F-FDG-PET/CT and diffusion-weighted MRI for monitoring a BRAF and CDK 4/6 inhibitor combination therapy in a murine model of human melanoma.

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 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 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 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 (∆TTL - 1.00 ± 0.53 vs. ∆TTL 0.85 ± 1.21; p < 0.001). In addition, tumor diffusivity was significantly elevated following the BRAF and CDK 4/6 inhibitor combination therapy (∆ADC 0.12 ± 0.14 × 10 mm/s; ∆ADC - 0.12 ± 0.06 × 10 mm/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 F-FDG-PET/CT and DW-MRI.