Characterizing the efficacy of cancer therapeutics in patient-derived xenograft models of metastatic breast cancer

• Published in: Breast cancer research and treatment 2018-07, Vol.170 (2), p.221-234
• Main Authors: Turner, Tia H., Alzubi, Mohammad A., Sohal, Sahib S., Olex, Amy L., Dozmorov, Mikhail G., Harrell, J. Chuck
• Format: Article
• Language: English
• Subjects: Animal models; Bortezomib; Breast cancer; Cancer metastasis; Cancer patients; Cancer research; Cancer therapies; Carboplatin; Cell culture; Chemotherapy; Cyclophosphamide; Cytokeratin; Cytotoxicity; Dacarbazine; Gene expression; Keratin; Liver; Mammary gland; Medicine; Medicine & Public Health; Metastases; Metastasis; Oncology; Preclinical Study; Ribonucleic acid; RNA; Tumor cells; Tumors; Vimentin; Xenografts
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-018-4748-4

Purpose Basal-like breast cancers are aggressive and often metastasize to vital organs. Treatment is largely limited to chemotherapy. This study aims to characterize the efficacy of cancer therapeutics in vitro and in vivo within the primary tumor and metastatic setting, using patient-derived xenograft (PDX) models. Methods We employed two basal-like, triple-negative PDX models, WHIM2 and WHIM30. PDX cells, obtained from mammary tumors grown in mice, were treated with twelve cancer therapeutics to evaluate their cytotoxicity in vitro. Four of the effective drugs—carboplatin, cyclophosphamide, bortezomib, and dacarbazine—were tested in vivo for their efficacy in treating mammary tumors, and metastases generated by intracardiac injection of tumor cells. Results RNA sequencing showed that global gene expression of PDX cells grown in the mammary gland was similar to those tested in culture. In vitro, carboplatin was cytotoxic to WHIM30 but not WHIM2, whereas bortezomib, dacarbazine, and cyclophosphamide were cytotoxic to both lines. Yet, these drugs were ineffective in treating both primary and metastatic WHIM2 tumors in vivo. Carboplatin and cyclophosphamide were effective in treating WHIM30 mammary tumors and reducing metastatic burden in the brain, liver, and lungs. WHIM2 and WHIM30 metastases showed distinct patterns of cytokeratin and vimentin expression, regardless of treatment, suggesting that different tumor cell subpopulations may preferentially seed in different organs. Conclusions This study highlights the utility of PDX models for studying the efficacy of therapeutics in reducing metastatic burden in specific organs. The differential treatment responses between two PDX models of the same intrinsic subtype, in both the primary and metastatic setting, recapitulates the challenges faced in treating cancer patients and highlights the need for combination therapies and predictive biomarkers.