Therapy response monitoring of the early effects of a new BRAF inhibitor on melanoma xenograft in mice: evaluation of 18F-FDG-PET and 18F-FLT-PET

Inhibition of the V600E mutated BRAF kinase gene (BRAF(V600E)) is an important and effective approach to treating melanomas. A new specific small molecule inhibitor of BRAF(V600E), PLX3603, showed potent melanoma growth-inhibiting characteristics in preclinical studies and is currently under clinical investigation. In this study we investigated the feasibility of F-18-FDG and F-18-FLT-PET to monitor the early effects of the BRAF(V600E) inhibitor in mice with melanoma xenografts. SCID/beige mice with subcutaneous (s.c.) A375 melanoma xenografts, expressing BRAF(V600E), received the BRAF(V600E) inhibitor twice daily orally (0, 25, 50 and 75mg/kg). At 1, 3 and 7days after start of therapy, the uptake of F-18-FDG and F-18-FLT in the tumor and normal tissues was determined in ex vivo tissue samples. Serial F-18-FDG and F-18-FLT-PET scans were acquired of animals at 1day before and 1, 3 and 7days after start of treatment with 75mg/kg BRAF(V600E) inhibitor. A dose-dependent decrease in F-18-FDG uptake in the A375 tumors was observed by ex vivo biodistribution analysis. Administration of 75mg/kg BRAF inhibitor for 1, 3 and 7days resulted in a significantly decreased F-18-FDG uptake in A375 tumors (41, 35 and 51%, respectively). F-18-FLT uptake in the A375 tumors was low at baseline and no significant changes in F-18-FLT uptake were observed at any of the doses administered. These effects were corroborated by serial in vivo(18)F-FDG and F-18-FLT-PET imaging. These data demonstrate that F-18-FDG-PET can be used as an imaging biomarker to noninvasively evaluate the early effects of PLX3603. Copyright (c) 2014 John Wiley & Sons, Ltd.