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Published on: February 3, 2015
Changes in HER2 expression in breast cancer xenografts after therapy can be quantified using PET and (18)F-labeled
Gabriela Kramer-Marek1, Dale O Kiesewetter, Jacek Capala
1National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Unlabelled:
In vivo imaging of human epidermal growth factor receptor type 2 (HER2) expression may allow direct assessment of HER2 status in tumor tissue and provide a means to quantify changes in receptor expression after HER2-targeted therapies. This work describes the in vivo characterization of the HER2-specific N-2-(4-(18)F-fluorobenzamido)ethyl]maleimide ((18)F-FBEM)-Z(HER2:342) Affibody molecule and its application to study the effect of 17 (dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) on HER2 expression by PET.
Methods:
To assess the correlation of signal observed by PET with receptor expression, we administered the tracer to athymic nude mice bearing subcutaneous human breast cancer xenografts with different levels of HER2 expression. To study the downregulation of HER2, we treated the mice with 4 doses (40 mg/kg) of 17-DMAG, an inhibitor of heat-shock protein 90, known to decrease HER2 expression. The animals were scanned before and after treatment. After the last scan, the mice were euthanized and tumors were frozen for receptor analysis.
Results:
The tracer was eliminated quickly from the blood and normal tissues, providing high tumor-to-blood and tumor-to-muscle ratios as early as 20 min after injection. The high-contrast images between normal and tumor tissue were recorded for BT474 and MCF7/clone18 tumors. Low but still detectable uptake was observed for MCF7 tumors, and none for MDA-MB-468. The signal correlated with the receptor expression as assessed by immunohistochemistry, Western blot, and enzyme-linked immunosorbent assay. The levels of HER2 expression estimated by post-treatment PET decreased 71% (P < 4 x 10(-6)) and 33% (P < 0.002), respectively, for mice bearing BT474 and MCF7/clone18 tumors. These changes were confirmed by the biodistribution studies, enzyme-linked immunosorbent assay, and Western blot.
Conclusion:
Our results suggest that the described (18)F-FBEM-Z(HER2:342) Affibody molecule can be used to assess HER2 expression in vivo by PET and monitor possible changes of receptor expression in response to therapeutic interventions.
Insights
This study introduces a novel PET imaging tracer, (18)F-FBEM-Z(HER2:342) Affibody, for in vivo assessment of human epidermal growth factor receptor type 2 (HER2) expression. The tracer effectively monitored HER2 changes in response to targeted therapy.
Area of Science:
- Oncology
- Radiochemistry
- Molecular Imaging
Background:
- Human epidermal growth factor receptor type 2 (HER2) is a key target in breast cancer therapy.
- In vivo assessment of HER2 expression can guide treatment decisions and monitor therapeutic response.
- Current methods for assessing HER2 status can be invasive and do not always reflect dynamic changes.
Purpose of the Study:
- To characterize the in vivo performance of a novel PET tracer, (18)F-FBEM-Z(HER2:342) Affibody molecule.
- To evaluate the tracer's ability to quantify changes in HER2 expression following targeted therapy.
- To assess the impact of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) on HER2 expression in preclinical models.
Main Methods:
- Development and characterization of the (18)F-FBEM-Z(HER2:342) Affibody tracer for PET imaging.
- Administration of the tracer to athymic nude mice bearing human breast cancer xenografts with varying HER2 expression levels.
- Treatment of mice with 17-DMAG to induce HER2 downregulation, with PET scans conducted before and after treatment.
- Ex vivo analysis of tumors using immunohistochemistry, Western blot, and ELISA to correlate PET signals with receptor levels.
Main Results:
- The (18)F-FBEM-Z(HER2:342) tracer demonstrated rapid blood clearance and high tumor-to-background ratios, enabling clear visualization of HER2-expressing tumors.
- PET signal intensity strongly correlated with HER2 expression levels determined by standard assays.
- PET imaging successfully quantified significant reductions in HER2 expression following 17-DMAG treatment (71% in BT474, 33% in MCF7/clone18 xenografts).
Conclusions:
- The (18)F-FBEM-Z(HER2:342) Affibody molecule is a promising PET tracer for non-invasive assessment of HER2 expression in vivo.
- This imaging approach can effectively monitor dynamic changes in HER2 receptor levels in response to therapeutic interventions.
- The findings support the potential clinical utility of this tracer for personalized HER2-targeted cancer therapy.
