Identification of novel therapeutic targets in microdissected clear cell ovarian cancers

Michael P. Stany, Vinod Vathipadiekal, Laurent Ozbun, Rebecca Stone, Samuel C. Mok, Hui Xue, Takashi Kagami, Yuwei Wang, Jessica N. McAlpine, David Bowtell, Peter W. Gout, Dianne M. Miller, C. Blake Gilks, David G. Huntsman, Susan L. Ellard, Yu Zhuo Wang, Pablo Vivas-Mejia, Gabriel Lopez-Berestein, Anil K. Sood, Michael J. Birrer

Research output: Contribution to journalArticle

Abstract

Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.

Original languageEnglish (US)
Article numbere21121
JournalPLoS One
Volume6
Issue number7
DOIs
StatePublished - 2011
Externally publishedYes

Fingerprint

ovarian neoplasms
Ovarian Neoplasms
Tumors
therapeutics
cells
neoplasms
Neoplasms
Microdissection
Therapeutics
Genes
Cells
Glucose
Chemotherapy
Cell growth
cell lines
Metabolism
Small Interfering RNA
Capsules
genomics
Laser Capture Microdissection

ASJC Scopus subject areas

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

Cite this

Stany, M. P., Vathipadiekal, V., Ozbun, L., Stone, R., Mok, S. C., Xue, H., ... Birrer, M. J. (2011). Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. PLoS One, 6(7), [e21121]. https://doi.org/10.1371/journal.pone.0021121

Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. / Stany, Michael P.; Vathipadiekal, Vinod; Ozbun, Laurent; Stone, Rebecca; Mok, Samuel C.; Xue, Hui; Kagami, Takashi; Wang, Yuwei; McAlpine, Jessica N.; Bowtell, David; Gout, Peter W.; Miller, Dianne M.; Gilks, C. Blake; Huntsman, David G.; Ellard, Susan L.; Wang, Yu Zhuo; Vivas-Mejia, Pablo; Lopez-Berestein, Gabriel; Sood, Anil K.; Birrer, Michael J.

In: PLoS One, Vol. 6, No. 7, e21121, 2011.

Research output: Contribution to journalArticle

Stany, MP, Vathipadiekal, V, Ozbun, L, Stone, R, Mok, SC, Xue, H, Kagami, T, Wang, Y, McAlpine, JN, Bowtell, D, Gout, PW, Miller, DM, Gilks, CB, Huntsman, DG, Ellard, SL, Wang, YZ, Vivas-Mejia, P, Lopez-Berestein, G, Sood, AK & Birrer, MJ 2011, 'Identification of novel therapeutic targets in microdissected clear cell ovarian cancers', PLoS One, vol. 6, no. 7, e21121. https://doi.org/10.1371/journal.pone.0021121
Stany, Michael P. ; Vathipadiekal, Vinod ; Ozbun, Laurent ; Stone, Rebecca ; Mok, Samuel C. ; Xue, Hui ; Kagami, Takashi ; Wang, Yuwei ; McAlpine, Jessica N. ; Bowtell, David ; Gout, Peter W. ; Miller, Dianne M. ; Gilks, C. Blake ; Huntsman, David G. ; Ellard, Susan L. ; Wang, Yu Zhuo ; Vivas-Mejia, Pablo ; Lopez-Berestein, Gabriel ; Sood, Anil K. ; Birrer, Michael J. / Identification of novel therapeutic targets in microdissected clear cell ovarian cancers. In: PLoS One. 2011 ; Vol. 6, No. 7.
@article{0eaa82739f814a50a6b62bc0592ab36c,
title = "Identification of novel therapeutic targets in microdissected clear cell ovarian cancers",
abstract = "Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.",
author = "Stany, {Michael P.} and Vinod Vathipadiekal and Laurent Ozbun and Rebecca Stone and Mok, {Samuel C.} and Hui Xue and Takashi Kagami and Yuwei Wang and McAlpine, {Jessica N.} and David Bowtell and Gout, {Peter W.} and Miller, {Dianne M.} and Gilks, {C. Blake} and Huntsman, {David G.} and Ellard, {Susan L.} and Wang, {Yu Zhuo} and Pablo Vivas-Mejia and Gabriel Lopez-Berestein and Sood, {Anil K.} and Birrer, {Michael J.}",
year = "2011",
doi = "10.1371/journal.pone.0021121",
language = "English (US)",
volume = "6",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - Identification of novel therapeutic targets in microdissected clear cell ovarian cancers

AU - Stany, Michael P.

AU - Vathipadiekal, Vinod

AU - Ozbun, Laurent

AU - Stone, Rebecca

AU - Mok, Samuel C.

AU - Xue, Hui

AU - Kagami, Takashi

AU - Wang, Yuwei

AU - McAlpine, Jessica N.

AU - Bowtell, David

AU - Gout, Peter W.

AU - Miller, Dianne M.

AU - Gilks, C. Blake

AU - Huntsman, David G.

AU - Ellard, Susan L.

AU - Wang, Yu Zhuo

AU - Vivas-Mejia, Pablo

AU - Lopez-Berestein, Gabriel

AU - Sood, Anil K.

AU - Birrer, Michael J.

PY - 2011

Y1 - 2011

N2 - Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.

AB - Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.

UR - http://www.scopus.com/inward/record.url?scp=79959923767&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959923767&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0021121

DO - 10.1371/journal.pone.0021121

M3 - Article

C2 - 21754983

AN - SCOPUS:79959923767

VL - 6

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

M1 - e21121

ER -