A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds

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From: Cell(Vol. 167, Issue 1)
Publisher: Elsevier B.V.
Document Type: Article
Length: 482 words

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To access, purchase, authenticate, or subscribe to the full-text of this article, please visit this link: http://dx.doi.org/10.1016/j.cell.2016.08.041 Byline: Alejandra Bruna (1,11), Oscar M. Rueda (1,11), Wendy Greenwood (1), Ankita Sati Batra (1), Maurizio Callari (1), Rajbir Nath Batra (1), Katherine Pogrebniak (1), Jose Sandoval (1), John W. Cassidy (1), Ana Tufegdzic-Vidakovic (1), Stephen-John Sammut (1), Linda Jones (1,2), Elena Provenzano (2), Richard Baird (1,2), Peter Eirew (3), James Hadfield (1), Matthew Eldridge (1), Anne McLaren-Douglas (4), Andrew Barthorpe (4), Howard Lightfoot (4), Mark J. O'Connor (5), Joe Gray (6), Javier Cortes (7), Jose Baselga (8), Elisabetta Marangoni (9), Alana L. Welm (10), Samuel Aparicio (3), Violeta Serra (7), Mathew J. Garnett (4), Carlos Caldas [carlos.caldas@cruk.cam.ac.uk] (1,2,12,*) Highlights * We developed a biobank of breast cancer patient-derived tumor xenografts (PDTXs) * PDTXs represent diverse molecular subtypes and retain intra-tumor heterogeneity * PDTX-derived tumor cells (PDTCs) were used for high-throughput drug testing * PDTXs/PDTCs are a robust platform for pre-clinical pharmacogenomic studies Summary The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape(http://caldaslab.cruk.cam.ac.uk/bcape)), including identification of biomarkers of response or resistance. Author Affiliation: (1) Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK (2) Cambridge Breast Unit, NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre at Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 2QQ, UK (3) Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada (4) Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK (5) DNA Damage Response Biology Area, Oncology IMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK (6) OHSU Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA (7) Vall d'Hebron Institute of Oncology, 08035 Barcelona, Spain (8) Human Oncology and Pathogenesis Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, NY 10065, USA (9) Translational Research Department, Institut Curie, 26 rue d'Ulm, Paris 75005, France (10) Huntsman Cancer Institute, Salt Lake City, UT 84112, USA * Corresponding author Article History: Received 5 February 2016; Revised 21 June 2016; Accepted 18 August 2016 (miscellaneous) Published: September 15, 2016 (footnote)11 Co-first author (footnote)12 Lead Contact

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Gale Document Number: GALE|A522260629