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

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Abstract

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.

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Acknowledgements

We thank our patient advocate Mrs. Cathy Greene. We thank Dr. Shunqiang Li of Washington University for the PDXs. We thank Brigham Young University DNA Sequencing Center for RNA-sequencing services and Virginia Commonwealth University Massey Cancer Center (MCC) core facilities; Mouse Models Core and FACS Core. Grant support: METAvivor (JCH), MCC pilot project (JCH, MGD). Services and products in support of the research project were generated by the VCU MCC Cancer Mouse Model Shared Resource, supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059. ALO was supported by CTSA award No. UL1TR000058 from the National Center for Advancing Translational Sciences.

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Authors and Affiliations

  1. Department of Pathology, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Tia H. Turner, Mohammad A. Alzubi, Sahib S. Sohal & J. Chuck Harrell

  2. Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Tia H. Turner, Amy L. Olex & J. Chuck Harrell

  3. Integrative Life Sciences Doctoral Program, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Mohammad A. Alzubi & J. Chuck Harrell

  4. Department of Biostatistics, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Mikhail G. Dozmorov

  5. Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA

    J. Chuck Harrell

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  1. Tia H. Turner
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Contributions

THT designed and performed the experiments, and wrote the manuscript; MAA assisted with in vivo studies and edited the manuscript; SSS assisted with in vivo studies and IHC experiments; ALO performed RNA-seq analyses and edited the manuscript; MGD performed RNA-seq analyses, statistical analyses, and edited the manuscript. JCH designed the experiments, supervised the studies, and wrote the manuscript.

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Correspondence to J. Chuck Harrell.

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Turner, T.H., Alzubi, M.A., Sohal, S.S. et al. Characterizing the efficacy of cancer therapeutics in patient-derived xenograft models of metastatic breast cancer. Breast Cancer Res Treat 170, 221–234 (2018). https://doi.org/10.1007/s10549-018-4748-4

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