B-cell lymphoma patient-derived xenograft models enable drug discovery and are a platform for personalized therapy

Leo Zhang, Krystle Nomie, Hui Zhang, Taylor Bell, Lan Pham, Sabah Kadri, Jeremy Segal, Shaoying Li, Shouhao Zhou, David Santos, Shawana Richard, Shruti Sharma, Wendy Chen, Onyekachukwu Oriabure, Yang Liu, Shengjian Huang, Hui Guo, Zhihong Chen, Wenjing Tao, Carrie LiJack Wang, Bingliang Fang, Jacqueline Wang, Lei Li, Maria Badillo, Makhdum Ahmed, Selvi Thirumurthi, Steven Y. Huang, Yiping Shao, Laura Lam, Qing Yi, Y. Lynn Wang, Michael Wang*

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Purpose: Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma patient-derived xenograft (PDX) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options. Experimental Design: We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice. We subjected the PDX models to histopathologic and phenotypical examination, sequencing, and drug efficacy analysis. Primary and acquired resistance to ibrutinib, an oral covalent inhibitor of Bruton tyrosine kinase, were investigated to elucidate the mechanisms underlying ibrutinib resistance and to identify drug treatments to overcome resistance. Results: The PDXs maintained the same biological, histopathologic, and immunophenotypical features, retained similar genetic mutations, and produced comparable drug responses with the original patient tumors. In the acquired ibrutinib-resistant PDXs, PLC-g2, p65, and Src were downregulated; however, a PI3K signaling pathway member was upregulated. Inactivation of the PI3K pathway with the inhibitor idelalisib in combination with ibrutinib significantly inhibited the growth of the ibrutinib-resistant tumors. Furthermore, we used a PDX model derived from a clinically ibrutinib-relapsed patient to evaluate various therapeutic choices, ultimately eliminating the tumor cells in the patient's peripheral blood. Conclusions: Our results demonstrate that the B-cell lymphoma PDX model is an effective system to predict and personalize therapies and address therapeutic resistance in B-cell lymphoma patients.

Original languageEnglish (US)
Pages (from-to)4212-4223
Number of pages12
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Zhang, L., Nomie, K., Zhang, H., Bell, T., Pham, L., Kadri, S., Segal, J., Li, S., Zhou, S., Santos, D., Richard, S., Sharma, S., Chen, W., Oriabure, O., Liu, Y., Huang, S., Guo, H., Chen, Z., Tao, W., ... Wang, M. (2017). B-cell lymphoma patient-derived xenograft models enable drug discovery and are a platform for personalized therapy. Clinical Cancer Research, 23(15), 4212-4223. https://doi.org/10.1158/1078-0432.CCR-16-2703