Malignant melanoma: evolving practice management in an era of increasingly effective systemic therapies

Newcomer, Ken; Robbins, Keenan J.; Perone, Jean‐Marc; Hinojosa, Fernando Lambreton; Chen, David; Jones, Susan; Kaufman, Charles; Weiser, Roi; Fields, Ryan C.; Tyler, Douglas S.

doi:10.1016/j.cpsurg.2021.101030

Cited by 10 publications

(9 citation statements)

References 347 publications

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“…To our knowledge, there is only one study that shows a potential susceptibility to antimetabolites, including methotrexate in p16/ CDKN2A -altered astrocytic tumors ( 46 ). While alterations of p16/ CDKN2A are widely reported in melanoma ( 47, 48 ), there is a lack of p16/ CDKN2A assessment in the routine clinical practice unless hereditary melanoma is suspected ( 49 ). Notably, recent surveys conducted among dermatologists, pathologists, and general practitioners from different countries including the United States indicate that only 7.3% of clinicians routinely assess p16 status for their diagnoses ( 50 ).…”

Section: Discussionmentioning

confidence: 99%

De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression

Tangudu,

Buj,

Wang

et al. 2024

Cancer Research Communications

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p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in ~50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway. However, the broader impact of p16/CDKN2A loss on other nucleotide metabolic pathways and potential therapeutic targets remains unexplored. Using CRISPR KO libraries in isogenic human and mouse melanoma cell lines, we determined several nucleotide metabolism genes essential for the survival of cells with loss of p16/CDKN2A. Consistently, many of these genes are upregulated in melanoma cells with p16 knockdown or endogenously low CDKN2A expression. We determined that cells with low p16/CDKN2A expression are sensitive to multiple inhibitors of de novo purine synthesis, including anti-folates. Finally, tumors with p16 knockdown were more sensitive to the anti-folate methotrexate in vivo than control tumors. Together, our data provide evidence to reevaluate the utility of these drugs in patients with p16/CDKN2Alow tumors as loss of p16/CDKN2A may provide a therapeutic window for these agents.

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Section: Discussionmentioning

confidence: 99%

De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression

Tangudu,

Buj,

Wang

et al. 2024

Cancer Research Communications

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“…The Cox model did not identify surgery as an independent prognostic factor. Surgical excision is currently regarded as the mainstay treatment choice for individuals with early-stage melanoma [23,24]. It is recommended that surgical resection remains an option for patients with melanoma metastases that are potentially amenable to complete surgical removal [25,26].…”

Section: Discussionmentioning

confidence: 99%

Competing‐risks model for predicting the prognosis of patients with regressive melanoma based on the SEER database

Huang,

Huang

et al. 2024

Malignancy Spectrum

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BackgroundThe relationship between the regression and prognosis of melanoma has been debated for years. When competing‐risk events are present, using traditional survival analysis methods may induce bias in the identified prognostic factors that affect patients with regressive melanoma.MethodsData on patients diagnosed with regressive melanoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) database during 2000–2019. Cumulative incidence function and Gray's test were used for the univariate analysis, and the Cox proportional‐hazards model and the Fine–Gray model were used for the multivariate analysis.ResultsA total of 1442 eligible patients were diagnosed with regressive melanoma, including 529 patients who died: 109 from regressive melanoma and 420 from other causes. The multivariate analysis using the Fine–Gray model revealed that SEER stage, surgery status, and marital status were important factors that affected the prognosis of regressive melanoma. Due to the existence of competing‐risk events, the Cox model may have induced biases in estimating the effect values, and the competing‐risks model was more advantageous in the analysis of multiple‐endpoint clinical survival data.ConclusionThe findings of this study may help clinicians to better understand regressive melanoma and provide reference data for clinical decisions.

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“…Melanoma is a malignant type of skin cancer that originates from melanocytes, a cell type that is essential for the melanin synthesis required for skin color [ 1 , 2 , 3 , 4 ]. The incidence of melanoma has been dramatically increasing worldwide over the last few decades [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

“…Melanoma, due to its malignant nature, has a poor prognosis, is mainly present in patients with advanced or metastatic disease, and is highly aggressive when compared to other skin cancers such as squamous and basal cell carcinomas [ 1 , 2 , 3 , 4 , 5 ]. The common etiological factors include exposure to ultraviolet radiation, having fair complexions such as red or blond hair, blue or green eyes, and family history of melanoma [ 4 , 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Melatonin as a Repurposed Drug for Melanoma Treatment

2023

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Melanoma is the most aggressive type of skin cancer, with a greater risk of metastasis and a higher prevalence and mortality rate. This cancer type has been demonstrated to develop resistance to the known treatment options such as conventional therapeutic agents and targeted therapy that are currently being used as the standard of care. Drug repurposing has been explored as a potential alternative treatment strategy against disease pathophysiologies, including melanoma. To that end, multiple studies have suggested that melatonin produced by the pineal gland possesses anti-proliferative and oncostatic effects in experimental melanoma models. The anticarcinogenic activity of melatonin is attributed to its ability to target a variety of oncogenic signaling pathways, including the MAPK pathways which are involved in regulating the behavior of cancer cells, including cell survival and proliferation. Additionally, preclinical studies have demonstrated that melatonin in combination with chemotherapeutic agents exerts synergistic effects against melanoma. The goal of this review is to highlight the mechanistic insights of melatonin as a monotherapy or combinational therapy for melanoma treatment.

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Malignant melanoma: evolving practice management in an era of increasingly effective systemic therapies

Cited by 10 publications

References 347 publications

De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression

De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression

Competing‐risks model for predicting the prognosis of patients with regressive melanoma based on the SEER database

Melatonin as a Repurposed Drug for Melanoma Treatment

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