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Establishment of patient-derived tumor xenograft models of epithelial ovarian cancer for pre-clinical evaluation of novel therapeutics
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
endocrine system
Cancer Research
Pathology
medicine.medical_specialty
endocrine system diseases
Antineoplastic Agents
Carcinoma, Ovarian Epithelial
Article
03 medical and health sciences
Mice
0302 clinical medicine
In vivo
Cell Line, Tumor
medicine
Carcinoma
Bioluminescence imaging
Animals
Humans
Neoplasms, Glandular and Epithelial
Ovarian Neoplasms
business.industry
Cancer
Ascites
Membrane Proteins
medicine.disease
Xenograft Model Antitumor Assays
Biomarker (cell)
Disease Models, Animal
030104 developmental biology
Long Interspersed Nucleotide Elements
Oncology
Drug development
030220 oncology & carcinogenesis
CA-125 Antigen
Cancer research
Immunohistochemistry
business
Ovarian cancer
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....5f4eaf638f01e86318b671b8797a1b9b