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Use of Ex Vivo Patient-Derived Tumor Organotypic Spheroids to Identify Combination Therapies for HER2 Mutant Non-Small Cell Lung Cancer.
Ivanova, Elena; Kuraguchi, Mari; Xu, Man; Portell, Andrew J; Taus, Luke; Diala, Irmina; Lalani, Alshad S; Choi, Jihyun; Chambers, Emily S; Li, Shuai; Liu, Shengwu; Chen, Ting; Barbie, Thanh U; Oxnard, Geoffrey R; Haworth, Jacob J; Wong, Kwok-Kin; Dahlberg, Suzanne E; Aref, Amir A; Barbie, David A; Bahcall, Magda; Paweletz, Cloud P; Jänne, Pasi A.
Afiliación
  • Ivanova E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Kuraguchi M; Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts.
  • Xu M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Portell AJ; Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts.
  • Taus L; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Diala I; Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts.
  • Lalani AS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Choi J; Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts.
  • Chambers ES; Belfer Center for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts.
  • Li S; Puma Biotechnology Inc., Los Angeles, California.
  • Liu S; Puma Biotechnology Inc., Los Angeles, California.
  • Chen T; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Barbie TU; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Oxnard GR; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Haworth JJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Wong KK; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Dahlberg SE; Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.
  • Aref AA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Barbie DA; Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
  • Bahcall M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Paweletz CP; Department of Medicine, Division of Hematology and Medical Oncology, New York University Langone Medical Center, New York, New York.
  • Jänne PA; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Clin Cancer Res ; 26(10): 2393-2403, 2020 05 15.
Article en En | MEDLINE | ID: mdl-32034078
PURPOSE: Evaluating drug responses using primary patient-derived cells ex vivo represents a potentially rapid and efficient approach to screening for new treatment approaches. Here, we sought to identify neratinib combinations in HER2 mutant non-small cell lung cancer (NSCLC) patient xenograft-derived organotypic spheroids (XDOTS) using a short-term ex vivo system. EXPERIMENTAL DESIGN: We generated two HER2-mutant NSCLC PDX models [DFCI359 (HER2 exon19 755_757LREdelinsRP) and DFCI315 (HER2 exon20 V777_G778insGSP)] and used the PDX tumors to generate XDOTS. Tumor spheroids were grown in a microfluidic device and treated ex vivo with neratinib-based drug combinations. Live/dead quantification was performed by dual-labeling deconvolution fluorescence microscopy. The most efficacious ex vivo combination was subsequently validated in vivo using the DFCI359 and DFCI315 PDXs and a HER2 YVMA genetically engineered mouse model. RESULTS: Both neratinib and afatinib, but not gefitinib, induced cell death in DFCI359 XDOTS. The combinations of neratinib/trastuzumab and neratinib/temsirolimus enhanced the therapeutic benefit of neratinib alone in DFCI315 and DFCI359. The combination of neratinib and trastuzumab in vivo was more effective compared with single-agent neratinib or trastuzumab and was associated with more robust inhibition of HER2 and downstream signaling. CONCLUSIONS: The XDOTS platform can be used to evaluate therapies and therapeutic combinations ex vivo using PDX tumors. This approach may accelerate the identification and clinical development of therapies for targets with no or few existing models and/or therapies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Carcinoma de Pulmón de Células no Pequeñas / Receptor ErbB-2 / Neoplasias Pulmonares / Mutación Límite: Animals / Female / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Carcinoma de Pulmón de Células no Pequeñas / Receptor ErbB-2 / Neoplasias Pulmonares / Mutación Límite: Animals / Female / Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos