Changes in tumor metabolism as readout for Mammalian target of rapamycin kinase inhibition by rapamycin in glioblastoma.
OBJECTIVE
Inhibition of the protein kinase mammalian target of rapamycin (mTOR) is being evaluated for treatment of a variety of malignancies. However, the effects of mTOR inhibitors are cytostatic and standard size criteria do not reliably identify responding tumors. The aim of this study was to evaluate whether response to mTOR inhibition could be assessed by positron emission tomography (PET) imaging of tumor metabolism.


METHODS
Glucose, thymidine, and amino acid utilization of human glioma cell lines with varying degrees of sensitivity to mTOR inhibition were assessed by measuring in vitro uptake of [18F]fluorodeoxyglucose ([18F]FDG), [18F]fluorothymidine ([18F]FLT), and [3H]l-tyrosine before and after treatment with the mTOR inhibitor rapamycin. The tumor metabolic activity in vivo was monitored by small-animal PET of tumor-bearing mice. The mechanisms underlying changes in metabolic activity were analyzed by measuring expression and functional activity of enzymes and transporters involved in the uptake of the studied imaging probes.


RESULTS
In sensitive cell lines, rapamycin decreased [18F]FDG and [18F]FLT uptake by up to 65% within 24 hours after the start of therapy. This was associated with inhibition of hexokinase and thymidine kinase 1. In contrast, [3H]l-tyrosine uptake was unaffected by rapamycin. The effects of rapamycin on glucose and thymidine metabolism could be imaged noninvasively by PET. In sensitive tumors, [18F]FDG and [18F]FLT uptake decreased within 48 hours by 56 +/- 6% and 52 +/- 8%, respectively, whereas there was no change in rapamycin-resistant tumors.


CONCLUSIONS
These encouraging preclinical data warrant clinical trials evaluating [18F]FDG and [18F]FLT-PET for monitoring treatment with mTOR inhibitors in patients.
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Liu Hua
LH
Wei
Helen
H
Su
Isabel J
IJ
Hildebrandt
Michael E
ME
Phelps
Johannes
J
Czernin
Wolfgang A
WA
Weber
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D049268:Positron-Emission Tomography; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D013936:Thymidine / Q000378:metabolism; D013937:Thymidine Kinase / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000187:drug effects / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D005462:Fluorine Radioisotopes; D019788:Fluorodeoxyglucose F18; D014443:Tyrosine; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; D013936:Thymidine; D020123:Sirolimus