BACKGROUND: The purpose of the study was to investigate a novel BRAF and CDK 4/6 inhibitor combination therapy in a murine model of BRAF-V600-mutant human melanoma monitored by (18)F-FDG-PET/CT and diffusion-weighted MRI (DW-MRI). METHODS: Human BRAF-V600-mutant melanoma (A375) xenograft-bearing balb/c nude mice (n = 21) were imaged by (18)F-FDG-PET/CT and DW-MRI before (day 0) and after (day 7) a 1-week BRAF and CDK 4/6 inhibitor combination therapy (n = 12; dabrafenib, 20 mg/kg/d; ribociclib, 100 mg/kg/d) or placebo (n = 9). Animals were scanned on a small animal PET after intravenous administration of 20 MBq (18)F-FDG. Tumor glucose uptake was calculated as the tumor-to-liver-ratio (TTL). Unenhanced CT data sets were subsequently acquired for anatomic coregistration. Tumor diffusivity was assessed by DW-MRI using the apparent diffusion coefficient (ADC). Anti-tumor therapy effects were assessed by ex vivo immunohistochemistry for validation purposes (microvascular density - CD31; tumor cell proliferation - Ki-67). RESULTS: Tumor glucose uptake was significantly suppressed under therapy (TTLTherapy - 1.00 +/- 0.53 vs. TTLControl 0.85 +/- 1.21; p < 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (ADCTherapy 0.12 +/- 0.14 x 10(-3) mm(2)/s; ADCControl - 0.12 +/- 0.06 x 10(-3) mm(2)/s; p < 0.001). Immunohistochemistry revealed a significant suppression of microvascular density (CD31, 147 +/- 48 vs. 287 +/- 92; p = 0.001) and proliferation (Ki-67, 3718 +/- 998 vs. 5389 +/- 1332; p = 0.007) in the therapy compared to the control group. CONCLUSION: A novel BRAF and CDK 4/6 inhibitor combination therapy exhibited significant anti-angiogenic and anti-proliferative effects in experimental human melanomas, monitored by (18)F-FDG-PET/CT and DW-MRI.
- Eschbach, R. S.
- Kazmierczak, P. M.
- Heimer, M. M.
- Todica, A.
- Hirner-Eppeneder, H.
- Schneider, M. J.
- Keinrath, G.
- Solyanik, O.
- Olivier, J.
- Kunz, W. G.
- Reiser, M. F.
- Bartenstein, P.
- Ricke, J.
- Cyran, C. C.
Keywords
- Aminopyridines/administration & dosage/therapeutic use
- Animals
- Antineoplastic Agents/administration & dosage/*therapeutic use
- Cyclin-Dependent Kinase 4/antagonists & inhibitors
- Cyclin-Dependent Kinase 6/antagonists & inhibitors
- Diffusion Magnetic Resonance Imaging/*methods
- Female
- Fluorodeoxyglucose F18/*pharmacokinetics
- Imidazoles/administration & dosage/therapeutic use
- Male
- Melanoma/*diagnostic imaging/drug therapy
- Mice
- Mice, Inbred BALB C
- Mice, Nude
- Oximes/administration & dosage/therapeutic use
- Positron Emission Tomography Computed Tomography/*methods
- Protein Kinase Inhibitors/administration & dosage/*therapeutic use
- Proto-Oncogene Proteins B-raf/antagonists & inhibitors
- Purines/administration & dosage/therapeutic use
- Radiopharmaceuticals/*pharmacokinetics
- 18f-fdg-pet
- BRAF inhibitor
- CDK inhibitor
- Diffusion-weighted MRI
- Melanoma
- Therapy monitoring
