Conventional chemotherapy and oncogenic pathway targeting in ovarian carcinosarcoma using a patient-derived tumorgraft

Gretchen Glaser, Saravut (John) Weroha, Marc A. Becker, Xiaonan Hou, Sergio Enderica-Gonzalez, Sean C. Harrington, Paul Haluska

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed.

Original languageEnglish (US)
Article numbere0126867
JournalPLoS One
Volume10
Issue number5
DOIs
StatePublished - May 11 2015

Fingerprint

Carcinosarcoma
Chemotherapy
Paclitaxel
drug therapy
paclitaxel
Heterografts
Carboplatin
Drug Therapy
Ifosfamide
ovarian neoplasms
mutation
Ovarian Neoplasms
Mutation
Phosphorylation
polymerase chain reaction
Somatomedins
comparative genomic hybridization
erbB-1 Genes
NAD ADP-ribosyltransferase
therapeutics

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Conventional chemotherapy and oncogenic pathway targeting in ovarian carcinosarcoma using a patient-derived tumorgraft. / Glaser, Gretchen; Weroha, Saravut (John); Becker, Marc A.; Hou, Xiaonan; Enderica-Gonzalez, Sergio; Harrington, Sean C.; Haluska, Paul.

In: PLoS One, Vol. 10, No. 5, e0126867, 11.05.2015.

Research output: Contribution to journalArticle

Glaser, Gretchen ; Weroha, Saravut (John) ; Becker, Marc A. ; Hou, Xiaonan ; Enderica-Gonzalez, Sergio ; Harrington, Sean C. ; Haluska, Paul. / Conventional chemotherapy and oncogenic pathway targeting in ovarian carcinosarcoma using a patient-derived tumorgraft. In: PLoS One. 2015 ; Vol. 10, No. 5.
@article{cc865e0c5b4a4ef2add19d36a45f177a,
title = "Conventional chemotherapy and oncogenic pathway targeting in ovarian carcinosarcoma using a patient-derived tumorgraft",
abstract = "Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed.",
author = "Gretchen Glaser and Weroha, {Saravut (John)} and Becker, {Marc A.} and Xiaonan Hou and Sergio Enderica-Gonzalez and Harrington, {Sean C.} and Paul Haluska",
year = "2015",
month = "5",
day = "11",
doi = "10.1371/journal.pone.0126867",
language = "English (US)",
volume = "10",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Conventional chemotherapy and oncogenic pathway targeting in ovarian carcinosarcoma using a patient-derived tumorgraft

AU - Glaser, Gretchen

AU - Weroha, Saravut (John)

AU - Becker, Marc A.

AU - Hou, Xiaonan

AU - Enderica-Gonzalez, Sergio

AU - Harrington, Sean C.

AU - Haluska, Paul

PY - 2015/5/11

Y1 - 2015/5/11

N2 - Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed.

AB - Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed.

UR - http://www.scopus.com/inward/record.url?scp=84930648346&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930648346&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0126867

DO - 10.1371/journal.pone.0126867

M3 - Article

C2 - 25962155

AN - SCOPUS:84930648346

VL - 10

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e0126867

ER -