Melanocortin 1 Receptor Is Expressed by Uveal Malignant Melanoma and Can Be Considered a New Target for Diagnosis and Immunotherapy

López, Mercedes; Pereda, Carlos; Ramírez, Marcos; Mendoza-Naranjo, Ariadna; Serrano, Antonio E.; Ferreira, Arturo; Poblete, Rodrigo; Kalergis, Alexis M.; Kiessling, Rolf; Salazar‐Onfray, Flavio

doi:10.1167/iovs.06-0090

Cited by 44 publications

(33 citation statements)

References 40 publications

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“…Immunohistochemistry staining showed MC1R expression in 95% of uveal Children, Social Class, Smoking and Uveal Melanoma 365 melanoma tissue, but not in adjacent normal tissue. 38 Expression of MC1R in normal melanocytes of the uvea could not be shown 39 but transcriptomic analyses have shown a differential expression of pigmentation-related genes in uveal melanoma compared to normal uveal melanocytes, with an up-regulation of MC1R. 40 An MC1R-associated phosphorization of the extracellular-signal regulated kinase (ERK) may result in unlimited cell proliferation and oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

Having Children, Social Characteristics, Smoking and the Risk of Uveal Melanoma: A Case-Control Study

Zinkhan

Stang

Jöckel

et al. 2013

Ophthalmic Epidemiology

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The observed association between lower socioeconomic level and increased odds for uveal melanoma possibly represents a higher occupational uveal melanoma risk for occupational categories that are usually associated with lower socioeconomic status. Concerning having children and uveal melanoma development, we hypothesize that the observed association is mediated through alpha-melanocyte-stimulating hormone, a hormone that increases during pregnancy and is linked to pigmentation alterations in pregnant women.

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Section: Discussionmentioning

confidence: 99%

Having Children, Social Characteristics, Smoking and the Risk of Uveal Melanoma: A Case-Control Study

Zinkhan

Stang

Jöckel

et al. 2013

Ophthalmic Epidemiology

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“…It has been shown to be expressed in 83% of melanoma cell lines, all tissue samples from primary and metastatic melanomas (n = 26) 9, and 95% of uveal melanomas 10. In addition, low levels of MC1R expression in normal tissues make this protein an attractive target for molecular imaging.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Melanoma Imaging with ⁶⁸Ga-Labeled α-Melanocyte-Stimulating Hormone Derivatives Using PET

et al. 2017

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It is estimated that melanoma accounted for 76,380 new cases and 10,130 deaths in the United States in 2016. The melanocortin 1 receptor (MC1R) is highly expressed in the vast majority of melanomas, which makes it an attractive target for molecular imaging and radionuclide therapy. Lactam bridge-cyclized α-melanocyte-stimulating hormone (Ac-Nle4-cyclo[Asp5-His-D-Phe7-Arg-Trp-Lys10]-NH2, or Nle-CycMSHhex) analogues have been successfully developed and studied for MC1R-targeted imaging, predominantly with single-photon emission computed tomography (SPECT). The goal of this study was to design and evaluate novel peptides for melanoma imaging with positron emission tomography (PET). We designed and synthesized three peptides, DOTA-PEG2-Nle-CycMSHhex (CCZ01047), DOTA-4-amino-(1-carboxymethyl) piperidine (Pip)-Nle-CycMSHhex (CCZ01048), and DOTA-Pip-Pip-Nle-CycMSHhex (CCZ01056). All three peptides exhibited high binding affinity to MC1R with sub-nanomolar Ki values, rapid internalization into B16F10 melanoma cells and high in vivo stability with more than 93% remaining intact at 15 min post-injection (p.i.) in blood plasma. All three 68Ga-labeled tracers produced high contrast PET images in C57BL/6J mice bearing B16F10 tumors, and their respective tumor uptakes were 8.0 ± 3.0, 12.3 ± 3.3, and 6.5 ± 1.4 %ID/g at 1 h p.i. Minimal normal organ activity was observed at 1 h p.i., except for kidneys (5.1 ± 1.4, 4.7 ± 0.5, and 6.2 ± 2.0 %ID/g, respectively), and thyroid (4.1 ± 0.6 %ID/g for CCZ01047 and 2.4 ± 0.6 %ID/g for CCZ01048). Due to high accumulation at tumor sites and rapid background clearance of 68Ga-CCZ01048, we further evaluated it at 2 h p.i., and a tumor uptake of 21.9 ± 4.6 %ID/g was observed, with background activity further decreased. Exceptional image contrast was also achieved, i.e. tumor-to-blood, tumor-to-muscle, tumor-to-bone and tumor-to-kidney ratios were 96.4 ± 13.9, 210.9 ± 20.9, 39.6 ± 11.9 and 4.0 ± 0.9, respectively. A blocking study was also performed by co-injection of excess amount of non-radioactive Ga-coupled of CCZ01048, which confirmed that the tumor uptake was MC1R mediated. In conclusion, the introduction of a cationic Pip linker to Nle-CycMSHhex, CCZ01048, not only improved tumor uptake, but also generated high tumor-to-normal tissue contrast with PET imaging in a preclinical melanoma model. Therefore, CCZ01048 is a promising candidate for PET imaging of melanoma, and potentially as a theranostic agent for radionuclide therapy of melanoma when labeled with α or β emitters.

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“…[117–118] Apart from its role as a key regulator of melanin synthesis the MC1R gene had been reported to exhibit potential immunogenicity. [119] The same authors[119] evaluated its expression in uveal melanoma. Their results demonstrated that MC1R was expressed by uveal melanoma cells to a significantly greater extent than other melanoma markers.…”

Section: Methodsmentioning

confidence: 99%

Melanoma: Stem cells, sun exposure and hallmarks for carcinogenesis, molecular concepts and future clinical implications

Kyrgidis¹,

Tzellos²,

Triaridis³

2010

J Carcinog

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Background:The classification and prognostic assessment of melanoma is currently based on morphologic and histopathologic biomarkers. Availability of an increasing number of molecular biomarkers provides the potential for redefining diagnostic and prognostic categories and utilizing pharmacogenomics for the treatment of patients. The aim of the present review is to provide a basis that will allow the construction–or reconstruction–of future melanoma research.Methods:We critically review the common medical databases (PubMed, EMBASE, Scopus and Cochrane CENTRAL) for studies reporting on molecular biomarkers for melanoma. Results are discussed along the hallmarks proposed for malignant transformation by Hanahan and Weinberg. We further discuss the genetic basis of melanoma with regard to the possible stem cell origin of melanoma cells and the role of sunlight in melanoma carcinogenesis.Results:Melanocyte precursors undergo several genome changes –UV-induced or not– which could be either mutations or epigenetic. These changes provide stem cells with abilities to self-invoke growth signals, to suppress antigrowth signals, to avoid apoptosis, to replicate without limit, to invade, proliferate and sustain angiogenesis. Melanocyte stem cells are able to progressively collect these changes in their genome. These new potential functions, drive melanocyte precursors to the epidermis were they proliferate and might cause benign nevi. In the epidermis, they are still capable of acquiring new traits via changes to their genome. With time, such changes could add up to transform a melanocyte precursor to a malignant melanoma stem cell.Conclusions:Melanoma cannot be considered a “black box” for researchers anymore. Current trends in the diagnosis and prognosis of melanoma are to individualize treatment based on molecular biomarkers. Pharmacogenomics constitute a promising field with regard to melanoma patients' treatment. Finally, development of novel monoclonal antibodies is expected to complement melanoma patient care while a number of investigational vaccines could find their way into everyday oncology practice.

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Melanocortin 1 Receptor Is Expressed by Uveal Malignant Melanoma and Can Be Considered a New Target for Diagnosis and Immunotherapy

Cited by 44 publications

References 40 publications

Having Children, Social Characteristics, Smoking and the Risk of Uveal Melanoma: A Case-Control Study

Having Children, Social Characteristics, Smoking and the Risk of Uveal Melanoma: A Case-Control Study

Preclinical Melanoma Imaging with ⁶⁸Ga-Labeled α-Melanocyte-Stimulating Hormone Derivatives Using PET

Melanoma: Stem cells, sun exposure and hallmarks for carcinogenesis, molecular concepts and future clinical implications

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Melanocortin 1 Receptor Is Expressed by Uveal Malignant Melanoma and Can Be Considered a New Target for Diagnosis and Immunotherapy

Cited by 44 publications

References 40 publications

Having Children, Social Characteristics, Smoking and the Risk of Uveal Melanoma: A Case-Control Study

Having Children, Social Characteristics, Smoking and the Risk of Uveal Melanoma: A Case-Control Study

Preclinical Melanoma Imaging with 68Ga-Labeled α-Melanocyte-Stimulating Hormone Derivatives Using PET

Melanoma: Stem cells, sun exposure and hallmarks for carcinogenesis, molecular concepts and future clinical implications

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Preclinical Melanoma Imaging with ⁶⁸Ga-Labeled α-Melanocyte-Stimulating Hormone Derivatives Using PET