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Cancer Discov. 2018 May;8(5):600-615. doi: 10.1158/2159-8290.CD-17-0935. Epub 2018 Feb 26.

Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts.

Author information

1
Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
2
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
3
Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
5
Harvard Medical School, Boston, Massachusetts.
6
Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
7
NEO New Oncology GmbH, Cologne, Germany.
8
Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
9
Department of Pathology, University Hospital Cologne, Cologne, Germany.
10
Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, Berlin, Germany.
11
Department of Hematology and Oncology, New York University Langone Medical School, New York, New York.
12
Center for Engineering in Medicine, Massachusetts General Hospital, Boston, Massachusetts.
13
Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
14
Shriners Hospital for Children, Boston, Massachusetts.
15
Howard Hughes Medical Institute, Chevy Chase, Maryland.
16
Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany. afarago@partners.org roman.thomas@uni-koeln.de.
17
German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany.
18
Massachusetts General Hospital Cancer Center, Boston, Massachusetts. afarago@partners.org roman.thomas@uni-koeln.de.

Abstract

Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.Significance: Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. Cancer Discov; 8(5); 600-15. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517.

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