title: Therapy 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.
abstract: 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.
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Edwin J W
authors.initials: EJ
authors.lastname: Geven
authors.affiliation: Roche Glycart AG, Schlieren, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Evers
authors.affiliation: F. Hoffmann-La Roche AG, pRED, Basel, Switzerland.
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Nayak
authors.affiliation: F. Hoffmann-La Roche AG, pRED, Basel, Switzerland.
authors.forename: Mats
authors.initials: M
authors.lastname: Bergström
authors.affiliation: F. Hoffmann-La Roche Ltd, Nutley, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Su
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Danny
authors.initials: D
authors.lastname: Gerrits
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Gerben M
authors.initials: GM
authors.lastname: Franssen
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D049268:Positron-Emission Tomography / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D019275:Radiopharmaceuticals / Q000494:pharmacology; D013936:Thymidine / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D013936:Thymidine
keywords: BRAF inhibitor; FDG-PET; FLT-PET; biomarker; therapy response monitoring