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Enhancing the efficacy of melanocortin 1 receptortargeted radiotherapy by pharmacologically upregulating the receptor in metastatic melanoma.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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Mengshi Li, Dijie Liu, Dongyoul Lee, Somya Kapoor, Katherine N GibsonCorley, Thomas P. Quinn, Edwin A Sagastume, Sarah L Mott, Susan A Walsh, Michael R Acevedo, Frances L Johnson, and Michael K. Schultz Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/ acs.molpharmaceut.9b00512 • Publication Date (Web): 18 Jul 2019 Downloaded from pubs.acs.org on July 19, 2019
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Pharmaceutics [203/212Molecular Pb]DOTA-MC1L
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Molecular Pharmaceutics
Enhancing the efficacy of melanocortin 1 receptortargeted
radiotherapy
by
pharmacologically
upregulating the receptor in metastatic melanoma. Mengshi Li1, Dijie Liu2, Dongyoul Lee3, Somya Kapoor1, Katherine N. Gibson-Corley4, Thomas P. Quinn5, Edwin A. Sagastume6, Sarah L. Mott7, Susan A. Walsh1, Michael R. Acevedo1 , Frances L. Johnson6,8, Michael K. Schultz*1,2,3,6,7 1. Department of Radiology, University of Iowa, Iowa City, IA, USA; 2. Department of Pediatrics, University of Iowa, Iowa City, IA, USA; 3. Human Toxicology Program, University of Iowa, Iowa City, IA, USA; 4. Department of Pathology, University of Iowa, Iowa City, IA, USA; 5. Department of Biochemistry, University of Missouri, Columbia, MO, USA; 6. Viewpoint Molecular Targeting, Inc., Coralville, IA, USA; 7. Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA; 8. Department of Internal Medicine, University of Iowa, Iowa City, Iowa, IA, USA.
KEYWORDS: melanoma, melanocortin 1 receptor, radionuclide therapy, histone deacetylase inhibitors, MAPK pathway inhibitors, BRAF inhibitors, MEK inhibitors.
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Molecular Pharmaceutics 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
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ABSTRACT:
Melanocortin 1 receptor (MC1R) is under investigation as a target for drug delivery for metastatic melanoma therapy and imaging. The purpose of this study was to determine the potential of using BRAF inhibitors (BRAFi) and histone deacetylase inhibitors (HDACi) to enhance the delivery of MC1R-targeted radiolabeled peptide ([212Pb]DOTA-MC1L) by pharmacologically upregulating MC1R expression in metastatic melanoma cells and tumors. MC1R expression was analyzed in de-identified melanoma biopsies by immunohistochemical staining. Upregulation of MC1R expression was determined in BRAFV600E cells (A2058) and BRAF wild-type melanoma cells (MEWO) by qRT-PCR, flow cytometry, and receptor-ligand binding assays. The role of microphthalmia-associated transcription factor (MITF) in the upregulation of MC1R was also examined in A2058 and MEWO cells. The effectiveness of [212Pb]DOTA-MC1L alpha-particle radiotherapy in combination with BRAFi and/or HDACi was determined in athymic nu/nu mice bearing A2058 and MEWO human melanoma xenografts. High expression of MC1R was observed in situ in clinical melanoma biopsies. BRAFi and HDACi significantly increased MC1R expression (up to 10-fold in mRNA and 4-fold in protein levels) via MITF-dependent pathways and this increase led to enhanced ligand binding on the cell surface. Inhibition of MITF expression antagonized the upregulation of MC1R in both BRAFV600E and BRAFWT cells. Combining [212Pb]DOTA-MC1L with BRAFi and/or HDACi improved tumor response by increasing the delivery of
212Pb
alpha-particle emissions to
melanoma tumors via augmented MC1R expression. These data suggest that FDA-approved HDACi and BRAFi could improve the effectiveness of MC1R-targeted therapies by enhancing drug delivery via upregulated MC1R.
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Molecular Pharmaceutics
INTRODUCTION:
Metastatic melanoma is a lethal form of skin cancer with one of the fastest growing incidences in the world.1 Recent breakthrough checkpoint-inhibitor immunotherapies and inhibitors of mitogen activated protein kinase (MAPK) pathway (including BRAF and MEK inhibitors) have significantly improved outcomes,2-4 but low response rates,5-8 acquired drug resistance,9-17 and serious side effects18-21 remain serious challenges to further improvements in outcomes for patients with late stage metastatic melanoma (5-yr survival
