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Noninvasive 89Zr-Transferrin PET Shows Improved Tumor Targeting Compared with 18F-FDG PET in MYC-Overexpressing Human Triple-Negative Breast Cancer.

ABSTRACT: The current standard for breast PET imaging is 18F-FDG. The heterogeneity of 18F-FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. 18F-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm3 MYC is a protein involved in oncogenesis and is overexpressed in triple-negative breast cancer (TNBC). Increased surface expression of transferrin receptor (TfR) is a downstream event of MYC upregulation and has been validated as a clinically relevant target for molecular imaging. Transferrin labeled with 89Zr has successfully identified MYC status in many cancer subtypes preclinically and been shown to predict response and changes in oncogene status via treatment with small-molecule inhibitors that target MYC and PI3K signaling pathways. We hypothesized that 89Zr-transferrin PET will noninvasively detect MYC and TfR and improve upon the current standard of 18F-FDG PET for MYC-overexpressing TNBC. Methods: In this study, 89Zr-transferrin and 18F-FDG imaging were compared in preclinical models of TNBC. TNBC cells (MDA-MB-157, MDA-MB-231, and Hs578T) were treated with bromodomain-containing protein 4 (BRD4) inhibitors JQ1 and OTX015 (0.5-1 ?M). Cell proliferation, gene expression, and protein expression were assayed to explore the effects of these inhibitors on MYC and TfR. Results: Head-to-head comparison showed that 89Zr-transferrin targets TNBC tumors significantly better (P < 0.05-0.001) than 18F-FDG through PET imaging and biodistribution studies in MDA-MB-231 and MDA-MB-157 xenografts and a patient-derived xenograft model of TNBC. c-Myc and TfR gene expression was decreased upon treatment with BRD4 inhibitors and c-MYC small interfering RNA (P < 0.01-0.001 for responding cell lines), compared with vehicle treatment. MYC and TfR protein expression, along with receptor-mediated internalization of transferrin, was also significantly decreased upon drug treatment in MDA-MB-231 and MDA-MB-157 cells (P < 0.01-0.001). Conclusion:89Zr-transferrin targets human TNBC primary tumors significantly better than 18F-FDG, as shown through PET imaging and biodistribution studies. 89Zr-transferrin is a useful tool to interrogate MYC via TfR-targeted PET imaging in TNBC.

SUBMITTER: Henry KE

PROVIDER: S-EPMC5750524 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Noninvasive 89Zr-Transferrin PET Shows Improved Tumor Targeting Compared with 18F-FDG PET in MYC-Overexpressing Human Triple-Negative Breast Cancer.

Henry Kelly E KE Dilling Thomas R TR Abdel-Atti Dalya D Edwards Kimberly J KJ Evans Michael J MJ Lewis Jason S JS

Journal of nuclear medicine : official publication, Society of Nuclear Medicine 20170828 1

The current standard for breast PET imaging is 18F-FDG. The heterogeneity of 18F-FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. 18F-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm3 MYC is a protein involved in oncogenesis and is overexpressed in triple-negative breast cancer (TNBC) ...[more]

PMID: 28848040

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Project description:PurposeWatchful waiting (WW) can be considered for patients with metastatic clear-cell renal cell carcinoma (mccRCC) with good or intermediate prognosis, especially those with <2 International Metastatic RCC Database Consortium criteria and ≤2 metastatic sites [referred to as watch and wait ("W&W") criteria]. The IMaging PAtients for Cancer drug SelecTion-Renal Cell Carcinoma study objective was to assess the predictive value of [18F]FDG PET/CT and [89Zr]Zr-DFO-girentuximab PET/CT for WW duration in patients with mccRCC.Experimental designBetween February 2015 and March 2018, 48 patients were enrolled, including 40 evaluable patients with good (n = 14) and intermediate (n = 26) prognosis. Baseline contrast-enhanced CT, [18F]FDG and [89Zr]Zr-DFO-girentuximab PET/CT were performed. Primary endpoint was the time to disease progression warranting systemic treatment. Maximum standardized uptake values (SUVmax) were measured using lesions on CT images coregistered to PET/CT. High and low uptake groups were defined on the basis of median geometric mean SUVmax of RECIST-measurable lesions across patients.ResultsThe median WW time was 16.1 months [95% confidence interval (CI): 9.0-31.7]. The median WW period was shorter in patients with high [18F]FDG tumor uptake than those with low uptake (9.0 vs. 36.2 months; HR, 5.6; 95% CI: 2.4-14.7; P < 0.001). Patients with high [89Zr]Zr-DFO-girentuximab tumor uptake had a median WW period of 9.3 versus 21.3 months with low uptake (HR, 1.7; 95% CI: 0.9-3.3; P = 0.13). Patients with "W&W criteria" had a longer median WW period of 21.3 compared with patients without: 9.3 months (HR, 1.9; 95% CI: 0.9-3.9; Pone-sided = 0.034). Adding [18F]FDG uptake to the "W&W criteria" improved the prediction of WW duration (P < 0.001); whereas [89Zr]Zr-DFO-girentuximab did not (P = 0.53).ConclusionsIn patients with good- or intermediate-risk mccRCC, low [18F]FDG uptake is associated with prolonged WW. This study shows the predictive value of the "W&W criteria" for WW duration and shows the potential of [18F]FDG-PET/CT to further improve this.

Project description:BACKGROUND:Stress exposure can significantly affect serotonergic signaling with a particular impact on 5-HT1A receptor expression. Positron emission tomography (PET) provides opportunities for molecular imaging of alterations in 5-HT1A receptor binding following stress exposure. Considering the possible role of 5-HT1A receptors in stress coping mechanisms, respective imaging approaches are of particular interest. MATERIAL AND METHODS:For twelve consecutive days, Sprague Dawley rats were exposed to daily transport with a 1?h stay in a laboratory or daily transport plus 1?h restraint in a narrow tube. Following, animals were subjected to ?PET imaging with 2'-methoxyphenyl-(N-2'-pyridinyl)-p-[18F]fluoro-benzamidoethylpiperazine ([18F]MPPF) and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). Behavioral and biochemical parameters were analyzed to obtain additional information. RESULTS:In rats with repeated transport, hippocampal [18F]MPPF binding exceeded that in the naive group, while no difference in [18F]FDG uptake was detected between the groups. A transient decline in body weight was observed in rats with transport or combined transport and restraint. Thereby, body weight development correlated with [18F]MPPF binding. CONCLUSIONS:Mild-to-moderate stress associated with daily transport and exposure to a laboratory environment can trigger significant alterations in hippocampal binding of the 5-HT1A receptor ligand [18F]MPPF. This finding indicates that utmost care is necessary to control and report transport and associated handling procedures for animals used in ?PET studies analyzing the serotonergic system in order to enhance the robustness of conclusions and allow replicability of findings. In view of earlier studies indicating that an increase in hippocampal 5-HT1A receptor expression may be associated with a resilience to stress, it would be of interest to further evaluate 5-HT1A receptor imaging approaches as a candidate biomarker for the vulnerability to stress.

Dataset Information

Noninvasive 89Zr-Transferrin PET Shows Improved Tumor Targeting Compared with 18F-FDG PET in MYC-Overexpressing Human Triple-Negative Breast Cancer.

Publications

Noninvasive <sup>89</sup>Zr-Transferrin PET Shows Improved Tumor Targeting Compared with <sup>18</sup>F-FDG PET in MYC-Overexpressing Human Triple-Negative Breast Cancer.

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