Human Breast Cancer Tumor Models: Molecular Imaging of Drug Susceptibility and Dosing during HER2/neu-targeted Therapy

Abstract

Purpose:To use near-infrared (NIR) optical imaging to assess the therapeutic susceptibility and drug dosing of orthotopic human breast cancers implanted in mice treated with molecularly targeted therapy. Materials and Methods:This study was approved by the institutional animal care and use committee. Imaging probes were synthesized by conjugating the human epidermal growth factor receptor type 2 (HER2)-specific antibody trastuzumab with fluorescent dyes. In vitro probe binding was assessed with flow cytometry. HER2-normal and HER2-overexpressing human breast cancer cells were orthotopically implanted in nude mice. Intravital laser scanning fluorescence microscopy was used to evaluate the in vivo association of the probe with the tumor cells. Mice bearing 3-5-mm-diameter tumors were intravenously injected with 0.4 nmol of HER2 probe before or after treatment. A total of 123 mice were used for all in vivo tumor growth and imaging experiments. Tumor fluorescence intensity was assessed, and standard fluorescence values were determined. Statistical significance was determined by performing standard analysis of variance across the imaging cohorts. Results:HER2 probe enabled differentiation between HER2-normal and HER2-overexpressing human breast cancer cells in vitro and in vivo, with binding levels correlating with tumor trastuzumab susceptibility. Serial imaging before and during trastuzumab therapy revealed a significant reduction (P Ͻ .05) in probe binding with treatment and thus provided early evidence of successful HER2 inhibition days before the overall reduction in tumor growth was apparent. Conclusion:NIR imaging with HER2-specific imaging probes enables evaluation of the therapeutic susceptibility of human mammary tumors and of drug dosing during HER2-targeted therapy with trastuzumab. This approach, combined with tomographic imaging techniques, has potential in the clinical setting for determining patient eligibility for and adequate drug dosing in molecularly targeted cancer therapies. RSNA, 2008

Effective Therapeutic Targeting of the Overexpressed HER-2 Receptor in a Highly Metastatic Orthotopic Model of Esophageal Carcinoma

“…Orthotopic models have previously been successfully used for evaluation of trastuzumab therapy for other tumor types (40)(41)(42). The efficacy of trastuzumab on HER-2-positive breast cancer has been shown in vitro and in orthotopic models as well as clinically in breast cancer patients (6)(7)(8)(9).…”

Targeting EGFR and HER2 for Molecular Imaging of Cancer

“…Research has also demonstrated that fluorescent dye-labeled trastuzumab enabled differentiation between breast cancer cells expressing high and low levels of HER2. Serial imaging before and during trastuzumab therapy revealed a significant reduction in probe uptake with treatment (Gee et al, 2008). Trastuzumab was also used to mediate the cellular internalization of pH-activatable fluorephores.…”

Towards detecting the HER-2 receptor and metabolic changes induced by HER-2-targeted therapies using medical imaging

“…Fluorescent detection techniques using fluorescencelabelled trastuzumab [39] and HER-2 Affibody [40] have also been applied to the detection of tumour response to trastuzumab therapy. Gee et al [39] administered trastuzumab conjugated to the NIR (near infrared) dye CY5.5 to nude mice bearing xenografts derived from breast tumour cell lines expressing high and normal levels of HER-2.…”

“…Gee et al [39] administered trastuzumab conjugated to the NIR (near infrared) dye CY5.5 to nude mice bearing xenografts derived from breast tumour cell lines expressing high and normal levels of HER-2. They showed that fluorescence detected by a whole-body multichannel imaging system on the surface of mice above the tumours corresponded with HER-2 expression.…”

“…In a further study of HER-2-overexpressing cells from xenografts, Gee et al [39] also found that the fluorescence from a further administration of tracer 14 days after initiating trastuzumab treatment was significantly lower than pre-treatment fluorescence levels, so predicting treatment response. They did not comment, however, on the potential interference from the non-labelled therapeutic trastuzumab that may have been present in the bloodstream during the follow-up scan but not during the pre-treatment scan.…”