title: B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy.
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-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.
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Leo
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Krystle
authors.initials: K
authors.lastname: Nomie
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Taylor
authors.initials: T
authors.lastname: Bell
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lan
authors.initials: L
authors.lastname: Pham
authors.affiliation: Divison of Genomic and Molecular Pathology, Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Sabah
authors.initials: S
authors.lastname: Kadri
authors.affiliation: Divison of Genomic and Molecular Pathology, Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Segal
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shaoying
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shouhao
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Santos
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shawana
authors.initials: S
authors.lastname: Richard
authors.affiliation: Divison of Genomic and Molecular Pathology, Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wendy
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Onyekachukwu
authors.initials: O
authors.lastname: Oriabure
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shengjian
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hui
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Tao
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carrie
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jack
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Thoracic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Bingliang
authors.initials: B
authors.lastname: Fang
authors.affiliation: Department of Thoracic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Maria
authors.initials: M
authors.lastname: Badillo
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Makhdum
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Gastroenterology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Selvi
authors.initials: S
authors.lastname: Thirumurthi
authors.affiliation: Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Laura
authors.initials: L
authors.lastname: Lam
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.affiliation: Divison of Genomic and Molecular Pathology, Department of Pathology, The University of Chicago, Chicago, Illinois.
authors.forename: Y Lynn
authors.initials: YL
authors.lastname: Wang
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. miwang@mdanderson.org.|Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018442:Lymphoma, B-Cell, Marginal Zone / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010880:Piperidines; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000225:Adenine; D000077329:Agammaglobulinaemia Tyrosine Kinase; D019869:Phosphatidylinositol 3-Kinases; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; C000625951:Btk protein, mouse