Abstract
Preclinical evaluation of therapeutic agents against metastatic breast cancer require cell lines and animal models that recapitulate clinical metastatic breast cancer as much as possible. We have previously used cell lines derived from the neu-N transgenic model to investigate anti-neu targeting of metastatic breast cancer using an alpha-emitter labeled antibody reactive with the rat variant of HER2/neu expressed by the neu-N model. To investigate alpha-particle emitter targeting of metastatic breast cancer using clinically relevant, commercially available anti-HER2/neu antibodies, we have developed cell lines derived from primary tumors and lung metastases from HuHER2 transgenic mice. We extracted primary mammary gland tumors, isolated the epithelial breast cancer cells, and established seven different cell lines. We also established 2 different cell lines from spontaneous lung metastases and cell lines from a serial transplantation of tumor tissues in HuHER2 transgenic mice. HuHER2 protein was overexpressed in all of the established cell lines. The mRNA level of ER (estrogen receptor) and PR (progesterone receptor) was relatively low in the cell lines compared to normal mammary gland (MG). As EMT markers, the expression of E-Cadherin in the cell lines was downregulated while the expression of TWIST1 and Vimentin were upregulated, relative to MG. Furthermore, trastuzumab directly inhibited cellular viability. Biodistribution studies with 111In-DTPA-trastuzumab in HuHER2 cell tumor xenografts demonstrated specific targeting with a clinically relevant antibody. Collectively, these cell lines show all the hallmarks of highly aggressive, metastatic breast cancer and are being used to evaluate combination therapy with alpha-particle emitter labeled HER2/neu reactive antibodies.
Highlights
Current cancer treatment is largely ineffective against widely disseminated metastatic breast cancer
To investigate alpha-particle emitter targeting of metastatic breast cancer using clinically relevant, commercially available anti-HER2/ neu antibodies, we have developed cell lines derived from primary tumors and lung metastases from HuHER2 transgenic mice
In this work we demonstrated reactivity of HuHER2 transgenic mouse model-derived tumor cell lines with commercially available antibodies (e.g., trastuzumab (Herceptin®) and pertuzumab (Perjeta®)) that are clinically relevant and that have been used in patient therapy
Summary
Current cancer treatment is largely ineffective against widely disseminated metastatic breast cancer. Stage IV breast cancer is defined by distant and widely disseminated metastases, including to the liver. 1 in 5 patients with stage IV breast cancer survives for more than 5 years, and patients with liver metastases have a median survival of less than 6 months [1]. Over the past several years, we have utilized a metastatic breast cancer model to investigate targeted radiopharmaceutical therapy (RPT) with alpha-particle emitters (αRPT). Using syngeneically-derived cells from this model we showed that 213Bi-labeled anti–HER-2/neu mAb improved the survival of mice with extensive mammary carcinoma metastases [2]. We explored the efficiency of the murine HER2-targeted antibody modified to deliver the α-particle emitter 225Ac compared to the β-particle emitter 90Y, and found that 225Ac-labeled antibody significantly extended the survival in the neu-N mice with metastatic disease [4]. The murine HER2-targeted antibody used for these studies and the neu-N model, is not cross-reactive with the human HER2/neu receptor making the evaluation of clinically relevant HER2-targeted antibodies such as trastuzumab and pertuzumab, impossible
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