期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 188, 期 5, 页码 1120-1131出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2018.01.019
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资金
- Canadian Institutes of Health Research [CIHR-MOP-191992]
- Canadian Cancer Society Research Institute Terry Fox Program [020003]
- Samuel Waxman Cancer Research Foundation
- Ontario Ministry of Health and Long Term Care
- Princess Margaret Cancer Foundation
- Canadian Institutes for Health Research [CIHR-CGS-200710MDR]
- J.W. Knox Ritchie Research Award
- Kristi Piia Callum Memorial Fund in Ovarian Cancer Research
- Teresina Florio Graduate Scholarship in Cancer Research
- Thomas G. Ryley Clinical Investigators Award
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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