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 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. 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: 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 Velculescu, Cloud Paweletz, Gordon B Mills, David M Livingston, Joan S Brugge, Ursula A Matulonis, Ronny Drapkin
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 5 Pg. 1263-1273 (Mar 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 27573169 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• CA-125 Antigen
• MUC16 protein, human
• Membrane Proteins

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Ascites (pathology)
• CA-125 Antigen (blood)
• Carcinoma, Ovarian Epithelial
• Cell Line, Tumor
• Disease Models, Animal
• Humans
• Long Interspersed Nucleotide Elements (genetics)
• Membrane Proteins (blood)
• Mice
• Neoplasms, Glandular and Epithelial (blood, drug therapy, genetics, pathology)
• Ovarian Neoplasms (blood, drug therapy, genetics, pathology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays (methods)