Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922.
For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials.


METHODS
The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E(max) and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was determined at different doses and different time points.


RESULTS
A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of (18)F-FDG per viable tumor volume was minimally affected by the treatment, whereas the (18)F-FLT uptake decreased in correlation with the growth inhibition.


CONCLUSIONS
The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. (18)F-FLT is a suitable tracer for the monitoring of effect, and the (18)F-FLT PET study might be performed within 3 d after dosing.
Clinical Imaging, Novartis Pharma AG, Basel, Switzerland. Mats.L.Bergstrom@GSK.com
Mats
M
Bergstrom
Azita
A
Monazzam
Pasha
P
Razifar
Susan
S
Ide
Raymond
R
Josephsson
Bengt
B
Langstrom
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D019788:Fluorodeoxyglucose F18; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012118:Resorcinols / Q000008:administration & dosage / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects*
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D019275:Radiopharmaceuticals; D012118:Resorcinols; D019788:Fluorodeoxyglucose F18