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1.
Acta Neuropathol ; 140(2): 209-225, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32519082

RESUMO

Pediatric brain tumors are the leading cause of cancer-related death in children. Patient-derived orthotopic xenografts (PDOX) of childhood brain tumors have recently emerged as a biologically faithful vehicle for testing novel and more effective therapies. Herein, we provide the histopathological and molecular analysis of 37 novel PDOX models generated from pediatric brain tumor patients treated at St. Jude Children's Research Hospital. Using a combination of histopathology, whole-genome and whole-exome sequencing, RNA-sequencing, and DNA methylation arrays, we demonstrate the overall fidelity and inter-tumoral molecular heterogeneity of pediatric brain tumor PDOX models. These models represent frequent as well as rare childhood brain tumor entities, including medulloblastoma, ependymoma, atypical teratoid rhabdoid tumor, and embryonal tumor with multi-layer rosettes. PDOX models will be valuable platforms for evaluating novel therapies and conducting pre-clinical trials to accelerate progress in the treatment of brain tumors in children. All described PDOX models and associated datasets can be explored using an interactive web-based portal and will be made freely available to the research community upon request.


Assuntos
Neoplasias Encefálicas , Modelos Animais de Doenças , Xenoenxertos , Animais , Criança , Humanos , Camundongos
2.
Neuro Oncol ; 23(6): 999-1011, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33320196

RESUMO

BACKGROUND: Immunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class I expression is unknown, which is critical for tumor recognition by conventional αßTCR T cells. METHODS: We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of 5 CAR targets (B7-H3, GD2, IL-13Rα2, EphA2, and HER2), and HLA class I. In addition, we generated B7-H3-CAR T cells and evaluated their antitumor activity in vitro and in vivo. RESULTS: We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL-13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage. CONCLUSIONS: Our study highlights the importance of studying target antigen and HLA class I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.


Assuntos
Neoplasias Encefálicas , Receptores de Antígenos Quiméricos , Animais , Antígenos de Superfície , Antígenos B7 , Neoplasias Encefálicas/terapia , Criança , Humanos , Camundongos , Linfócitos T , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nat Commun ; 12(1): 4089, 2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215733

RESUMO

Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. Here we report establishment of 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulate histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and include rare subgroups not well-represented by existing models. We deploy 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predict variable in vivo response to PI3K/mTOR and MEK pathway inhibitors. These unique new models and an online interactive data portal for exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.


Assuntos
Heterogeneidade Genética/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/genética , Animais , Neoplasias Encefálicas , Linhagem Celular Tumoral , Proliferação de Células , Criança , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Invest New Drugs ; 25(4): 285-95, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17384918

RESUMO

OBJECTIVE: ABT-751 is a novel antimitotic agent that binds tubulin at the colchicine binding site. ABT-751 is undergoing Phase I trials in children, but has not been evaluated against a range of pediatric tumor models in vivo. MATERIALS AND METHODS: ABT-751 was evaluated against 27 subcutaneously implanted xenograft models of childhood cancer including neuroblastoma [4], osteosarcoma [4], Ewing sarcoma [2] rhabdomyosarcoma [8], medulloblastoma [1] and eight kidney cancer lines (six Wilms tumors, two rhabdoid). ABT-751 was administered at 100 mg/kg P.O. on a schedule of 5 days on, 5 days off, 5 days on, repeating the cycle at 21 days. Tumor diameters were measured at 7 day intervals for a period of 12 weeks. Three measures of antitumor activity were used: (1) clinical response criteria [e.g., partial response (PR), complete response (CR), etc.]; (2) treated to control (T/C) tumor volume at day 21; and (3) a time to event measure based on the median event free survival (EFS) of treated and control lines. RESULTS: ABT-751 induced regression in 4 of 25 models (16%) including models of neuroblastoma that are refractory to vincristine and paclitaxel. Other regressions occurred in rhabdomyosarcoma and Wilms tumor models. ABT-751 significantly increased event free survival (EFS > 2.0) in eight models (33%) in addition to those with objective responses. CONCLUSIONS: ABT-751 demonstrated intermediate activity against this tumor panel. Neuroblastoma models appear somewhat more sensitive to this agent, with objective regressions also in rhabdomyosarcoma and Wilms tumor. ABT-751 was also active in several tumor lines intrinsically refractory to vincristine or paclitaxel.


Assuntos
Antimitóticos/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Sulfonamidas/uso terapêutico , Animais , Antimitóticos/administração & dosagem , Linhagem Celular Tumoral , Criança , Feminino , Humanos , Camundongos , Camundongos SCID , Pediatria , Sulfonamidas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
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