title: Focal adhesion kinase: an alternative focus for anti-angiogenesis therapy in ovarian cancer.
abstract: This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAK(Y397) were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRT-PCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P<0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P<0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P<0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors.
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Stone
authors.affiliation: Department of Bioinformatics and Computational Biology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Baggerly
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Guillermo N
authors.initials: GN
authors.lastname: Armaiz-Pena
authors.affiliation: Department of Obstetrics and Gynecology; Hospital of Fudan University; Shanghai, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Sanguino
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Duangmani
authors.initials: D
authors.lastname: Thanapprapasr
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Dalton
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Bottsford-Miller
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Behrouz
authors.initials: B
authors.lastname: Zand
authors.affiliation: Department of Bioinformatics and Computational Biology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Rehan
authors.initials: R
authors.lastname: Akbani
authors.affiliation: Department of Bioinformatics and Computational Biology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Alpa M
authors.initials: AM
authors.lastname: Nick
authors.affiliation: Department of Obstetrics and Gynecology; The University of Iowa; Iowa City, IA USA.
authors.forename: Koen
authors.initials: K
authors.lastname: DeGeest
authors.affiliation: Department of Experimental Therapeutics; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.affiliation: Department of Psychology; The University of Iowa; Iowa City, IA USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Lutgendorf
authors.affiliation: Department of Gynecologic Oncology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA; Department of Cancer Biology; The University of Texas M.D. Anderson Cancer Center; Houston, TX USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018628:Gene Dosage; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009375:Neoplasms, Glandular and Epithelial / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; C527797:N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014443:Tyrosine; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: angiogenesis; cancer/molecular biology; metastasis; targeted therapy
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