Imaging and biodistribution of Her2/neu expression in non-small cell lung cancer xenografts with 64Cu-labeled trastuzumab PET (original) (raw)

Non-small cell lung carcinomas (NSCLC) overexpress the Her2/ /neu gene in approximately 59% of cases. Trastuzumab, a humanized monoclonal antibody, interferes with Her2 signaling and is approved for the treatment of Her2/ /neu overexpressing breast cancer. However, its therapeutic use in Her2/ /neu overexpressing NSCLC remains obscure. The present study aimed to determine the role of 64 Cu-labeled trastuzumab positron emission tomography (PET) for non-invasive imaging of Her2/ /neu expression in NSCLC. Trastuzumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with 64 Cu. The molecular specificity of DOTA-trastuzumab was determined in NSCLC cell lines with Her2/ /neu overexpression (NCI-H2170) and negative expression (NCI-H520). Imaging of Her2/ /neu expression was performed in NCI-H2170 tumor-bearing mice with 64 Cu-DOTA-trastuzumab PET and 64 Cu-DOTA-IgG. In vitro studies revealed specific binding of DOTA-trastuzumab in the Her2/ /neu positive NCI-H2170 cells, while no binding was seen in the Her2/ /neu negative NCI-H520 cell line. Biodistribution and PET studies revealed a significantly high accumulation of 64 Cu-DOTA-trastuzumab in the Her2/ /neu overexpressing NCI-H2170 tumor at 24 and 48 h post-injection (21.4 ± 1.4% and 23.2 ± 5.1% injection dose/ /gram (% ID/g), respectively). PET imaging of Her2/ / neu negative NCI-H520 tumors showed much less uptake of 64 Cu-DOTA-trastuzumab (4.0% ID/g). The NCI-H2170 tumor uptake of 64 Cu-DOTA-trastuzumab was significantly higher than that of 64 Cu-DOTA-IgG (P < 0.0001). 64 Cu-DOTA-trastuzumab showed a very clear image of a Her2/ /neu positive tumor and appeared to be effective as a PET tracer for imaging of Her2/neu gene expression in NSCLC, suggesting its potential clinical use for identifying patients that might benefit from trastuzumab-based therapy. (Cancer Sci 2010; 101: 1045-1050 L ung cancer is one of the world's leading causes of death, with a 5-year survival rate of less than 10%. (1) Activation of ras genes and human epidermal growth factor receptor 2 (Her2/neu) genes is encountered in subpopulations of non-small cell lung carcinoma (NSCLC) patients and has been linked to shortened survival. Overexpression of the Her2/neu gene is closely associated with intrinsic multiple drug resistance in NSCLC cell lines. (2) Her2/neu is a transmembrane tyrosine kinase belonging to the surface receptor family. It does not bind ligand but instead acts as a preferred heterodimerization partner for ligand-activated sibling members to amplify mitotic signaling. (3) Trastuzumab, a humanized monoclonal antibody that targets Her2/neu, inhibits neoplastic cell proliferation both in vitro and in vivo. (4) In breast cancer, overexpression of Her2/neu is seen in 40% of cases, and its activation follows heterodimerization with a member of the EGFR family and triggers important biological effects such as proliferation, migration and differenti-ation. (5) Trastuzumab significantly increases the survival of patients with advanced metastatic breast cancer. Overexpression of Her2/neu is reported in up to 59% of cases of NSCLC and the 2+/3+ overexpression rate is 5-20% in adenocarcinomas. (8-10) As in breast cancer, studies have suggested that the overexpression of Her2/neu in NSCLC is associated with a worse prognosis than negative expression of Her2/ neu. The role of trastuzumab targeting Her2/neu expression in the NSCLC has been largely marginalized. Even though NSCLC is usually chemoresistant, the synergistic effect between trastuzumab and chemotherapeutic agents was found to be greater in Her2/neu positive NSCLC than in breast cancer cell lines. NSCLC patients with Her2/neu overexpression (3+) in immunohistochemistry (IHC) had better survival when treated with trastuzumab-based therapy than the overall population, but only a small percentage of patients benefited. (10) The marked variation in functional anatomy and pathophysiology within human tumors and within individual patients may account for the high variability of responses observed in patients.