title: The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.
abstract: More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA; Center for Functional Cancer Epigenomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
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authors.affiliation: Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
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authors.lastname: Kallgren
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA; Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
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authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA; Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA; Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
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authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA; Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA; Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
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authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA; Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA; Center for Functional Cancer Epigenomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA; Center for Functional Cancer Epigenomics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.
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authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: dweinstock@partners.org.
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mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D019070:Cell Lineage; D005260:Female; D020869:Gene Expression Profiling; D016158:Genes, p53; D064593:Heterografts; D006801:Humans; D020407:Internet; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D007942:Leukemia, Experimental / Q000188:drug therapy; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D009368:Neoplasm Transplantation; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D020543:Proteome; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D011897:Random Allocation; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012107:Research Design; D014015:Tissue Banks; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007546:Isoquinolines; C000602644:NVP-CGM097; D009363:Neoplasm Proteins; D010879:Piperazines; D020543:Proteome; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2