Journal article
Enhancing the Efficacy of Melanocortin 1 Receptor-Targeted Radiotherapy by Pharmacologically Upregulating the Receptor in Metastatic Melanoma
Molecular pharmaceutics, Vol.16(9), pp.3904-3915
09/03/2019
DOI: 10.1021/acs.molpharmaceut.9b00512
PMCID: PMC6765223
PMID: 31318566
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 (BRAF
i
) and histone deacetylase inhibitors (HDAC
i
) to enhance the delivery of MC1R-targeted radiolabeled peptide ([
212
Pb]DOTA-MC1L) by pharmacologically upregulating the 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 BRAF
V600E
cells (A2058) and BRAF wild-type melanoma cells (MEWO) by quantitative real-time polymerase chain reaction, 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 [
212
Pb]DOTA-MC1L
α
-particle radiotherapy in combination with BRAF
i
and/or HDAC
i
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. BRAF
i
and HDAC
i
significantly increased the 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 BRAF
V600E
and BRAF
WT
cells. Combining [
212
Pb]DOTA-MC1L with BRAF
i
and/or HDAC
i
improved the tumor response by increasing the delivery of
212
Pb
α
-particle emissions to melanoma tumors via augmented MC1R expression. These data suggest that FDA-approved HDAC
i
and BRAF
i
could improve the effectiveness of MC1R-targeted therapies by enhancing drug delivery via upregulated MC1R.
Details
- Title: Subtitle
- Enhancing the Efficacy of Melanocortin 1 Receptor-Targeted Radiotherapy by Pharmacologically Upregulating the Receptor in Metastatic Melanoma
- Creators
- Mengshi Li - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesDijie Liu - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesDongyoul Lee - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesSomya Kapoor - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesKatherine N Gibson-Corley - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesThomas P Quinn - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesEdwin A Sagastume - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesSarah L Mott - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesSusan A Walsh - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesMichael R Acevedo - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesFrances L Johnson - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United StatesMichael K Schultz - Department of Radiology, University of Iowa, Iowa City, Iowa 52242, United States Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242, United States Human Toxicology Program, University of Iowa, Iowa City, Iowa 52242, United States Department of Pathology, University of Iowa, Iowa City, Iowa 52242, United States Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, United States Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, United States Department of Biochemistry, University of Missouri, Columbia, Missouri 65211, United States Viewpoint Molecular Targeting, Inc., Coralville, Iowa 52241, United States
- Resource Type
- Journal article
- Publication Details
- Molecular pharmaceutics, Vol.16(9), pp.3904-3915
- DOI
- 10.1021/acs.molpharmaceut.9b00512
- PMID
- 31318566
- PMCID
- PMC6765223
- NLM abbreviation
- Mol Pharm
- ISSN
- 1543-8384
- eISSN
- 1543-8392
- Grant note
- DOI: 10.13039/100000097, name: National Center for Research Resources, award: 1-S10-RR0125036-01; DOI: 10.13039/100005187, name: U.S. Nuclear Regulatory Commission, award: NRC-HQ-84-14-FOA-0003; DOI: 10.13039/100000002, name: National Institutes of Health, award: 1-S10-RR025439-01, 1P50CA174521-01A1, 1R43CA203430-01, K25CA172218-01A1
- Language
- English
- Date published
- 09/03/2019
- Academic Unit
- Radiology; Stead Family Department of Pediatrics; Radiation Oncology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984216568402771
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