Abstract 2860: 89Zr-trastuzumab immunoPET imaging to monitor src status after treatment in HER2 breast cancer

Abstract

Abstract Around 30% of patients with early stage breast cancer have recurrent disease due to resistance. One of the putative causes of acquired resistance can be attributed to the hyperactivation of Src kinases, which are particularly stabilized by aberrant HER2 signaling, which itself is overexpressed in nearly 30% of early stage breast cancers. HER2 downstream effectors include Src, thus, we aim to investigate the use of a HER2-specific monoclonal antibody positron emission tomography (PET) probe, 89Zr-trastuzumab, to monitor Src therapy via surrogate HER2 expression. We hypothesize that 89Zr-trastuzumab can be a surrogate imaging tool for monitoring Src treatment. 89Zr-trastuzumab was previously developed and has demonstrated excellent specificity for breast cancer. Dasatinib-treated HER2+ BT474 (IC50 ~ 1.3 μM), SK-BR-3 (IC50 ~ 5.5 µM), and JIMT-1 (IC50 ~ 8 μM) breast cancer cells lines have shown a negative correlation between treatment and HER2. We next conducted tumorigenic studies using athymic nu/nu mice bearing JIMT-1 or BT474 xenografts, which were treated for 7 or 14 days with dasatinib (75 mg/kg/day). At the end of each treatment, the tumors were subsequently imaged with 18F-FDG, and then followed by 89Zr-trastuzumab, 24 h later. Images were analyzed using AsiPro (show version here and decay-corrected to the time of injection. Tumor uptake values were measured by drawing volumes-of-interest, expressed as % injected dose per gram (%ID/g) of tissue on regions showing the most binding. 18F-FDG did not demonstrate a predictive response in both treated and placebo tumors, whereas, HER2 PET was able to show differential response in treated vs. control cohorts. In JIMT-1 mice imaged with 89Zr-trastuzumab, a two-fold difference (p < 0.01) was observed between untreated and both treated groups (8.0 ± 1.5 %ID/g, n= 7 vs. 7-day treated: 3.8 ± 1.5 %ID/g, n=4, and 14-day-treated: 4.5 ± 1.3 %ID/g, n= 4) mice imaged with 89Zr-trastuzumab. Confirmatory ex vivo western blots of JIMT-1 tumors have shown a decrease in HER2 as treatment time increases, with a decrease in p-Src (Y-416). In vivo studies with BT-474 xenografts are currently underway. Immunohistochemistry on excised tumors, as well as treatment on a metastatic patient-derived xenograft model is currently in progress. We have shown that HER2 PET can potentially be a surrogate marker of Src treatment. The findings from this study potentially afford a powerful tool to non-invasively detect and monitor changes in Src-targeted therapy in man at the early phases of treatment. Citation Format: Brooke N. McKnight, Nerissa T. Viola-Villegas. 89Zr-trastuzumab immunoPET imaging to monitor src status after treatment in HER2 breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2860. doi:10.1158/1538-7445.AM2017-2860