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

Research output: Contribution to journalArticle

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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

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B-Cell Lymphoma
Drug Discovery
Heterografts
Therapeutics
Neoplasms
Phosphatidylinositol 3-Kinases
Pharmaceutical Preparations
Mantle-Cell Lymphoma
Follicular Lymphoma
Burkitt Lymphoma
PCI 32765
Lymphoma
B-Lymphocytes
Research Design
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Zhang, Leo ; Nomie, Krystle ; Zhang, Hui ; Bell, Taylor ; Pham, Lan ; Kadri, Sabah ; Segal, Jeremy ; Li, Shaoying ; Zhou, Shouhao ; Santos, David ; Richard, Shawana ; Sharma, Shruti ; Chen, Wendy ; Oriabure, Onyekachukwu ; Liu, Yang ; Huang, Shengjian ; Guo, Hui ; Chen, Zhihong ; Tao, Wenjing ; Li, Carrie ; Wang, Jack ; Fang, Bingliang ; Wang, Jacqueline ; Li, Lei ; Badillo, Maria ; Ahmed, Makhdum ; Thirumurthi, Selvi ; Huang, Steven Y. ; Shao, Yiping ; Lam, Laura ; Yi, Qing ; Wang, Y. Lynn ; Wang, Michael. / B-cell lymphoma patient-derived xenograft models enable drug discovery and are a platform for personalized therapy. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4212-4223.
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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.",
author = "Leo Zhang and Krystle Nomie and Hui Zhang and Taylor Bell and Lan Pham and Sabah Kadri and Jeremy Segal and Shaoying Li and Shouhao Zhou and David Santos and Shawana Richard and Shruti Sharma and Wendy Chen and Onyekachukwu Oriabure and Yang Liu and Shengjian Huang and Hui Guo and Zhihong Chen and Wenjing Tao and Carrie Li and Jack Wang and Bingliang Fang and Jacqueline Wang and Lei Li and Maria Badillo and Makhdum Ahmed and Selvi Thirumurthi and Huang, {Steven Y.} and Yiping Shao and Laura Lam and Qing Yi and Wang, {Y. Lynn} and Michael Wang",
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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, Li, C, Wang, J, Fang, B, Wang, J, Li, L, Badillo, M, Ahmed, M, Thirumurthi, S, Huang, SY, Shao, Y, Lam, L, Yi, Q, Wang, YL & Wang, M 2017, 'B-cell lymphoma patient-derived xenograft models enable drug discovery and are a platform for personalized therapy', Clinical Cancer Research, vol. 23, no. 15, pp. 4212-4223. https://doi.org/10.1158/1078-0432.CCR-16-2703

B-cell lymphoma patient-derived xenograft models enable drug discovery and are a platform for personalized therapy. / Zhang, Leo; Nomie, Krystle; Zhang, Hui; Bell, Taylor; Pham, Lan; Kadri, Sabah; Segal, Jeremy; Li, Shaoying; Zhou, Shouhao; Santos, David; Richard, Shawana; Sharma, Shruti; Chen, Wendy; Oriabure, Onyekachukwu; Liu, Yang; Huang, Shengjian; Guo, Hui; Chen, Zhihong; Tao, Wenjing; Li, Carrie; Wang, Jack; Fang, Bingliang; Wang, Jacqueline; Li, Lei; Badillo, Maria; Ahmed, Makhdum; Thirumurthi, Selvi; Huang, Steven Y.; Shao, Yiping; Lam, Laura; Yi, Qing; Wang, Y. Lynn; Wang, Michael.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4212-4223.

Research output: Contribution to journalArticle

TY - JOUR

T1 - B-cell lymphoma patient-derived xenograft models enable drug discovery and are a platform for personalized therapy

AU - Zhang, Leo

AU - Nomie, Krystle

AU - Zhang, Hui

AU - Bell, Taylor

AU - Pham, Lan

AU - Kadri, Sabah

AU - Segal, Jeremy

AU - Li, Shaoying

AU - Zhou, Shouhao

AU - Santos, David

AU - Richard, Shawana

AU - Sharma, Shruti

AU - Chen, Wendy

AU - Oriabure, Onyekachukwu

AU - Liu, Yang

AU - Huang, Shengjian

AU - Guo, Hui

AU - Chen, Zhihong

AU - Tao, Wenjing

AU - Li, Carrie

AU - Wang, Jack

AU - Fang, Bingliang

AU - Wang, Jacqueline

AU - Li, Lei

AU - Badillo, Maria

AU - Ahmed, Makhdum

AU - Thirumurthi, Selvi

AU - Huang, Steven Y.

AU - Shao, Yiping

AU - Lam, Laura

AU - Yi, Qing

AU - Wang, Y. Lynn

AU - Wang, Michael

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

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U2 - 10.1158/1078-0432.CCR-16-2703

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