18F-FLT Positron Emission Tomography (PET) is a Pharmacodynamic Marker for EWS-FLI1 Activity and Ewing Sarcoma.
Ewing sarcoma is a bone and soft-tissue tumor that depends on the activity of the EWS-FLI1 transcription factor for cell survival. Although a number of compounds have been shown to inhibit EWS-FLI1 in vitro, a clinical EWS-FLI1-directed therapy has not been achieved. One problem plaguing drug development efforts is the lack of a suitable, non-invasive, pharmacodynamic marker of EWS-FLI1 activity. Here we show that18F-FLT PET (18F- 3'-deoxy-3'-fluorothymidine positron emission tomography) reflects EWS-FLI1 activity in Ewing sarcoma cells both in vitro and in vivo.18F-FLT is transported into the cell by ENT1 and ENT2, where it is phosphorylated by TK1 and trapped intracellularly. In this report, we show that silencing of EWS-FLI1 with either siRNA or small-molecule EWS-FLI1 inhibitors suppressed the expression of ENT1, ENT2, and TK1 and thus decreased18F-FLT PET activity. This effect was not through a generalized loss in viability or metabolic suppression, as there was no suppression of18F-FDG PET activity and no suppression with chemotherapy. These results provide the basis for the clinical translation of18F-FLT as a companion biomarker of EWS-FLI1 activity and a novel diagnostic imaging approach for Ewing sarcoma.
Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Christy L
CL
Osgood
Vanderbilt University Institute of Imaging Science, USA.
Mohammed N
MN
Tantawy
Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Nichole
N
Maloney
Van Andel Research Institute, Grand Rapids, MI, USA.
Zachary B
ZB
Madaj
Van Andel Research Institute, Grand Rapids, MI, USA.
Anderson
A
Peck
Van Andel Research Institute, Grand Rapids, MI, USA.
Elissa
E
Boguslawski
Van Andel Research Institute, Grand Rapids, MI, USA.
Jennifer
J
Jess
Vanderbilt University Institute of Imaging Science, USA.
Jason
J
Buck
Van Andel Research Institute, Grand Rapids, MI, USA.
Mary E
ME
Winn
Vanderbilt University Institute of Imaging Science, USA.
H Charles
HC
Manning
Division of Pediatric Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Van Andel Research Institute, Grand Rapids, MI, USA.|Helen De Vos Children's Hospital, Grand Rapids, MI, USA.|Michigan State University School of Medicine, Department of Pediatrics, MI, USA.
Patrick J
PJ
Grohar
Eur J Cell Biol. 2009 Dec;88(12):779-85
19726104
Eur J Cancer. 2016 Mar;55:81-97
26820682
PLoS One. 2013 Jul 22;8(7):e69714
23894528
Clin Cancer Res. 2014 Mar 1;20(5):1190-203
24277455
PLoS Med. 2007 Apr;4(4):e122
17425403
Biochem Pharmacol. 2010 Nov 15;80(10):1528-36
20723540
Anal Cell Pathol. 2001;23(1):11-9
11790855
PLoS One. 2009;4(4):e5415
19404404
Int J Cancer. 2012 Nov 1;131(9):2153-64
22323082
Nat Med. 2009 Jul;15(7):750-6
19584866
Genome Res. 2013 Nov;23 (11):1797-809
23940108
Cancer Res. 2003 Jul 15;63(14):4268-74
12874036
PLoS One. 2014 Sep 23;9(9):e108193
25247710
Eur J Cancer. 2012 Dec;48(18):3499-513
22658807
J Natl Cancer Inst. 2011 Jun 22;103(12):962-78
21653923
Eur J Cancer. 2012 Mar;48(4):579-85
22088484
Cancer Res. 2003 May 15;63(10 ):2681-7
12750297
PLoS Genet. 2014 Jul 10;10(7):e1004475
25010205
J Nucl Med. 2013 Mar;54(3):424-30
23341544
Expert Opin Ther Targets. 2005 Aug;9(4):825-30
16083345
J Nucl Med. 2002 Sep;43(9):1210-7
12215561
Nucl Med Biol. 2004 Oct;31(7):829-37
15464384
Clin Cancer Res. 2012 Mar 1;18(5):1303-12
22170262
Cancer Discov. 2014 Nov;4(11):1326-41
25186949
Pediatr Blood Cancer. 2009 Mar;52(3):324-7
18989890
Clin Cancer Res. 2016 Aug 15;22(16):4105-18
26979396
Sarcoma. 2011;2011:598704
21052502
Mol Ther. 2003 Jun;7(6):811-6
12788655
Appl Radiat Isot. 2015 Mar;97:47-51
25531913
Cancer Discov. 2014 Nov;4(11):1342-53
25223734
Nucl Med Commun. 2015 Jul;36(7):695-701
25768337
Mol Pharmacol. 2008 Nov;74(5):1372-80
18669604
Nature. 1992 Sep 10;359(6391):162-5
1522903
Neoplasia. 2011 Feb;13(2):145-53
21403840
Am J Nucl Med Mol Imaging. 2015 Oct 12;5(5):431-56
26550536
Nat Med. 1998 Nov;4(11):1334-6
9809561