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
N1 - ©2017 American Association for Cancer Research.
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-γ2, 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. Clin Cancer Res; 23(15); 4212-23. ©2017 AACR.
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-γ2, 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. Clin Cancer Res; 23(15); 4212-23. ©2017 AACR.
KW - Animals
KW - Burkitt Lymphoma/drug therapy
KW - Disease Models, Animal
KW - Drug Discovery
KW - Drug Resistance, Neoplasm/genetics
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Humans
KW - Lymphoma, B-Cell, Marginal Zone/drug therapy
KW - Lymphoma, Follicular/drug therapy
KW - Lymphoma, Large B-Cell, Diffuse/classification
KW - Lymphoma, Mantle-Cell/drug therapy
KW - Mice
KW - Phosphatidylinositol 3-Kinases/genetics
KW - Precision Medicine
KW - Protein Kinase Inhibitors/administration & dosage
KW - Protein-Tyrosine Kinases/genetics
KW - Pyrazoles/administration & dosage
KW - Pyrimidines/administration & dosage
KW - Signal Transduction/drug effects
KW - Xenograft Model Antitumor Assays
U2 - 10.1158/1078-0432.CCR-16-2703
DO - 10.1158/1078-0432.CCR-16-2703
M3 - Article
C2 - 28348046
SN - 1078-0432
VL - 23
SP - 4212
EP - 4223
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 15
ER -