Establishment of patient-derived tumor xenograft models of epithelial ovarian cancer for preclinical evaluation of novel therapeutics

Joyce F. Liu, Sangeetha Palakurthi, Qing Zeng, Shan Zhou, Elena Ivanova, Wei Huang, Ioannis K. Zervantonakis, Laura M. Selfors, Yiping Shen, Colin C. Pritchard, Mei Zheng, Vilmos Adleff, Eniko Papp, Huiying Piao, Marian Novak, Susan Fotheringham, Gerburg M. Wulf, Jessie English, Paul T. Kirschmeier, Victor E. VelculescuCloud Paweletz, Gordon B. Mills, David M. Livingston, Joan S. Brugge, Ursula A. Matulonis, Ronny Drapkin

    Research output: Contribution to journalArticle

    29 Scopus citations

    Abstract

    Purpose: Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States, with high rates of recurrence and eventual resistance to cytotoxic chemotherapy. Model systems that allow for accurate and reproducible target discovery and validation are needed to support further drug development in this disease. Experimental Design: Clinically annotated patient-derived xenograft (PDX) models were generated from tumor cells isolated from the ascites or pleural fluid of patients undergoing clinical procedures. Models were characterized by IHC and by molecular analyses. Each PDX was luciferized to allow for reproducible in vivo assessment of intraperitoneal tumor burden by bioluminescence imaging (BLI). Plasma assays for CA125 and human LINE-1 were developed as secondary tests of in vivo disease burden. Results: Fourteen clinically annotated and molecularly characterized luciferized ovarian PDX models were generated. Luci-ferized PDX models retain fidelity to both the nonluciferized PDX and the original patient tumor, as demonstrated by IHC, array CGH, and targeted and whole-exome sequencing analyses. Models demonstrated diversity in specific genetic alterations and activation of PI3K signaling pathway members. Response of luciferized PDX models to standard-of-care therapy could be reproducibly monitored by BLI or plasma markers. Conclusions: We describe the establishment of a collection of 14 clinically annotated and molecularly characterized luciferized ovarian PDX models in which orthotopic tumor burden in the intraperitoneal space can be followed by standard and reproducible methods. This collection is well suited as a platform for proof-of-concept efficacy and biomarker studies and for validation of novel therapeutic strategies in ovarian cancer.

    Original languageEnglish (US)
    Pages (from-to)1263-1273
    Number of pages11
    JournalClinical Cancer Research
    Volume23
    Issue number5
    DOIs
    StatePublished - Mar 1 2017

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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    Liu, J. F., Palakurthi, S., Zeng, Q., Zhou, S., Ivanova, E., Huang, W., Zervantonakis, I. K., Selfors, L. M., Shen, Y., Pritchard, C. C., Zheng, M., Adleff, V., Papp, E., Piao, H., Novak, M., Fotheringham, S., Wulf, G. M., English, J., Kirschmeier, P. T., ... Drapkin, R. (2017). Establishment of patient-derived tumor xenograft models of epithelial ovarian cancer for preclinical evaluation of novel therapeutics. Clinical Cancer Research, 23(5), 1263-1273. https://doi.org/10.1158/1078-0432.CCR-16-1237