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Am J Pathol. 2018 May;188(5):1120-1131. doi: 10.1016/j.ajpath.2018.01.019. Epub 2018 Feb 16.

A Genomically Characterized Collection of High-Grade Serous Ovarian Cancer Xenografts for Preclinical Testing.

Author information

1
Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; Department of Gynecologic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
3
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
4
Department of Pathology, University Health Network, Toronto, Ontario, Canada.
5
Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Gynecologic Oncology, University Health Network, Toronto, Ontario, Canada.
6
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York. Electronic address: benjamin.neel@nyumc.org.

Abstract

High-grade serous ovarian cancer (HGSC) is the leading cause of morbidity and mortality from gynecologic malignant tumors. Overall survival remains low because of the nearly ubiquitous emergence of platinum resistance and the paucity of effective next-line treatments. Current cell culture-based models show limited similarity to HGSC and are therefore unreliable predictive models for preclinical evaluation of investigational drugs. This deficiency could help explain the low overall rate of successful drug development and the decades of largely unchanged approaches to HGSC treatment. We used gene expression, copy number variation, and exome sequencing analyses to credential HGSC patient-derived xenografts (PDXs) as effective preclinical models that recapitulate the features of human HGSC. Mice bearing PDXs were also treated with standard-of-care carboplatin therapy. PDXs showed similar sensitivity to carboplatin as the patient's tumor at the time of sampling. PDXs also recapitulated the diversity of genomic alterations (copy number variation and mutation profiles) previously described in large data sets that profiled HGSC. Furthermore, mRNA profiling showed that the PDXs represent all HGSC subtypes with the exception of the immunoreactive group. Credentialing of PDX models of HGSC should aid progress in HGSC research by providing improved preclinical models of HGSC that can be used to test novel targets and more accurately evaluate their likelihood of success.

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