title: Establishment of Patient-Derived Tumor Xenograft Models of Epithelial Ovarian Cancer for Preclinical Evaluation of Novel Therapeutics.
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 reproduciblein vivoassessment of intraperitoneal tumor burden by bioluminescence imaging (BLI). Plasma assays for CA125 and human LINE-1 were developed as secondary tests ofin vivodisease burden.Results:Fourteen clinically annotated and molecularly characterized luciferized ovarian PDX models were generated. Luciferized 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.Clin Cancer Res; 23(5); 1263-73. ©2016 AACR.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. joyce_liu@dfci.harvard.edu.
authors: Joyce F
authors: JF
authors: Liu
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Sangeetha
authors: S
authors: Palakurthi
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Qing
authors: Q
authors: Zeng
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Shan
authors: S
authors: Zhou
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Elena
authors: E
authors: Ivanova
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Wei
authors: W
authors: Huang
authors: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors: Ioannis K
authors: IK
authors: Zervantonakis
authors: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors: Laura M
authors: LM
authors: Selfors
authors: Department of Pathology, Children's Hospital Boston, Boston, Massachusetts.
authors: Yiping
authors: Y
authors: Shen
authors: Department of Laboratory Medicine, University of Washington, Seattle, Washington.
authors: Colin C
authors: CC
authors: Pritchard
authors: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors: Mei
authors: M
authors: Zheng
authors: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Vilmos
authors: V
authors: Adleff
authors: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Eniko
authors: E
authors: Papp
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Huiying
authors: H
authors: Piao
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Marian
authors: M
authors: Novak
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Susan
authors: S
authors: Fotheringham
authors: Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors: Gerburg M
authors: GM
authors: Wulf
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Jessie
authors: J
authors: English
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Paul T
authors: PT
authors: Kirschmeier
authors: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Victor E
authors: VE
authors: Velculescu
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Cloud
authors: C
authors: Paweletz
authors: Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Gordon B
authors: GB
authors: Mills
authors: Department of Genetics, Harvard Medical School, Boston, Massachusetts.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: David M
authors: DM
authors: Livingston
authors: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
authors: Joan S
authors: JS
authors: Brugge
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Ursula A
authors: UA
authors: Matulonis
authors: Department of Obstetrics and Gynecology, Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Ronny
authors: R
authors: Drapkin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001201:Ascites / Q000473:pathology; D018394:CA-125 Antigen / Q000097:blood; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D008565:Membrane Proteins / Q000097:blood; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000970:Antineoplastic Agents; D018394:CA-125 Antigen; C451759:MUC16 protein, human; D008565:Membrane Proteins