital in Catania, Italy; the Ophthalmology Clinic of the University of Turin in Italy; as well as the Department of General and Paediatric Ophthalmology, Medical University of Lublin in Poland. All patients enrolled in the study had blood samples examined for the presence of ctDNA with GNA11 and GNAQ gene mutations and the expression of multiple microRNAs: miR-506-514 cluster, hsa-miR-592, and hsa-miR-199a-5p, using the digital PCR droplet system.
An interesting study employing gene expression profiling (GEP) enabled us to divide UM into two molecular subtypes. US subtypes are referred to as class 1 and class 2 and differ by a subset of 15 gene expressions. The class 1 expression profile is a good prognostic biomarker and is found in approximately 66% of cases. On the contrary, the class 2 profile is a poor prognostic biomarker [20]. Recently, Opa-interacting protein 4 (PRAME)—cancer-testis antigen 130 expressed in UM—has been defined as a new biomarker. This biomarker improves the prognostic specificity of the 15-gene GEP profile prognostic specificity [21]. Moreover, PRAME may also be considered a novel immunotherapy target as it is not expressed in normal cells. Monoclonal antibodies and cytotoxic T lymphocytes reactive against PRAME may become a new therapeutic option and are currently being investigated [22][23].

3. Nanomedicine

Nanomedicine is a field at the interface of medicine and pharmacy encompassing very small technologies, ranging from 1 to 1000 nm, to treat or diagnose diseases. The use of nanoscale materials allows for an appropriate concentration of a drug at the target site of action. It can be understood as a part of personalized medicine in this sense [24]. Nanomaterials used in medicine and pharmacy can be divided into three main types: polymers, inorganic nanoparticles, and lipid technologies, especially liposomes. These technologies have found their practical application and, currently, there are medicinal products on the market using all the forms mentioned above. One of the first FDA-approved drugs used in oncology were liposomal forms of doxorubicin (Doxil, Janssen) and an Escherichia coli-derived conjugate of L-asparaginase with monomethoxypolyethylene glycol for the treatment of acute lymphoblastic leukemia (Oncaspar, Servier) (Mitchell MJ, 2021). The first nanosystem approved for use in photodynamic therapy was verteporfin in liposomal form (Visudyne, Novartis; Bausch and Lomb), which is currently used in AMD and CNV photodynamic therapy as well as for uveal melanoma [25][26]. Nanotechnologies play a crucial role in advancing personalized medicine in oncology. They enhance the delivery of drugs directly to tumor sites by efficiently overcoming biological barriers. Additionally, nanotechnologies are valuable for enhancing the physical and chemical characteristics of drugs, contributing to their increased efficacy in treating cancer. A good example that confirms the advantages of nanomedicine to improve personalized medicine is imatinib, the first drug in the targeted therapy of chronic myeloid leukemia with the expression of the BCR-ABL fusion protein. The increase in drug delivery using nanomaterials has been shown to improve survival by 40% in a mouse leukemia model [27]. Nanomedicine may be particularly important in ophthalmology due to the specific structure of the eye and biological barriers that represent an obstacle to drug delivery [28]. Therefore, it seems that nanomedicine can be very helpful in UM therapy, where overcoming biological barriers of the eye and effective drug delivery to the tumor site are of particular importance. Current nanomedicine research on uveal melanoma uses nanoparticles to deliver cytostatic drugs and genes and increases the effectiveness of brachytherapy or photodynamic therapy. In addition to therapeutic nanoparticles, contrast agents have also been developed, which, given in the form of nanoparticles, increase the quality of the radiological images [29]. One of the most dynamically developing areas of nanomedicine is the delivery systems of miRNA—an important regulator of gene expression and one of the important molecular targets in the development of anticancer therapies. Disturbances of miRNA expression in UM are classified as epigenetic mechanisms responsible for tumorigenesis and metastasis [30]. Preclinical studies have shown that therapeutic miRNAs can inhibit the proliferation of UM tumor cells, reduce their growth, prevent metastasis, and increase susceptibility to radiation therapy. Unfortunately, the stability of miRNAs in vivo is low due to the destructive effect of serum nuclease, among other reasons. This makes it difficult to achieve the right concentration in cancer cells. To overcome this problem and protect against the degradation of miRNA molecules, drug delivery systems based on organic (polymers, liposomes, micelles, etc.) and inorganic nanoparticles of gold, silver, iron oxide, silicon, etc. [31] can be used. The synergistic cytotoxic effect of a type I topoisomerase inhibitor and miRNA was shown in the study by Milain Rois et al. [32]. It turned out that both compounds, conjugated with gold nanoparticles as carriers, showed a stronger carrier cytotoxic effect against human uveal melanoma cells. The authors emphasized that the use of gold nanoparticles as a carrier of miRNA allows to increase internalization into cells and, in the case of a cytostatic drug, solves the problem of its poor solubility in water. This technology increased the anticancer efficacy of both substances [32].
In addition to gold nanoparticles, one of the most commonly used compounds as a drug carrier in nanomedicine is albumin. This approach has also been used in the experimental therapy of uveal melanoma. Albumin-based nanostructures containing AZD8055 (ABN-AZD), a potent inhibitor of mTOR kinase, proved to be selective and showed toxicity only to uveal melanoma cells, while not affecting keratinocyte cells. Moreover, these nanostructures showed excellent in vivo activity, reducing tumor size compared to free AZD8055 in mouse models [33].
In addition to developing completely new therapeutic methods, nanomedicine is also an excellent tool for preparing new formulations and new routes of administration of known anticancer drugs. One such approach concerns an encapsulated lipid nanostructure of sorafenib for the treatment of UM. The developed technology could overcome the biological barriers to the eye and is an important step in the development of topical application of anticancer agents used in UM [34]. Another solution that used increased penetration into eye tissues and extended release was a curcumin-loaded nanoparticle/hydrogel formulation. In addition to favorable pharmacokinetic parameters, the new curcumin formulation showed significant antitumor activity against MP-38 human uveal melanoma cells [35]. Chlorin e6, a photosensitizer used in photodynamic therapy for cancer, is another example of a well-known substance used in the development of a nanoparticle. The authors of one the study proposed an innovative approach to the diagnosis and treatment of UM by using multifunctional chlorin e6 (Ce6) in poly-lactic-co-glycolic acid (PLGA) NPs and wrapping Fe III-tannic acid (Fe III-TA) nanoparticles (FTCPNPs), combining photothermal therapy (PTT) and photodynamic therapy (PDT). FTCPNPs is actually a theranostic, as it not only induces apoptosis of tumor cells through mitochondrial damage, but also works as a MRI contrast agent [36].
It should also be emphasized that apart from their undoubted advantages, nanomaterials can also be dangerous, and the assessment of their safety profile is a challenge for science and regulatory agencies. In the study of Ding et al. [37], it was shown that carbon dot (C-dot) nanoparticles at a certain concentration could increase the growth of uveal melanoma cells in a zebrafish model and nude mouse xenograft. The postulated mechanism of this phenomenon is that C-dot induces a moderate increase in ROS, resulting in the activation of the Akt/mTOR pathway and increasing glutamate metabolism, which can ultimately cause the excessive growth and aggressiveness of UM cells, as well as metastasis [37].
In 2020, at the annual ARVO conference, an interim analysis of a phase 1b/2 clinical trial of AU-a011—novel light-activated nanomedicine to treat UM was published [38]. AU-011, developed by Aura Biosciences, Inc., is a targeted therapy based on a viral carrier and a phototoxic drug. This conjugate irradiated by 689 nm wavelength light causes an increased concentration of singlet oxygen and necrosis of the cancer cell. Furthermore, damaged cells induce an antitumor immune response by releasing damage-associated molecular patterns [39]. The results of this interim analysis are very promising, as tumor growth control was observed in more than 60% of the patients, visual acuity remained unchanged in more than 90% and the safety profile was favorable.

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