Abstract
Improved MC1R-targeted molecular imaging for metastatic melanoma by up-regulation of MC1R expression with MAPK pathway inhibitors and epigenetic modulators
The Journal of nuclear medicine (1978), Vol.59(2), p.362
02/01/2018
DOI: 10.2967/jnm592abs
Abstract
Background: Melanocortin subtype-1 receptor (MC1R) has been long investigated as a potential target to deliver radiation dose to melanoma for molecular imaging and radionuclide therapy. Despite the development of numerous MC1R-targeted peptide ligands in the past few decades, efforts have been largely restricted to B16 murine melanoma cells and tumors that highly express the MCR1 receptor. However, heterogeneous (and often low) MC1R expression in human melanoma cells has stalled clinical translation of the approach. Hypothesis: FDA-approved MAPK pathway inhibitors (BRAFi and MEKi) and histone deacetylase inhibitors (HDACi) can be used to pharmacologically up-regulate MC1R expression in human metastatic melanoma cells and tumors to improve imaging. Methods: BRAF V600E cells (A375, A2058, SK-MEL-3), BRAF wild-type cells (MEWO) and BRAFi-resistant cells (451LUBR) were exposed to BRAFi, MEKi or HDACi before analysis of MC1R expression by qRT-PCR, immunoblotting, flow cytometry and [125I]Nle4,D-Phe7,α-MSH binding. In vivo melanoma tumor imaging was performed in athymic nu/nu mice bearing A375, A2058 and 451LUBR tumors that were subjected to BRAFi (vemurafenib) and/or HDACi (4-phenylbutyrate; PBA). Imaging was performed using a Re-cyclized MC1R-targeted peptide that was labeled with 203Pb for SPECT and 68Ga for PET. Images were analyzed using Inveon Research Workplace (Siemens Healthcare). Results: Up-regulated MC1R expression and increased binding with [125I]Nle4D,Phe7,α-MSH were found in human melanoma cells following exposure to MAPK inhibitors and HDAC inhibitors. Enhanced accumulation of MC1R-targeted imaging tracer resulted in improved SPECT and PET images of human melanoma tumor xenografts in mice. Conclusion: Clinically approved MAPKi and HDACi can be used to pharmacologically up-regulate MC1R in human melanoma cells and tumors-and significantly improve MC1Rtageted molecular imaging of human melanoma tumor xenografts in mice.
Details
- Title: Subtitle
- Improved MC1R-targeted molecular imaging for metastatic melanoma by up-regulation of MC1R expression with MAPK pathway inhibitors and epigenetic modulators
- Creators
- Mengshi Li - University of Iowa, RadiologyDijie Liu - University of Iowa, Stead Family Department of PediatricsDongyoul LeeSomya Kapoor - University of Iowa, Radiation OncologyThomas P QuinnFrances L Johnson - University of Iowa, Internal MedicineMichael K Schultz - University of Iowa, Radiation Oncology
- Resource Type
- Abstract
- Publication Details
- The Journal of nuclear medicine (1978), Vol.59(2), p.362
- DOI
- 10.2967/jnm592abs
- ISSN
- 0161-5505
- eISSN
- 1535-5667
- Publisher
- Society of Nuclear Medicine
- Language
- English
- Date published
- 02/01/2018
- Academic Unit
- Radiology; Stead Family Department of Pediatrics; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984217550602771
Metrics
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