Imaging spontaneous MMTVneu transgenic murine mammary tumors: targeting metabolic activity versus genetic products
Mathew L Thakur1, Devakumar Devadhas, Kaijun Zhang
1Department of Radiology, Kimmel Cancer Center, Philadelphia, Pennsylvania, USA. Mathew.Thakur@jefferson.edu
Unlabelled:
Despite the great strides made in imaging breast cancer (BC) in humans, the current imaging modalities miss up to 30% of BC, do not distinguish malignant lesions from benign ones, and require histologic examinations for which invasive biopsy must be performed. Annually in the United States, approximately 5.6 million biopsies find benign lesions. More than 50% of human BCs overexpress cyclin D1, and all BCs exhibit VPAC1 oncogene products. Together, these gene products may provide an excellent biomarker for the early and accurate detection of BC. We have evaluated 4 biologically active peptide analogs that have high affinity for VPAC1. The transgenic MMTVneu mice spontaneously develop BC and metastatic lesions that overexpress cyclin D1 and VPAC1 biomarkers. The MMTVneu mouse, therefore, provides an excellent animal model that mimics the pathogenesis of human BC. The objective of this investigation was to determine the ability of 1 of the peptide analogs, (64)Cu-TP3805, to detect BC in MMTVneu mice using (18)F-FDG as a gold standard.
Methods:
The transgenic MMTVneu mouse colony was maintained. Offspring were screened for transgenic status by reverse transcriptase polymerase chain reaction (RT-PCR). Nine mice with visible, palpable, or unknown metastatic lesions were entered into the protocol. (18)F-FDG (6,475 +/- 1,628 kBq [175 +/- 44 microCi]) PET served as a control, followed by a CT scan and 24-48 h later by PET with (64)Cu-TP3805 (4,588 +/- 962 kBq [124 +/- 26 microCi]). RT-PCR on excised tumors determined VPAC1 expression, and histology ascertained the pathology.
Results:
Ten tumors were detected by PET. Four tumors were detected both by (18)F-FDG and by (64)Cu-TP3805. Additionally, 4 tumors were imaged with (64)Cu-TP3805 only. These 8 tumors overexpressed VPAC1 receptors and were malignant by histology. The 2 remaining tumors were visualized with (18)F-FDG only. These tumors did not express the VPAC1 oncogene product and had benign histology. The standard uptake value ranged from 3.1 to 18.3 for (64)Cu-TP3805 and 0.9 to 1.4 for (18)F-FDG.
Conclusion:
(64)Cu-TP3805 identified all malignant lesions unequivocally that overexpressed the VPAC1 oncogene surface product. The 2 benign tumors that did not express the VPAC1 receptor were not imaged. (64)Cu-TP3805 promises to have the potential for the early and accurate imaging of primary and metastatic BC.
Insights
A new peptide analog, Cu-TP3805, accurately images breast cancer (BC) in mice by targeting VPAC1 receptors. This offers potential for earlier and more precise BC detection than current methods.
Area of Science:
- Oncology
- Radiopharmaceuticals
- Molecular Imaging
Background:
- Current breast cancer (BC) imaging misses up to 30% of cases and cannot reliably distinguish malignant from benign lesions, necessitating invasive biopsies.
- Overexpression of cyclin D1 and VPAC1 oncogene products in BC presents potential biomarkers for early and accurate detection.
- The MMTVneu mouse model spontaneously develops BC with overexpression of cyclin D1 and VPAC1, mimicking human disease.
Purpose of the Study:
- To evaluate the efficacy of the peptide analog (64)Cu-TP3805 for detecting breast cancer (BC) in MMTVneu mice.
- To compare the diagnostic performance of (64)Cu-TP3805 with (18)F-FDG PET as a gold standard.
- To assess the correlation between VPAC1 receptor expression and tumor malignancy.
Main Methods:
- MMTVneu mice were screened for transgenic status using RT-PCR.
- (18)F-FDG PET/CT was performed, followed by (64)Cu-TP3805 PET 24-48 hours later.
- VPAC1 expression was determined by RT-PCR on excised tumors, and histology confirmed pathology.
Main Results:
- Ten tumors were detected by PET imaging.
- (64)Cu-TP3805 identified 8 malignant tumors overexpressing VPAC1, including 4 also detected by (18)F-FDG.
- Two benign tumors lacking VPAC1 expression were detected by (18)F-FDG only, not by (64)Cu-TP3805.
- Standard uptake values for (64)Cu-TP3805 ranged from 3.1 to 18.3, significantly higher than 0.9 to 1.4 for (18)F-FDG.
Conclusions:
- (64)Cu-TP3805 unequivocally identified all malignant lesions overexpressing VPAC1.
- Benign tumors lacking VPAC1 were not imaged by (64)Cu-TP3805, demonstrating specificity.
- (64)Cu-TP3805 shows significant potential for early and accurate imaging of primary and metastatic breast cancer.
