Original Research

PET of Poly (ADP-Ribose) Polymerase Activity in Cancer: Preclinical Assessment and First In-Human Studies

Published Online:Nov 14 2016https://doi.org/10.1148/radiol.2016161929

Correction(s) for this article

Abstract

Our data support the feasibility of evaluating fluorine 18 fluorthanatrace as a quantifiable biomarker of poly (adenosine diphosphate–ribose) polymerase expression in clinical trials.

Purpose

To demonstrate that positron emission tomography (PET) with fluorine 18 (¹⁸F) fluorthanatrace (FTT) depicts activated poly (adenosine diphosphate–ribose)polymerase (PARP) expression and is feasible for clinical trial evaluation.

Materials and Methods

All studies were conducted prospectively from February 2012 through July 2015 under protocols approved by the local animal studies committee and institutional review board. The area under the receiver operating characteristic curve (AUC, in g/mL· min) for ¹⁸F-FTT was assessed in normal mouse organs before and after treatment with olaparib (n = 14), a PARP inhibitor, or iniparib (n = 11), which has no PARP inhibitory activity. Murine biodistribution studies were performed to support human translational studies. Eight human subjects with cancer and eight healthy volunteers underwent imaging to verify the human radiation dosimetry of ¹⁸F-FTT. The Wilcoxon signed rank test was used to assess for differences among treatment groups for the mouse studies.

Results

In mice, olaparib, but not iniparib, significantly reduced the ¹⁸F-FTT AUC in the spine (median difference before and after treatment and interquartile range [IQR]: −17 g/mL· min and 10 g/mL · min, respectively [P = .0001], for olaparib and −3 g/mL · min and 13 g/mL · min [P = .70] for iniparib) and in nodes (median difference and interquartile range [IQR] before and after treatment: −23 g/mL · min and 13 g/mL · min [P = .0001] for olaparib; −9 g/mL · min and 17 g/mL · min [P = .05] for iniparib). The effective dose was estimated at 6.9 mSv for a 370-MBq ¹⁸F-FTT dose in humans. In humans, the organs with the highest uptake on images were the spleen and pancreas. Among five subjects with measurable tumors, increased ¹⁸F-FTT uptake was seen in one subject with pancreatic adenocarcinoma and another with liver cancer.

Conclusion

The results suggest that ¹⁸F-FTT uptake reflects PARP expression and that its radiation dosimetry profile is compatible with those of agents currently in clinical use.

^© RSNA, 2016

Online supplemental material is available for this article.

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Article History

Received August 16, 2016; revision requested September 13; revision received September 27; accepted October 4; final version accepted October 20.
Published online: Nov 14 2016
Published in print: Feb 2017

Vol. 282, No. 2

Supplemental Material

Funding/Support

Supported by Mallinckrodt Institute of Radiology Department Funding and the Washington University Office of Technology Management Bear Cub Fund. F.J.B. and D.L.C. (in part) are supported by the National Institutes of Health (grant HL121218).

Abbreviations

Abbreviations:
AUC	area under the receiver operating characteristic curve
FTT	fluorthanatrace
IQR	interquartile range
PARP	poly (adenosine diphosphate–ribose)polymerase

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