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. Velculescu & 6 others Cloud Paweletz, Gordon B. Mills, David M. Livingston, Joan S. Brugge, Ursula A. Matulonis, Ronny Drapkin

Research output: Research - peer-reviewArticle

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.

LanguageEnglish (US)
Pages1263-1273
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number5
DOIs
StatePublished - Mar 1 2017

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Heterografts
Neoplasms
Therapeutics
Ovarian epithelial cancer
Tumor Burden
Ovarian Neoplasms
Exome
Validation Studies
Standard of Care
Phosphatidylinositol 3-Kinases
Ascites
Cause of Death
Research Design
Biomarkers
Recurrence
Drug Therapy
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Establishment of patient-derived tumor xenograft models of epithelial ovarian cancer for preclinical evaluation of novel therapeutics. / Liu, Joyce F.; Palakurthi, Sangeetha; Zeng, Qing; Zhou, Shan; Ivanova, Elena; Huang, Wei; Zervantonakis, Ioannis K.; Selfors, Laura M.; Shen, Yiping; Pritchard, Colin C.; Zheng, Mei; Adleff, Vilmos; Papp, Eniko; Piao, Huiying; Novak, Marian; Fotheringham, Susan; Wulf, Gerburg M.; English, Jessie; Kirschmeier, Paul T.; Velculescu, Victor E.; Paweletz, Cloud; Mills, Gordon B.; Livingston, David M.; Brugge, Joan S.; Matulonis, Ursula A.; Drapkin, Ronny.

In: Clinical Cancer Research, Vol. 23, No. 5, 01.03.2017, p. 1263-1273.

Research output: Research - peer-reviewArticle

Liu, JF, Palakurthi, S, Zeng, Q, Zhou, S, Ivanova, E, Huang, W, Zervantonakis, IK, Selfors, LM, Shen, Y, Pritchard, CC, Zheng, M, Adleff, V, Papp, E, Piao, H, Novak, M, Fotheringham, S, Wulf, GM, English, J, Kirschmeier, PT, Velculescu, VE, Paweletz, C, Mills, GB, Livingston, DM, Brugge, JS, Matulonis, UA & Drapkin, R 2017, 'Establishment of patient-derived tumor xenograft models of epithelial ovarian cancer for preclinical evaluation of novel therapeutics' Clinical Cancer Research, vol 23, no. 5, pp. 1263-1273. DOI: 10.1158/1078-0432.CCR-16-1237
Liu, Joyce F. ; Palakurthi, Sangeetha ; Zeng, Qing ; Zhou, Shan ; Ivanova, Elena ; Huang, Wei ; Zervantonakis, Ioannis K. ; Selfors, Laura M. ; Shen, Yiping ; Pritchard, Colin C. ; Zheng, Mei ; Adleff, Vilmos ; Papp, Eniko ; Piao, Huiying ; Novak, Marian ; Fotheringham, Susan ; Wulf, Gerburg M. ; English, Jessie ; Kirschmeier, Paul T. ; Velculescu, Victor E. ; Paweletz, Cloud ; Mills, Gordon B. ; Livingston, David M. ; Brugge, Joan S. ; Matulonis, Ursula A. ; Drapkin, Ronny. / Establishment of patient-derived tumor xenograft models of epithelial ovarian cancer for preclinical evaluation of novel therapeutics. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 5. pp. 1263-1273
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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.",
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T1 - Establishment of patient-derived tumor xenograft models of epithelial ovarian cancer for preclinical evaluation of novel therapeutics

AU - Liu,Joyce F.

AU - Palakurthi,Sangeetha

AU - Zeng,Qing

AU - Zhou,Shan

AU - Ivanova,Elena

AU - Huang,Wei

AU - Zervantonakis,Ioannis K.

AU - Selfors,Laura M.

AU - Shen,Yiping

AU - Pritchard,Colin C.

AU - Zheng,Mei

AU - Adleff,Vilmos

AU - Papp,Eniko

AU - Piao,Huiying

AU - Novak,Marian

AU - Fotheringham,Susan

AU - Wulf,Gerburg M.

AU - English,Jessie

AU - Kirschmeier,Paul T.

AU - Velculescu,Victor E.

AU - Paweletz,Cloud

AU - Mills,Gordon B.

AU - Livingston,David M.

AU - Brugge,Joan S.

AU - Matulonis,Ursula A.

AU - Drapkin,Ronny

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

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