Review: The Key Factors to Melanomagenesis

Mihulecea, Cristina-Raluca; Rotaru, Maria

doi:10.3390/life13010181

Cited by 6 publications

(4 citation statements)

References 94 publications

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“…It is generated through the enzymatic conversion of L-tyrosine to dopaquinone, leading to the formation of various melanin oligomers, including constituents of eumelanin and pheomelanin ( 14 – 18 ). While melanin is known to provide protection against skin cancers, including cutaneous melanoma, its presence may also be implicated in the malignant transformation of melanocytes ( 19 ). The biosynthesis of melanin is regulated by various factors, including sun exposure and hormonal influences at different levels ( 20 , 21 ).…”

Section: Discussionmentioning

confidence: 99%

Case report: Exceptional disease progression in a 70-year-old patient: generalized melanosis and melanuria in the course of metastatic melanoma - a case study

Calik,

Dzięgiel,

Sauer

2024

Front. Oncol.

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This case study documents an extraordinary disease progression in a 70-year-old patient diagnosed with metastatic melanoma. The patient’s condition advanced to an unusual manifestation characterized by generalized melanosis and melanuria, a rare and foreboding complication of metastatic melanoma. The clinical presentation involved rapid-onset skin darkening, primarily affecting the face and torso, along with darkened urine, marking the onset of melanuria. Despite extensive diagnostic evaluations, including abdominal ultrasound, neck ultrasound, thoracic CT scans, and endoscopic examinations, the exact metastatic sites remained elusive, demonstrating the diagnostic challenges associated with this condition. Laboratory tests revealed abnormal hematological and biochemical markers, along with elevated S100 protein levels, indicating disease progression. The patient underwent a surgical skin biopsy that confirmed the diagnosis of metastatic melanoma, leading to a multidisciplinary approach to treatment. Following this, the patient-initiated chemotherapy with dacarbazine (DTIC). Regrettably, this was necessitated by the absence of reimbursement for BRAF and MEK inhibitors as well as immunotherapy, and it subsequently led to rapid disease progression and a decline in the patient’s clinical condition. The patient’s condition further complicated with erysipelas and increased distress, ultimately leading to their unfortunate demise. This case highlights the aggressive nature of generalized melanosis, characterized by a rapid clinical course, substantial pigmentation, and limited response to conventional chemotherapy. Importantly, the patient had a BRAF mutation, emphasizing the urgency of exploring alternative treatment strategies. Patients with a BRAF mutation are excellent candidates for BRAF and MEK inhibitor treatment, potentially allowing them to extend their lifespan if this therapy were available. The challenges encountered in diagnosing, managing, and treating this aggressive form of metastatic melanoma underline the need for early detection, tailored therapeutic approaches, and ongoing research efforts to improve patient outcomes in such cases.

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Section: Discussionmentioning

confidence: 99%

Case report: Exceptional disease progression in a 70-year-old patient: generalized melanosis and melanuria in the course of metastatic melanoma - a case study

Calik,

Dzięgiel,

Sauer

2024

Front. Oncol.

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“…Melanoma, a tumor that develops from an uncontrolled proliferation of melanocytes, is the most malignant form of skin cancer [ 1 – 4 ] and its worldwide incidence and mortality has been risen rapidly [ 5 – 7 ]. Melanoma contributes to more than 80% of skin cancer fatalities and, according to the latest SEER data, melanoma is the fifth most common cancer diagnosis in the US (excluding nonmelanoma skin cancers), with 97,610 estimated new cases in 2023 (National Cancer Institute Melanoma of the Skin-Cancer Stat Facts.…”

Section: Introductionmentioning

confidence: 99%

Identification and characterization of a new potent inhibitor targeting CtBP1/BARS in melanoma cells

Filograna,

De Tito,

Monte

et al. 2024

J Exp Clin Cancer Res

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Background The C-terminal-binding protein 1/brefeldin A ADP-ribosylation substrate (CtBP1/BARS) acts both as an oncogenic transcriptional co-repressor and as a fission inducing protein required for membrane trafficking and Golgi complex partitioning during mitosis, hence for mitotic entry. CtBP1/BARS overexpression, in multiple cancers, has pro-tumorigenic functions regulating gene networks associated with “cancer hallmarks” and malignant behavior including: increased cell survival, proliferation, migration/invasion, epithelial-mesenchymal transition (EMT). Structurally, CtBP1/BARS belongs to the hydroxyacid-dehydrogenase family and possesses a NAD(H)-binding Rossmann fold, which, depending on ligands bound, controls the oligomerization of CtBP1/BARS and, in turn, its cellular functions. Here, we proposed to target the CtBP1/BARS Rossmann fold with small molecules as selective inhibitors of mitotic entry and pro-tumoral transcriptional activities. Methods Structured-based screening of drug databases at different development stages was applied to discover novel ligands targeting the Rossmann fold. Among these identified ligands, N-(3,4-dichlorophenyl)-4-{[(4-nitrophenyl)carbamoyl]amino}benzenesulfonamide, called Comp.11, was selected for further analysis. Fluorescence spectroscopy, isothermal calorimetry, computational modelling and site-directed mutagenesis were employed to define the binding of Comp.11 to the Rossmann fold. Effects of Comp.11 on the oligomerization state, protein partners binding and pro-tumoral activities were evaluated by size-exclusion chromatography, pull-down, membrane transport and mitotic entry assays, Flow cytometry, quantitative real-time PCR, motility/invasion, and colony assays in A375MM and B16F10 melanoma cell lines. Effects of Comp.11 on tumor growth in vivo were analyzed in mouse tumor model. Results We identify Comp.11 as a new, potent and selective inhibitor of CtBP1/BARS (but not CtBP2). Comp.11 directly binds to the CtBP1/BARS Rossmann fold affecting the oligomerization state of the protein (unlike other known CtBPs inhibitors), which, in turn, hinders interactions with relevant partners, resulting in the inhibition of both CtBP1/BARS cellular functions: i) membrane fission, with block of mitotic entry and cellular secretion; and ii) transcriptional pro-tumoral effects with significantly hampered proliferation, EMT, migration/invasion, and colony-forming capabilities. The combination of these effects impairs melanoma tumor growth in mouse models. Conclusions This study identifies a potent and selective inhibitor of CtBP1/BARS active in cellular and melanoma animal models revealing new opportunities to study the role of CtBP1/BARS in tumor biology and to develop novel melanoma treatments.

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“…Melanoma originates from melanocytes that have undergone malignant transformation [ 2 , 3 , 4 ], and these cells are most abundant in the basal layer of epidermis, which is why cutaneous melanoma is the most common type. However, this neoplasm can also be found in less obvious locations, such as the uvea, gastrointestinal tract, genitourinary tract and the meninges [ 3 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Current Treatment of Melanoma Brain Metastases

Nowacka,

Fajkiel-Madajczyk,

Ohla

et al. 2023

Cancers

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Melanoma is a type of skin cancer in which there is a strong correlation between its occurrence and exposure to ultraviolet radiation. Although it is not the most common skin cancer, it has the highest mortality rate of all skin cancers. The prognosis of patients is significantly worsened by melanoma metastasis to the brain, which often occurs in patients with advanced disease. The formation and development of melanoma metastases to the brain involve a very complex process, and their mechanisms are not fully understood. One of the ways for metastatic melanoma cells to survive and develop cancer in the brain environment is the presence of oncogenic BRAF mutation, which occurs in up to 50% of metastatic melanoma cases. Before discovering new methods of treating metastases, the overall survival of patients with this disease was 6 months. Currently, research is being conducted on new drugs using immunotherapy (immune checkpoint inhibitors: anti-PD-1, anti-CTLA-4) and targeted therapy (BRAF and MEK inhibitors) to improve the prognosis of patients. In this article, we summarize the current state of knowledge about the results of treating brain metastases with new systemic therapies.

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Review: The Key Factors to Melanomagenesis

Cited by 6 publications

References 94 publications

Case report: Exceptional disease progression in a 70-year-old patient: generalized melanosis and melanuria in the course of metastatic melanoma - a case study

Case report: Exceptional disease progression in a 70-year-old patient: generalized melanosis and melanuria in the course of metastatic melanoma - a case study

Identification and characterization of a new potent inhibitor targeting CtBP1/BARS in melanoma cells

Current Treatment of Melanoma Brain Metastases

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