18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer.
OBJECTIVE
To evaluate 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography imaging ((18)FDG-PET) as a predictive, noninvasive, pharmacodynamic (PD) biomarker of response following administration of a small-molecule insulin-like growth factor-1 receptor and insulin receptor (IGF-1R/IR) inhibitor, OSI-906.


METHODS
In vitro uptake studies of (3)H-2-deoxy glucose following OSI-906 exposure were conducted evaluating correlation of dose with inhibition of IGF-1R/IR as well as markers of downstream pathways and glucose metabolism. Similarly, in vivo PD effects were evaluated in human tumor cell line xenografts propagated in athymic nude mice by (18)FDG-PET at 2, 4, and 24 hours following a single treatment of OSI-906 for the correlation of inhibition of receptor targets and downstream markers.


RESULTS
Uptake of (3)H-2-deoxy glucose and (18)FDG was significantly diminished following OSI-906 exposure in sensitive tumor cells and subcutaneous xenografts (NCI-H292) but not in an insensitive model lacking IGF-1R expression (NCI-H441). Diminished PD (18)FDG-PET, collected immediately following the initial treatment agreed with inhibition of pIGF-1R/pIR, reduced PI3K (phosphoinositide 3-kinase) and MAPK (mitogen activated protein kinase) pathway activity, and predicted tumor growth arrest as measured by high-resolution ultrasound imaging.


CONCLUSIONS
(18)FDG-PET seems to serve as a rapid, noninvasive PD marker of IGF-1R/IR inhibition following a single dose of OSI-906 and should be explored clinically as a predictive clinical biomarker in patients undergoing IGF-1R/IR-directed cancer therapy.
Department of Biomedical Engineering, The Vanderbilt University Institute of Imaging Science, Nashville, Tennessee 37232-2310, USA.
Eliot T
ET
McKinley
Joseph E
JE
Bugaj
Ping
P
Zhao
Saffet
S
Guleryuz
Christine
C
Mantis
Prafulla C
PC
Gokhale
Robert
R
Wild
H Charles
HC
Manning
D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D011719:Pyrazines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D019788:Fluorodeoxyglucose F18; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
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