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

Drapkin, B. J., George, J., Christensen, C. L., Mino-Kenudson, M., Dries, R., Sundaresan, T., et al. (2018). Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts. Cancer Discovery, 8(5), 600-615. doi:10.1158/2159-8290.CD-17-0935.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-740E-C Version Permalink: http://hdl.handle.net/21.11116/0000-0003-740F-B
Genre: Journal Article

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© 2018 American Association for Cancer Research
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 Creators:
Drapkin, B. J., Author
George, J., Author
Christensen, C. L., Author
Mino-Kenudson, M., Author
Dries, R., Author
Sundaresan, T., Author
Phat, S., Author
Myers, D. T., Author
Zhong, J., Author
Igo, P., Author
Hazar-Rethinam, M. H., Author
Licausi, J. A., Author
Gomez-Caraballo, M., Author
Kem, M., Author
Jani, K. N., Author
Azimi, R., Author
Abedpour, N., Author
Menon, R., Author
Lakis, S., Author
Heist, R. S., Author
Büttner, R., AuthorHaas, S.1, Author              Sequist, L. V., AuthorShaw, A. T., AuthorWong, K. K., AuthorHata, A. N., AuthorToner, M., AuthorMaheswaran, S., AuthorHaber, D. A., AuthorPeifer, M., AuthorDyson, N., AuthorThomas, R. K., AuthorFarago, A. F., Author more..
Affiliations:
1Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              

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 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-naive 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. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 517.

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Language(s): eng - English
 Dates: 2018-02-262018-05
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1158/2159-8290.CD-17-0935
ISSN: 2159-8290 (Electronic)2159-8274 (Print)
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Title: Cancer Discovery
Source Genre: Journal
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Publ. Info: Philadelphia, PA : American Association for Cancer Research
Pages: - Volume / Issue: 8 (5) Sequence Number: - Start / End Page: 600 - 615 Identifier: -