Open AccessTherapy response monitoring of the early effects of a new BRAF inhibitor on melanoma xenograft in mice: evaluation of 18 F‐FDG‐PET and 18 F‐FLT‐PET
Author(s) -
Geven Edwin J. W.,
Evers Stefan,
Nayak Tapan K.,
Bergström Mats,
Su Fei,
Gerrits Danny,
Franssen Gerben M.,
Boerman Otto C.
Publication year - 2014
Publication title -
contrast media & molecular imaging
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.714
H-Index - 50
eISSN - 1555-4317
pISSN - 1555-4309
DOI - 10.1002/cmmi.1619
Subject(s) - melanoma , in vivo , biodistribution , medicine , cancer research , ex vivo , v600e , pharmacology , chemistry , biology , mutation , biochemistry , microbiology and biotechnology , gene
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 18 F‐FDG and 18 F‐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 75 mg/kg). At 1, 3 and 7 days after start of therapy, the uptake of 18 F‐FDG and 18 F‐FLT in the tumor and normal tissues was determined in ex vivo tissue samples. Serial 18 F‐FDG and 18 F‐FLT‐PET scans were acquired of animals at 1 day before and 1, 3 and 7 days after start of treatment with 75 mg/kg BRAF V600E inhibitor. A dose‐dependent decrease in 18 F‐FDG uptake in the A375 tumors was observed by ex vivo biodistribution analysis. Administration of 75 mg/kg BRAF inhibitor for 1, 3 and 7 days resulted in a significantly decreased 18 F‐FDG uptake in A375 tumors (41, 35 and 51%, respectively). 18 F‐FLT uptake in the A375 tumors was low at baseline and no significant changes in 18 F‐FLT uptake were observed at any of the doses administered. These effects were corroborated by serial in vivo 18 F‐FDG and 18 F‐FLT‐PET imaging. These data demonstrate that 18 F‐FDG‐PET can be used as an imaging biomarker to noninvasively evaluate the early effects of PLX3603. Copyright © 2014 John Wiley & Sons, Ltd.