Abstract 1205:In vivoanimal models with patient-derived tumor xenografts for better clinical prediction

More predictive in vivo animal tumor models are urgently needed to test efficacy of newly developed cancer therapies and predict clinical response. At SRI we have developed highly innovative and predictive models initiated with single tumor cells isolated from cancer patient specimens, including colon, lung, and breast tumor xenografts. These tumors propagated in immunocompromised mice recapitulate primary tumor heterogeneity as shown by histology. In our models, the tumor cells are implanted subcutaneously to evaluate inhibition of primary tumor, or at orthotopic sites to recapitulate advanced metastatic disease and analyze circulating tumor cells (CTCs) or disseminated tumor cells (DTCs). Tumor cells are also implanted in organs, e.g. kidney capsule, to mimic the vascularized tumor microenvironment or in the human skin graft to analyze the tumor interactions with human stroma and vasculature, and the effect of treatment on angiogenesis. The cellular suspension method offers several advantages over the widely employed tumor fragments, including the ability to assess the phenotype of tumor cell populations, tumorigenicity, and tumor initiating cells. Cells isolated from tumors of mice in control and treatment groups are mouse-lineage depleted prior to evaluation in a number of in vitro or ex vivo assays, including migration and invasion through extracellular matrix proteins. To determine whether treatment affects frequency of tumor initiating cells (TICs) and metastasis initiating cells (MICs), we will perform in vivo limiting dilution assay (LDA). Moreover, to evaluate the ability of our tumor models to induce angiogenesis we utilized the chicken embryo chorioallantoic membrane (CAM) assay and scored the vascularity of mouse lineage-depleted tumor cells using an established CAM scoring guide with 5 as the highest score and 0 as the lowest score. One patient derived ER- invasive ductal carcinoma breast cancer (SRI-B1) with high growth rate demonstrated strong pro-angiogenic activity, inducing blood vessels in the CAM assay with a score of 4 compared to 5 for a VEGF positive control and 0 of negative control. The high vascular density induced by SRI-B1 tumor cells correlated with in vivo metastatic dissemination to distant organs upon orthotopic implantation in NOD/SCID mice, suggesting that tumor models can be screened in the CAM assay to evaluate their metastatic potential. We plan to further use these models to test the anticancer activity of experimental therapies that target metastasis. Citation Format: Jun Li, Jessica Kalra, Dominic Dinh, Wan-ru Chao, Xiaohe Liu, Lidia Sambucetti, Lucia Beviglia. In vivo animal models with patient-derived tumor xenografts for better clinical prediction. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1205. doi:10.1158/1538-7445.AM2014-1205