HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Supplemental Data All Versions of this Article: jnumed.109.062224v1 50/8/1340    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in JNM Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McLarty, K. Articles by Reilly, R. M. Search for Related Content PubMed PubMed Citation Articles by McLarty, K. Articles by Reilly, R. M.

Micro-SPECT/CT with ¹¹¹In-DTPA-Pertuzumab Sensitively Detects Trastuzumab-Mediated HER2 Downregulation and Tumor Response in Athymic Mice Bearing MDA-MB-361 Human Breast Cancer Xenografts

¹ Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada; ² Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; ³ Department of Medical Biophysics and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; ⁴ Ontario Cancer Institute and Department of Pathology, University Health Network, Toronto, Ontario, Canada; and ⁵ Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada

Correspondence: For correspondence or reprints contact: Raymond M. Reilly, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, ON, Canada M5S 3M2. E-mail: raymond.reilly{at}utoronto.ca

Pertuzumab is a HER2 dimerization inhibitor that binds to an epitope unique from that of trastuzumab. Our objective was to determine whether SPECT with ¹¹¹In-diethylenetriaminepentaacetic acid–pertuzumab (¹¹¹In-DTPA-pertuzumab) could sensitively detect an early molecular response to trastuzumab manifested by HER2 downregulation and a later tumor response revealed by a decreased number of HER2-positive viable tumor cells. Methods: Changes in HER2 density in SKBr-3 and MDA-MB-361 BC cells exposed to trastuzumab (14 µg/mL) in vitro were measured by saturation binding assays using ¹¹¹In-DTPA-pertuzumab and by confocal immunofluorescence microscopy and flow cytometry with fluorescein isothiocyanate–labeled HER2/neu antibodies. Imaging of HER2 downregulation was studied in vivo in athymic mice with subcutaneous MDA-MB-361 tumors treated for 3 d with trastuzumab (4 mg/kg) or nonspecific human IgG (hIgG) or phosphate-buffered saline (PBS). Imaging of tumor response to trastuzumab was studied in mice bearing subcutaneous MDA-MB-361 xenografts treated with trastuzumab (4 mg/kg), followed by weekly doses of nonspecific hIgG or rituximab or PBS (2 mg/kg). Mice were imaged on a micro-SPECT/CT system at 72 h after injection of ¹¹¹In-DTPA-pertuzumab. Tumor and normal-tissue biodistribution was determined. Results: ¹¹¹In-DTPA-pertuzumab saturation binding to SKBr-3 and MDA-MB-361 cells was significantly decreased at 72 h after exposure in vitro to trastuzumab (14 µg/mL), compared with untreated controls (62% ± 2%, P < 0.0001; 32% ± 9%, P < 0.0002, respectively). After 3 d of trastuzumab, in vivo tumor uptake of ¹¹¹In-DTPA-pertuzumab decreased 2-fold in trastuzumab- versus PBS-treated mice (13.5 ± 2.6 percentage injected dose per gram [%ID/g] vs. 28.5 ± 9.1 %ID/g, respectively; P < 0.05). There was also a 2-fold decreased tumor uptake in trastuzumab- versus PBS-treated mice by image volume-of-interest analysis (P = 0.05), suggesting trastuzumab-mediated HER2 downregulation. After 3 wk of trastuzumab, tumor uptake of ¹¹¹In-DTPA-pertuzumab decreased 4.5-fold, compared with PBS-treated mice (7.6 ± 0.4 vs. 34.6 ± 9.9 %ID/g, respectively; P < 0.001); this decrease was associated with an almost-completed eradication of HER2-positive tumor cells determined immunohistochemically. Conclusion: ¹¹¹In-DTPA-pertuzumab sensitively imaged HER2 downregulation after 3 d of treatment with trastuzumab and detected a reduction in viable HER2-positive tumor cells after 3 wk of therapy in MDA-MB-361 human breast cancer xenografts.

Key Words: HER2 • trastuzumab • molecular imaging • tumor response • pertuzumab

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.

Related articles in JNM:

This Month in JNM

JNM 2009 50: 11A-12A. [Full Text]  

This article has been cited by other articles:

				K. McLarty, A. Fasih, D. A. Scollard, S. J. Done, D. C. Vines, D. E. Green, D. L. Costantini, and R. M. Reilly 18F-FDG Small-Animal PET/CT Differentiates Trastuzumab-Responsive from Unresponsive Human Breast Cancer Xenografts in Athymic Mice J. Nucl. Med., November 1, 2009; 50(11): 1848 - 1856. [Abstract] [Full Text] [PDF]