[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

Cawthorne, Christopher, Burrows, Natalie, Gieling, Roben, Morrow, Christopher, Forster, Duncan, Gregory, Jamil, Radigois, Radigois, Smigova, Alison, Babur, Muhammad, Simpson, Kathryn, Hodgkinson, Cassandra, Brown, Gavin, McMahon, Adam, Dive, Caroline, Hiscock, Duncan, Wilson, Ian and Williams, Kaye (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). pp. 819-828. ISSN 1535-7163

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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′-[18F]fluorothymidine ([18F]-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 HCT116 colorectal xenografts were imaged at baseline with [18F]-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 [18F]-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 [18F]-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 [18F]-FLT uptake, as did treatment of HCT116 liver metastases with GDC-0941. These results indicate that [18F]-FLT is a strong candidate for the noninvasive measurement of GDC-0941 action.

Item Type:	Article
Subjects:	B800 Medical Technology
Department:	Faculties > Health and Life Sciences > Applied Sciences
Depositing User:	Paul Burns
Date Deposited:	13 Jul 2018 09:54
Last Modified:	11 Oct 2019 14:17
URI:	http://nrl.northumbria.ac.uk/id/eprint/34976

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