Monitoring therapeutic response of human ovarian cancer to trastuzumab by SPECT imaging with 99mTc-peptide-ZHER2:342

Abstract

IntroductionPatients with human epidermal growth factor receptor 2 (HER2)-positive cancer are candidates for treatment with the anti-HER2 antibody trastuzumab. How to systemically assess tumor HER2 expression and identifying appropriate use of anti-HER2 therapies by noninvasive imaging in vivo is an urgent issue. The purpose of this study was to evaluate SPECT imaging of 99mTc-Gly-(D)Ala-Gly-Gly-ZHER2:342 (99mTc-peptide-ZHER2:342) for monitoring therapeutic response to trastuzumab in nude mice bearing HER2-positive SKOV-3 xenografts. MethodsNude mice bearing HER2-positive SKOV-3 xenografts were treated with trastuzumab (treatment group) or saline (control) with ten mice in each group. Mice in trastuzumab-treated group were given trastuzumab intraperiotoneally 4mg/kg on day 1 and 2mg/kg on day 8; Mice in control group were given physiological saline on day 1 and 8. Mice body weights and tumour volume were monitored every three days during treatment. In vivo SPECT imaging was performed in mice of the two groups using 99mTc-peptide-ZHER2:342 before treatment, on day 8 and 15 after treatment. Radiolabeled probe uptake in tumours was measured as the ratio of radioactive counts in the tumour to that in the contralateral equivalent region (T/NT). After SPECT imaging on day 15, all the mice were euthanized, biodistribution studies of the SKOV-3 xenografts were carried out to validate the imaging results and HER2 expression of the transplanted tumours was analyzed by immunohistochemistry (IHC). Correlation analysis was performed between T/NT ratios acquired by in vivo SPECT imaging on day 15 and the HER2 level of tumours. In vitro cell binding capacity of 99mTc-ZHER2:342 with SKOV-3 cells in the absence and presence of varying amount of trastuzumab were also conducted in the study. ResultsTwenty mice body weight in the two groups gradually increased during treatment, but there was no statistical difference (p>0.05). Though volumes of SKOV-3 xenografts gradually increased in each group during the treatment, the transplanted tumours in trastuzumab-treated group had a slower growth than those in control group (p<0.05). Compared with the baseline, the results of in vivo imaging showed that radionuclide accumulation in transplanted tumours reduced significantly in trastuzumab-treated group after treatment (p<0.05), whereas the tumour accumulation in control group increased after treatment. Biodistribution studies demonstrated that the results corresponded well with in vivo imaging data. Immunohistochemical staining confirmed the significant reduction in tumor HER2 level upon trastuzumab treatment, and there was an obviously positive correlation between T/NT ratios and HER2 level of tumours with correlation coefficient rs=0.919, p<0.05. There was no significant significance in cell binding ratios between varying amount of trastuzumab and the absence of trastuzumab (p>0.05). ConclusionsThe early response to trastuzumab in mice bearing SKOV-3 xenografts was successfully monitored by SPECT imaging using 99mTc-peptide-ZHER2:342. This approach may be valuable in monitoring the therapeutic response in HER 2-positive tumours under HER2-targeted therapy.