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Research ArticleCANCER IMAGING

68Ga-DOTA-GGNle-CycMSHhex targets the melanocortin-1 receptor for melanoma imaging

Jianquan Yang https://orcid.org/0000-0003-0687-6145, Jingli Xu, Rene Gonzalez, Thomas Lindner https://orcid.org/0000-0003-0290-484X, Clemens Kratochwil https://orcid.org/0000-0003-1334-8260 [email protected], and Yubin Miao https://orcid.org/0000-0002-6607-4403 [email protected]
Science Translational Medicine • 7 Nov 2018 • Vol 10, Issue 466 • DOI: 10.1126/scitranslmed.aau4445
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Visualizing the target

Metastatic melanoma (skin cancer) has a high mortality rate. Yang et al. designed radiolabeled positron emission tomography and fluorescent imaging probes targeting melanocortin-1 receptor, which is overexpressed in melanoma cells. The probes detected melanoma cells in vitro, in xenografts and mouse models, and in metastases in two patients with melanoma. These results suggest that melanocortin-1 receptor-targeting probes may be useful for melanoma imaging.

Abstract

Melanocortin-1 receptor (MC1R) is a molecular target for melanoma imaging and therapy because of its overexpression on rodent and human melanoma cells. Here, we evaluated the MC1R targeting and specificity of 68Ga-DOTA-GGNle-CycMSHhex and Cy5.5-GGNle-CycMSHhex using murine and human melanoma cells, and murine and xenografted tumors. 68Ga-DOTA-GGNle-CycMSHhex was used first in human as an imaging probe to evaluate the possibility of radionuclide therapy in patients with advanced-stage melanoma. 68Ga-DOTA-GGNle-CycMSHhex and Cy5.5-GGNle-CycMSHhex displayed MC1R-specific targeting properties in murine and human melanoma cells, as well as in murine melanoma and human melanoma–xenografted tumors. Both B16/F10 and M21 melanoma lesions could be easily imaged by positron emission tomography using 68Ga-DOTA-GGNle-CycMSHhex. The first-in-human images of melanoma brain metastases in patients demonstrated the clinical relevance of MC1R as a molecular target for melanoma imaging, highlighting the potential of 68Ga-DOTA-GGNle-CycMSHhex as an MC1R-targeting melanoma imaging probe and underscoring the need to develop MC1R-targeting therapeutic agents for treating patients with metastatic melanoma.
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Science Translational Medicine
Volume 10 • Issue 466 • 7 November 2018
PubMed: 30404861

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Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 11 June 2018
Accepted: 15 October 2018

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Acknowledgments

We thank F. Gallazzi, L. Cheuy, N. Serkova, and K. Huber for technical assistance and E. R. Prossnitz for helpful discussions. Funding: This work was supported in part by NIH grant number R01CA225837 and the University of Colorado Denver start-up fund. Microscopy imaging experiments were performed in the University of Colorado Anschutz Medical Campus Advance Light Microscopy Core supported in part by NIH/NCATS Colorado CTSI grant number UL1 TR001082. PET imaging experiments were conducted in the University of Colorado Anschutz Medical Campus Animal Imaging Shared Resources supported in part by the University of Colorado Cancer Center (NCI P30 CA046934) and the Colorado Clinical and Translational Sciences Institute (NIH/NCATS UL1 TR001082). Author contributions: J.Y. and J.X. were responsible for the execution of experiments, data collection, and statistical analysis. J.Y. also contributed to manuscript preparation. R.G. contributed to research project organization and execution and review and critique of the manuscript. T.L. contributed to human doses production. C.K. was responsible for first-in-human studies on patients with melanoma, image data interpretation, and review and critique of the manuscript. Y.M. was responsible for research project conception, organization, and execution; contributed to the statistical analysis design and execution; wrote the first draft of the manuscript; and reviewed and edited the final draft of the manuscript. Competing interests: Y.M. is an inventor on awarded U.S. patents (US-8,986,651-B2, US-9,493,537-B2, and US-10,047,135-B2) held by the University of New Mexico that cover compounds with reduced ring size for use in diagnosing and treating melanoma, including metastatic melanoma and methods related to same. The other authors declare that they have no competing interests. Data and materials availability: All data associated with this study are present in the paper. Request for peptides will be handled by the corresponding authors through a licensing agreement (for commercial purposes) or a material transfer agreement (for research and noncommercial purposes).

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Affiliations

Jianquan Yang https://orcid.org/0000-0003-0687-6145
Department of Radiology, University of Colorado Denver, Aurora, CO 80045, USA.
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Jingli Xu
Department of Radiology, University of Colorado Denver, Aurora, CO 80045, USA.
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Rene Gonzalez
Department of Medical Oncology, University of Colorado Denver, Aurora, CO 80045, USA.
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Thomas Lindner https://orcid.org/0000-0003-0290-484X
Department of Nuclear Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
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Clemens Kratochwil* https://orcid.org/0000-0003-1334-8260 [email protected]
Department of Nuclear Medicine, University Hospital Heidelberg, 69120 Heidelberg, Germany.
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Yubin Miao* https://orcid.org/0000-0002-6607-4403 [email protected]
Department of Radiology, University of Colorado Denver, Aurora, CO 80045, USA.
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Notes

*Corresponding author. Email: [email protected] (Y.M.); [email protected] (C.K.)

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Science Translational Medicine
Volume 10|Issue 466
November 2018
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Received:11 June 2018
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