Identification of novel therapeutic targets in microdissected clear cell ovarian cancers

Michael P. Stany, Vinod Vathipadiekal, Laurent Ozbun, Rebecca L. 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 journalArticlepeer-review

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

ASJC Scopus subject areas

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

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