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Cutaneous Malignant Melanoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The MC1R (melanocortin 1 receptor) gene on chromosome 16q24.3 spans 8.8 kb and encodes a 317 aa, 34.7 kDa protein (MC1R), which is a receptor for melanocyte-stimulating hormone (MSH). Mutations in MC1R produce loss of function of MC1R, leading to increased pheomelanin production, lighter skin and hair color, and increased risk for melanoma and non-melanoma skin cancer.
Actions of Dopamine on the Skin and the Skeleton
Published in Nira Ben-Jonathan, Dopamine, 2020
The melanocortin 1 receptor (MC1R) is a Gs protein-coupled receptor that regulates skin pigmentation, UV responses, and also the risk of melanoma. It is a highly polymorphic gene whose loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and suboptimal DNA repair. MC1R signaling, executed via adenylyl cyclase activation and cAMP generation, is hormonally controlled by positive agonists such as α-MSH and ACTH, a negative agonist agouti signaling protein, and the neutral antagonist β-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis.
Statistical Measures of Interaction for Evaluating a Predictive Biomarker
Published in Satrajit Roychoudhury, Soumi Lahiri, Statistical Approaches in Oncology Clinical Development, 2018
Kricker et al. [13] reported a case–control study of melanoma with individuals having single primary melanoma as controls and those with multiple primary melanomas as cases. We illustrate the concepts described earlier using sun exposure and the MC1R gene measured in 743 cases and 1,525 controls. Sun exposure of each person is binary, indicating the presence or absence of at least 814 kJ/m2 of early-life ambient ultraviolet averaged at birth and age 10 (see Kricker et al. [13] for details). The binary biomarker of each person is the presence or absence of at least one red hair color variant in the MC1R gene. We use these data to examine whether MC1R may be a predictive biomarker for sun exposure in melanoma, that is, whether the effect of sun exposure on melanoma varies according to the level of MC1R.
Oncologist-led germline genetic testing for uveal melanoma
Published in Ophthalmic Genetics, 2023
Brittany Gillies, Hatem Krema, Anning Chao, Leonardo Lando, Kirsten M. Farncombe, Marcus Butler, Filiberto Altomare, Raymond H. Kim
For the individuals identified to have variants of uncertain significance (VUS), patients were offered a genetic counselling appointment to review the results. The majority of VUS were identified in the MC1R gene (12/15), which has been recently removed from our genetic testing panels due to limited clinical utility (22). Polymorphisms in the MC1R gene are extremely common with greater than half of the general population carrying one or more variants (53). Many variants demonstrate reduced penetrance and evidence is controversial for association with cutaneous melanoma (35–37,53). Mainstreaming models differ across genetics centres in whether patients with a VUS are seen for genetic counselling or reviewed by e-consult; our process involved contacting these patients as per the preference of the ordering oncologists. This also provided a central point of contact for patients to stay in touch with, regarding variant reclassification updates in keeping with shared responsibility for re-contact (38).
An evaluation of setmelanotide injection for chronic weight management in adult and pediatric patients with obesity due to Bardet–Biedl syndrome
Published in Expert Opinion on Pharmacotherapy, 2023
Julia Lazareva, Sheila M. Brady, Jack A. Yanovski
In the brain, MC4Rs help regulate hunger, satiety, and energy expenditure. Setmelanotide binds to the MC4R, and upon activating it, triggers intracellular cAMP production, as endogenous αMSH does [39,40]. This action increases the activity of the hypothalamic MC4R pathway to reduce hyperphagia, thus promoting weight loss (Figure 1). The drug has a considerably higher affinity than αMSH for the MC4R (Ki 0.71 vs. 26 nM for αMSH) and a lower EC50 for cAMP generation (EC50 1.5 versus 30 nM for αMSH) in vitro [39]. Setmelanotide also potently stimulates the Gαq system, increasing phospholipase C [18]. Setmelanotide has very low activity at the MC2R (EC50 >10 µM), but has demonstrable activity at melanocortin 3 (MC3) and melanocortin 1 (MC1) receptors, though the effect is ~20-fold less than for MC4R [37,40]. Since the MC1 receptor is expressed on melanocytes, activity of setmelanotide often results in accumulation of melanin and increased skin pigmentation [37]. In vitro data suggest that semelanotide may induce MC4R internalization with continued signaling that is irreversible by MC4R antagonists, perhaps in part explaining its potency relative to endogenous αMSH [41].
Emerging drugs for the treatment of scleroderma: a review of recent phase 2 and 3 trials
Published in Expert Opinion on Emerging Drugs, 2020
David Roofeh, Alain Lescoat, Dinesh Khanna
Non-canonical and canonical TGF-β signaling plays a central role in fibrosis and despite disappointing results of Riociguat, other drugs targeting these pathways need to be tested in SSc, alone or in combination. Pirfenidone down-regulates smad3 dependent- and Akt-dependent TGF-β signaling in primary human lung fibroblasts [93] and is endorsed for the management of idiopathic pulmonary fibrosis. The multicenter randomized placebo-controlled Scleroderma Lung Study III will evaluate the benefit of pirfenidone as add-on to a background therapy of MMF (NCT03221257). Selected TGF-β targeting by fresolimumab, an engineered human monoclonal Ig that neutralizes the three major isoforms of TGF-β, namely, β1, β2, and β3, has shown promising results on mRSS in explorative studies although its effects still need to be explored in RCTs [94]. A Phase 1b trial targeting TGF-β1 and β3 (due to potential toxicity associated with targeting β2) showed benefits on skin score and was well tolerated [95]. MT-7117 is a novel orally administered, small molecule, which acts as an agonist of melanocortin-1 receptor (MC1R). MC1R is activated by α-melanocyte-stimulating hormone which can be locally synthesized in response to sunlight exposure. In a bleomycin skin model, treatment with MCIR agonist reduced skin fibrosis and collagen content [96].