Novel Stably Transplantable Xenograft Models of Human Breast Cancer for Evaluation of Experimental Therapeutics.

Abstract

Abstract In translational breast cancer research, our ability to evaluate clinical responses of human tumors to new therapeutic agents is severely limited experimentally. For example, it is not possible to evaluate the response of a single tumor to multiple candidate therapeutic agents. Conversely, the limited number of well-characterized in vivo preclinical human tumor models currently available precludes evaluation of multiple clinically relevant tumors with candidate therapeutic agents. These limitations severely impinge on our ability to develop and test novel therapeutic agents, particularly those that may target tumor-initiating “cancer stem cells”, which are relatively resistant to chemotherapy and radiation and may be responsible for disease recurrence and metastases.Historically, in vivo experimental therapeutic research has relied on either genetically engineered animal models, or “xenograft” transplantation models in which established human cancer cell lines are transplanted into immunocompromised host mice. However, each type of model has significant limitations. We sought to circumvent some of these limitations by propagating a cohort of human tumors as stably transplantable xenograft tissue lines grown in the absence of engineered or immortalized fibroblasts by transplanting clinical biopsies directly into the mammary fat pad of SCID/Beige immunocompromised mice (lacking B-cell, T-cell, and NK cell function) without intervening culture in vitro.Thus far, we have established 13 independent stably transplantable xenograft lines representing nine “triple-negative” (ER-PR-HER2-), two HER2+, and two ER+ breast cancers. Established xenograft lines show phenotypic similarity to the primary tumor with respect to histology and gene expression. Xenografts are being characterized genetically by whole genome sequencing as well as for the diversity of tumor-initiating cell types present. These models are proving useful for the evaluation of experimental therapeutics for their ability to inhibit tumor growth, and for their ability to target the subset cancer cells capable of regenerating tumors upon transplantation, with the goals of overcoming chemoresistance, preventing disease recurrence, and eliminating metastases. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1159.