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Therapeutics, Targets, and Chemical Biology

FLT-PET Is Superior to FDG-PET for Very Early Response Prediction in NPM-ALK-Positive Lymphoma Treated with Targeted Therapy

Zhoulei Li, Nicolas Graf, Ken Herrmann, Alexandra Jünger, Michaela Aichler, Annette Feuchtinger, Anja Baumgart, Axel Walch, Christian Peschel, Markus Schwaiger, Andreas Buck, Ulrich Keller and Tobias Dechow
Zhoulei Li
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Nicolas Graf
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Ken Herrmann
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Alexandra Jünger
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Michaela Aichler
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Annette Feuchtinger
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Anja Baumgart
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Axel Walch
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Christian Peschel
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Markus Schwaiger
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Andreas Buck
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Ulrich Keller
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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Tobias Dechow
Authors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, GermanyAuthors' Affiliations: 1Nuclear Medicine, 2III. Medical Department, Technische Universität München; 3Pathology, Helmholtz Zentrum München, Munich, Germany; 4Nuclear Medicine, Universitätsklinik Würzburg, Würzburg, Germany; and 5Onkologie Ravensburg, Ravensburg, Germany
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DOI: 10.1158/0008-5472.CAN-12-0635 Published October 2012
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Abstract

The prognosis of relapsed or refractory aggressive lymphoma is poor. The huge variety of currently evolving targeted treatment approaches would benefit from tools for early prediction of response or resistance. We used various ALK-positive anaplastic large cell lymphoma (ALCL) cell lines to evaluate two inhibitors, the HSP90 inhibitor NVP-AUY922, and the mTOR inhibitor everolimus, both of which have shown to interfere with ALK-dependent oncogenic signal transduction. Their therapeutic effect was determined in vitro by MTT assay, [18F]fluorodeoxyglucose (FDG)- and [18F]fluorothymidine (FLT)-uptake, and by biochemical analysis of ALK-induced signaling. Micro-FDG- and FLT-positron emission tomography (PET) imaging studies in immunodeficient mice bearing ALCL xenotransplants were carried out with the cell lines SUDHL-1 and Karpas299 to assess early treatment response to NVP-AUY922 or everolimus in vivo. SUDHL-1 cells showed sensitivity to both inhibitors in vitro. Importantly, we detected a significant reduction of FLT-uptake in SUDHL-1 bearing animals using both inhibitors compared with baseline as early as 5 days after initiation of targeted therapy. Immunostaining showed a decrease in Ki-67 and an increase in cleaved caspase-3 staining. In contrast, FDG-uptake did not significantly decrease at early time points. Karpas299 xenotransplants, which are resistant to NVP-AUY922 and sensitive to everolimus treatment, showed an increase of mean FLT-uptake on day 2 after administration of NVP-AUY299, but a significant reduction in FLT-uptake upon everolimus treatment. In conclusion, we show that FLT-PET but not FDG-PET is able to predict response to treatment with specific inhibitors very early in the course of treatment and thus enables early prediction of treatment efficacy. Cancer Res; 72(19); 5014–24. ©2012 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received February 20, 2012.
  • Revision received July 17, 2012.
  • Accepted July 18, 2012.
  • ©2012 American Association for Cancer Research.
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Cancer Research: 72 (19)
October 2012
Volume 72, Issue 19
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FLT-PET Is Superior to FDG-PET for Very Early Response Prediction in NPM-ALK-Positive Lymphoma Treated with Targeted Therapy
Zhoulei Li, Nicolas Graf, Ken Herrmann, Alexandra Jünger, Michaela Aichler, Annette Feuchtinger, Anja Baumgart, Axel Walch, Christian Peschel, Markus Schwaiger, Andreas Buck, Ulrich Keller and Tobias Dechow
Cancer Res October 1 2012 (72) (19) 5014-5024; DOI: 10.1158/0008-5472.CAN-12-0635

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FLT-PET Is Superior to FDG-PET for Very Early Response Prediction in NPM-ALK-Positive Lymphoma Treated with Targeted Therapy
Zhoulei Li, Nicolas Graf, Ken Herrmann, Alexandra Jünger, Michaela Aichler, Annette Feuchtinger, Anja Baumgart, Axel Walch, Christian Peschel, Markus Schwaiger, Andreas Buck, Ulrich Keller and Tobias Dechow
Cancer Res October 1 2012 (72) (19) 5014-5024; DOI: 10.1158/0008-5472.CAN-12-0635
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