Dataset Information

Preclinical and first-in-human-brain-cancer applications of [¹⁸F]poly (ADP-ribose) polymerase inhibitor PET/MR.

ABSTRACT:

Background

We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [¹⁸F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes.

Methods

We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [¹⁸F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with brain cancers to undergo dynamic [¹⁸F]PARPi acquisition on a dedicated positron emission tomography/magnetic resonance (PET/MR) scanner. Lesion diagnosis was established by pathology when available or by Response Assessment in Neuro-Oncology (RANO) or RANO-BM response criteria. Resected tissue also underwent PARPi-FL staining and PARP1 immunohistochemistry.

Results

In a preclinical mouse model, we illustrated that [¹⁸F]PARPi crossed the blood-brain barrier and specifically bound to PARP1 overexpressed in cancer cell nuclei. In humans, we demonstrated high [¹⁸F]PARPi uptake on PET/MR in active brain cancers and low uptake in treatment-related changes independent of blood-brain barrier disruption. Immunohistochemistry results confirmed higher PARP1 expression in cancerous than in noncancerous tissue. Specificity was also corroborated by blocking fluorescent tracer uptake with an excess unlabeled PARP inhibitor in patient cancer biospecimen.

Conclusions

Although larger studies are necessary to confirm and further explore this tracer, we describe the promising performance of [¹⁸F]PARPi as a diagnostic tool to evaluate patients with brain cancers and possible treatment-related changes.

SUBMITTER: Young RJ

PROVIDER: S-EPMC7758909 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Publications

Preclinical and first-in-human-brain-cancer applications of [<sup>18</sup>F]poly (ADP-ribose) polymerase inhibitor PET/MR.

Young Robert J RJ Demétrio De Souza França Paula P Pirovano Giacomo G Piotrowski Anna F AF Nicklin Philip J PJ Riedl Christopher C CC Schwartz Jazmin J Bale Tejus A TA Donabedian Patrick L PL Kossatz Susanne S Burnazi Eva M EM Roberts Sheryl S Lyashchenko Serge K SK Miller Alexandra M AM Moss Nelson S NS Fiasconaro Megan M Zhang Zhigang Z Mauguen Audrey A Reiner Thomas T Dunphy Mark P MP

Neuro-oncology advances 20200101 1

<h4>Background</h4>We report preclinical and first-in-human-brain-cancer data using a targeted poly (ADP-ribose) polymerase 1 (PARP1) binding PET tracer, [<sup>18</sup>F]PARPi, as a diagnostic tool to differentiate between brain cancers and treatment-related changes.<h4>Methods</h4>We applied a glioma model in p53-deficient nestin/tv-a mice, which were injected with [<sup>18</sup>F]PARPi and then sacrificed 1 h post-injection for brain examination. We also prospectively enrolled patients with br ...[more]

PMID: 33392502

Similar Datasets

Project description: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.

Project description:The poly-(adenosine diphosphate-ribose) polymerase (PARP) family of proteins participates in numerous functions, most notably the DNA damage response. Cancer vulnerability to DNA damage has led to development of several PARP inhibitors (PARPi). This class of drugs has demonstrated therapeutic efficacy in ovarian, breast, and prostate cancers, but with variable response. Consequently, clinics need to select patients likely to benefit from these targeted therapies. In vivo imaging of 18F-fluorthanatrace uptake has been shown to correspond to PARP-1 expression in tissue. This study characterized the pharmacokinetics of 18F-fluorthanatrace and tested kinetic and static models to guide metric selection in future studies assessing 18F-fluorthanatrace as a biomarker of response to PARPi therapy. Methods: Fourteen prospectively enrolled ovarian cancer patients were injected with 18F-fluorthanatrace and imaged dynamically for 60 min after injection followed by up to 2 whole-body scans, with venous blood activity and metabolite measurements. SUVmax and SUVpeak were extracted from dynamic images and whole-body scans. Kinetic parameter estimates and SUVs were assessed for correlations with tissue PARP-1 immunofluorescence (n = 7). Simulations of population kinetic parameters enabled estimation of measurement bias and precision in parameter estimates. Results: 18F-fluorthanatrace blood clearance was variable, but labeled metabolite profiles were similar across patients, supporting use of a population parent fraction curve. The total distribution volume from a reversible 2-tissue-compartment model and Logan reference tissue distribution volume ratio (DVR) from the first hour of PET acquisition correlated with tumor PARP-1 expression by immunofluorescence (r = 0.76 and 0.83, respectively; P < 0.05). DVR bias and precision estimates were 6.4% and 29.1%, respectively. SUVmax and SUVpeak acquired from images with midpoints of 57.5, 110 ± 3, and 199 ± 4 min highly correlated with PARP-1 expression (mean ± SD, r ≥ 0.79; P < 0.05). Conclusion: Tumor SUVmax and SUVpeak at 55-60 min after injection and later and DVR from at least 60 min appear to be robust noninvasive measures of PARP-1 binding. 18F-fluorthanatrace uptake in ovarian cancer was best described by models of reversible binding. However, pharmacokinetic patterns of tracer uptake were somewhat variable, especially at later time points.

Dataset Information

Preclinical and first-in-human-brain-cancer applications of [¹⁸F]poly (ADP-ribose) polymerase inhibitor PET/MR.

Background

Methods

Results

Conclusions

Publications

Preclinical and first-in-human-brain-cancer applications of [<sup>18</sup>F]poly (ADP-ribose) polymerase inhibitor PET/MR.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Preclinical and first-in-human-brain-cancer applications of [18F]poly (ADP-ribose) polymerase inhibitor PET/MR.

Background

Methods

Results

Conclusions

Publications

Preclinical and first-in-human-brain-cancer applications of [<sup>18</sup>F]poly (ADP-ribose) polymerase inhibitor PET/MR.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Preclinical and first-in-human-brain-cancer applications of [¹⁸F]poly (ADP-ribose) polymerase inhibitor PET/MR.