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.
authors.affiliation: Walter Reed Army Medical Center, Washington DC, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Stany
authors.forename: Vinod
authors.initials: V
authors.lastname: Vathipadiekal
authors.forename: Laurent
authors.initials: L
authors.lastname: Ozbun
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Mok
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.forename: Takashi
authors.initials: T
authors.lastname: Kagami
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Jessica N
authors.initials: JN
authors.lastname: McAlpine
authors.forename: David
authors.initials: D
authors.lastname: Bowtell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gout
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Miller
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ellard
authors.forename: Yu-Zhuo
authors.initials: YZ
authors.lastname: Wang
authors.forename: Pablo
authors.initials: P
authors.lastname: Vivas-Mejia
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics; D005947:Glucose / Q000172:deficiency; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D042282:Microdissection; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D058990:Molecular Targeted Therapy; D009336:Necrosis; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077210:Sunitinib; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011758:Pyrroles; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D005947:Glucose; D000077210:Sunitinib