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[18F]-FLT Positron Emission Tomography Can Be Used to Image the Response of Sensitive Tumors to PI3-Kinase Inhibition with the Novel Agent GDC-0941

Williams, K. J.; Wilson, I.; Brown, G.; Hodgkinson, C.; Babur, M.; Smigova, A.; Radigois, M.; Forster, D.; Morrow, C. J.; Gieling, R. G.; Burrows, N.; Hiscock, D.; McMahon, A.; Dive, C.; Cawthorne, Christopher; Burrows, Natalie; Gieling, Roben G.; Morrow, Christopher J.; Forster, Duncan; Gregory, Jamil; Radigois, Marc; Smigova, Alison; Babur, Muhammad; Simpson, Kathryn; Hodgkinson, Cassandra; Brown, Gavin; McMahon, Adam; Dive, Caroline; Hiscock, Duncan; Wilson, Ian; Williams, Kaye J.

Authors

K. J. Williams

I. Wilson

G. Brown

C. Hodgkinson

M. Babur

A. Smigova

M. Radigois

D. Forster

C. J. Morrow

R. G. Gieling

N. Burrows

D. Hiscock

A. McMahon

C. Dive

Christopher Cawthorne C.Cawthorne@hull.ac.uk

Natalie Burrows

Roben G. Gieling

Christopher J. Morrow

Duncan Forster

Jamil Gregory

Marc Radigois

Alison Smigova

Muhammad Babur

Kathryn Simpson

Cassandra Hodgkinson

Gavin Brown

Adam McMahon

Caroline Dive

Duncan Hiscock

Ian Wilson

Kaye J. Williams



Abstract

The phosphoinositide 3-kinase (PI3K) pathway is deregulated in a range of cancers, and several targeted inhibitors are entering the clinic. This study aimed to investigate whether the positron emission tomography tracer 3′-deoxy-3′-[ 18 F]fluorothymidine ([ 18 F]-FLT) is suitable to mark the effect of the novel PI3K inhibitor GDC-0941, which has entered phase II clinical trial. CBA nude mice bearing U87 glioma and HCT1 16 colorectal xenografts were imaged at baseline with [ 18 F]-FLT and at acute (18 hours) and chronic (186 hours) time points after twice-daily administration of GDC-0941 (50 mg/kg) or vehicle. Tumor uptake normalized to blood pool was calculated, and tissue was analyzed at sacrifice for PI3K pathway inhibition and thymidine kinase (TK1) expression. Uptake of [ 18 F]-FLT was also assessed in tumors inducibly overexpressing a dominant-negative form of the PI3K p85 subunit p85α, as well as HCT116 liver metastases after GDC-0941 therapy. GDC-0941 treatment induced tumor stasis in U87 xenografts, whereas inhibition of HCT116 tumors was more variable. Tumor uptake of [ 18 F]-FLT was significantly reduced following GDC-0941 dosing in responsive tumors at the acute time point and correlated with pharmacodynamic markers of PI3K signaling inhibition and significant reduction in TK1 expression in U87, but not HCT116, tumors. Reduction of PI3K signaling via expression of Δp85α significantly reduced tumor growth and [ 18 F]-FLT uptake, as did treatment of HCT116 liver metastases with GDC-0941. These results indicate that [ 18 F]-FLT is a str ong candidate for the noninvasive measurement of GDC-0941 action. ©2013 American Association for Cancer Research.

Journal Article Type Article
Publication Date May 1, 2013
Journal Molecular cancer therapeutics
Print ISSN 1538-8514
Electronic ISSN 1538-8514
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 12
Issue 5
Pages 819-828
APA6 Citation Cawthorne, C., Burrows, N., Gieling, R. G., Morrow, C. J., Forster, D., Gregory, J., …Williams, K. J. (2013). [18F]-FLT Positron Emission Tomography Can Be Used to Image the Response of Sensitive Tumors to PI3-Kinase Inhibition with the Novel Agent GDC-0941. Molecular Cancer Therapeutics, 12(5), 819-828. doi:10.1158/1535-7163.mct-12-0905
DOI https://doi.org/10.1158/1535-7163.mct-12-0905
Keywords Cancer Research; Oncology
Publisher URL http://mct.aacrjournals.org/content/12/5/819
PMID 23427298
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