The emerging role of anti-angiogenic therapy in ovarian cancer (Review)

Conteduca,Vincenza; Kopf,Barbara; Burgio,Salvatore Luca; Bianchi,Emanuela; Amadori,Dino; De Giorgi,Ugo

doi:10.3892/ijo.2014.2334

The emerging role of anti-angiogenic therapy in ovarian cancer (Review)

Authors:
- Vincenza Conteduca
- Barbara Kopf
- Salvatore Luca Burgio
- Emanuela Bianchi
- Dino Amadori
- Ugo De Giorgi
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Affiliations: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.) - IRCCS, Meldola (FC), Italy, Istituto Oncologico della Svizzera Italiana (IOSI), Ospedale San Giovanni, Bellinzona, Switzerland
Published online on: March 10, 2014 https://doi.org/10.3892/ijo.2014.2334
Pages: 1417-1424

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Abstract

The introduction of new therapeutic agents into clinical practice of ovarian cancer, in addition to the role of surgery and chemotherapy, has been the subject of numerous studies because this tumor remains worldwide the most lethal gynecological cancer. It is now known that angiogenesis plays a vital role for ovarian physiology, but also in ovarian carcinogenesis and so it has become the main target of ovarian cancer treatment. In this review, the most common molecular pathways of angiogenesis have been investigated leading to the identification of novel targets, including monoclonal antibodies and tyrosine kinase inhibitors. The fundamental targets of anti-angiogenic drugs are vascular endothelial growth factor receptor and its ligand, but also platelet-derived growth factor, fibroblast growth factor and angiopoietin. Moreover, improved knowledge of angiogenic process allowed the discovery of other molecules, such as semaphorins, neuropilins, clusterin, some transcriptional factors, and the identification of features, including stemness, epithelial-mesenchymal transition, downregulation of certain microRNAs, the alteration of immune system, that contribute to angiogenesis and possibly to resistance mechanisms. The following patent and literature review aim to highlight recent findings of approved and novel anti-angiogenic drugs that make the treatment of patients with ovarian cancer a rapidly growing field of oncology.

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1.	Ferlay J, Shin H-R, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar : PubMed/NCBI
2.	Jelovac D and Armstrong DK: Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin. 61:183–203. 2011. View Article : Google Scholar
3.	Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T and Thun MJ: Cancer statistics, 2008. CA Cancer J Clin. 58:71–96. 2008. View Article : Google Scholar
4.	Howlader N, Noone AM, Krapcho M, Garshell J, Neyman N, Altekruse SF, Kosary CL, et al: SEER Cancer Statistics Review. 1975–2010, National Cancer Institute; Bethesda, MD: http://seer.cancer.gov/csr/1975_2010/, based on November 2012 SEER data submission, posted to the SEER web site, 2013.
5.	Folkman J: Tumor angiogenesis. Therapeutic implications. N Engl J Med. 285:1182–1186. 1971. View Article : Google Scholar : PubMed/NCBI
6.	Conway E-M, Collen D and Carmeliet P: Molecular mechanisms of blood vessel growth. Cardiovasc Res. 49:507–521. 2001. View Article : Google Scholar : PubMed/NCBI
7.	Chavakis E and Dimmeler S: Regulation of endothelial cell survival and apoptosis during angiogenesis. Arterioscler Thromb Vasc Biol. 22:887–893. 2002. View Article : Google Scholar : PubMed/NCBI
8.	Van der Bilt AR, de Vries EG, de Jong S, Timmer-Bosscha H, van der Zee AG and Reyners AK: Turning promise into progress for antiangiogenic agents in epithelial ovarian cancer. Crit Rev Oncol Hematol. 84:224–242. 2012.PubMed/NCBI
9.	Claesson-Welsh L and Welsh M: VEGFA and tumour angiogenesis. J Intern Med. 273:114–127. 2013. View Article : Google Scholar : PubMed/NCBI
10.	Olsson AK, Dimberg A, Kreuger J and Claesson-Welsh L: VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 7:359–371. 2006. View Article : Google Scholar : PubMed/NCBI
11.	Hicklin DJ and Ellis LM: Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 23:1011–1027. 2005. View Article : Google Scholar : PubMed/NCBI
12.	Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vinent L, Costa C, MacDonald DD, et al: VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 6:820–827. 2005. View Article : Google Scholar
13.	Lichtenberger BM, Tan PK, Niederleithner H, Ferrara N, Petzelbauer P and Sibilia M: Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell. 6:268–279. 2010. View Article : Google Scholar : PubMed/NCBI
14.	Trinh XB, Tjalma WA, Vermeulen PB, Van den Eynden G, Van der Auwera I, Van Laere SJ, Helleman J, et al: The VEGF pathway and the AKT/mTOR/p70S6K1 signalling pathway in human epithelial ovarian cancer. Br J Cancer. 100:971–978. 2009. View Article : Google Scholar : PubMed/NCBI
15.	Zhang A, Meng L, Wang Q, Chen G, Wang S, Zhou J, Lu Y, et al: Enhanced in vitro invasiveness of ovarian cancer cells through up-regulation of VEGF and induction of MMP-2. Oncol Rep. 15:831–836. 2006.
16.	Artini PG, Ruggiero M, Monteleone P, Carpi A, Cristello F, Cela V, Genazzani AR, et al: Vascular endothelial growth factor and its soluble receptor in benign and malignant ovarian tumors. Biomed Pharmacother. 62:373–377. 2008. View Article : Google Scholar : PubMed/NCBI
17.	Lawicki S, Będkowska GE, Gacuta-Szumarska E and Szmitkowski M: The plasma concentration of VEGF, HE4 and CA125 as a new biomarkers panel in different stages and sub-types of epithelial ovarian tumors. J Ovarian Res. 6:452013. View Article : Google Scholar : PubMed/NCBI
18.	Lu KH, Patterson AP, Wang L, Marquez RT, Atkinson EN, Baggerly KA, Ramoth LR, et al: Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin Cancer Res. 10:3291–3300. 2004. View Article : Google Scholar : PubMed/NCBI
19.	Li L, Wang L, Zhang W, Tang B, Zhang J, Song H, Yao D, et al: Correlation of serum VEGF levels with clinical stage, therapy efficacy, tumor metastasis and patient survival in ovarian cancer. Anticancer Res. 24:1973–1979. 2004.PubMed/NCBI
20.	Rudlowski C, Pickart AK, Fuhljahn C, Friepoertner T, Schlehe B, Biesterfeld S and Schroeder W: Prognostic significance of vascular endothelial growth factor expression in ovarian cancer patients: a long-term follow-up. Int J Gynecol Cancer. 16:183–189. 2006. View Article : Google Scholar
21.	Yu L, Deng L, Li J, Zhang Y and Hu L: The prognostic value of vascular endothelial growth factor in ovarian cancer: a systematic review and meta-analysis. Gynecol Oncol. 128:391–396. 2013. View Article : Google Scholar : PubMed/NCBI
22.	Hu L, Hoffmann J, Zaloudak C, Ferrara N, Hamilton T and Jaffe RB: Vascular endothelial growth factor immunoneutralization plus paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol. 161:1917–1924. 2002. View Article : Google Scholar
23.	Byrne AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI, Yancopoulos GD, et al: Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res. 9:5721–5728. 2003.
24.	Tran J, Master Z, Yu JL, Rak J, Dumont DJ and Kerbel RS: A role of surviving in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci USA. 99:4349–4354. 2002. View Article : Google Scholar
25.	Martin L and Schilder R: Novel approaches in advancing the treatment of epithelial ovarian cancer: the role of angiogenesis inhibition. J Clin Oncol. 25:2894–2901. 2007. View Article : Google Scholar : PubMed/NCBI
26.	Osada R, Horiuchi A, Kikuchi N, Ohira S, Ota M, Katsuyama Y and Konishi I: Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas. Hum Pathol. 37:1414–1425. 2006.
27.	Fu Y, Lai Y, Wang Q, Liu X, He W, Zhang H, Fan C, et al: Overexpression of clusterin promotes angiogenesis via the vascular endothelial growth factor in primary ovarian cancer. Mol Med Rep. 7:1726–1732. 2013.PubMed/NCBI
28.	Eckhoff K, Flurschütz R, Trillsch F, Mahner S, Jänicke F and Milde-Langosch K: The prognostic significance of Jun transcription factors in ovarian cancer. J Cancer Res Clin Oncol. 139:1673–1680. 2013. View Article : Google Scholar : PubMed/NCBI
29.	Mahner S, Baasch C, Schwarz J, Hein S, Wölber L, Jänicke F and Milde-Langosch K: C-Fos expression is a molecular predictor of progression and survival in epithelial ovarian carcinoma. Br J Cancer. 99:1269–1275. 2008. View Article : Google Scholar : PubMed/NCBI
30.	Kusumbe AP, Mali AM and Bapat SA: CD133-expressing stem cells associated with ovarian metastases establish an endothelial hierarchy and contribute to tumor vasculature. Stem Cells. 27:498–508. 2009. View Article : Google Scholar : PubMed/NCBI
31.	Kryczek I, Liu S, Roh M, Vatan L, Szeliga W, Wei S, et al: Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells. Int J Cancer. 130:29–39. 2012. View Article : Google Scholar : PubMed/NCBI
32.	Burgos-Ojeda D, Rueda BR and Buckanovich RJ: Ovarian cancer stem cell markers: Prognostic and therapeutic implications. Cancer Lett. 322:1–7. 2012. View Article : Google Scholar : PubMed/NCBI
33.	Alvero AB, Fu HH, Holmberg J, Visintin I, Mor L, Marquina CC, Oldtman J, et al: Stem-like ovarian cancer cells can serve as tumor vascular progenitors. Stem Cells. 27:2405–2413. 2009. View Article : Google Scholar : PubMed/NCBI
34.	Liang D, Ma Y, Liu J, Trope CG, Holm R, Nesland JM and Suo Z: The hypoxic microenvironment upgrades stem-like properties of ovarian cancer cells. BMC Cancer. 12:2012012. View Article : Google Scholar : PubMed/NCBI
35.	Heddleston JM, Li Z, Lathia JD, Bao S, Hjelmeland AB and Rich JN: Hypoxia inducible factors in cancer stem cells. Br J Cancer. 102:789–795. 2010. View Article : Google Scholar : PubMed/NCBI
36.	Yin G, Alvero AB, Craveiro V, Holmberg JC, Fu HH, Montagna MK, Yang Y, et al: Constitutive proteasomal degradation of TWIST-1 in epithelial-ovarian cancer stem cells impacts differentiation and metastatic potential. Oncogene. 32:39–49. 2012. View Article : Google Scholar : PubMed/NCBI
37.	Cao L, Shao M, Schilder J, Guise T, Mohammad KS and Matei D: Tissue transglutaminase links TGF-beta, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer. Oncogene. 31:2521–2534. 2012. View Article : Google Scholar : PubMed/NCBI
38.	Jiao J, Huang L, Ye F, Shi M, Cheng X, Wang X, Hu D, et al: Cyclin D1 affects epithelial-mesenchymal transition in epithelial ovarian cancer stem cell-like cells. Onco Targets Ther. 6:667–677. 2013.
39.	Yang H and Chen B: CD147 in ovarian and other cancers. Int J Gynecol Cancer. 23:2–8. 2013. View Article : Google Scholar : PubMed/NCBI
40.	Yang H, Zou W and Chen B: Overexpression of CD147 in ovarian cancer is initiated by the hypoxic microenvironment. Cell Biol Int. 37:1139–1142. 2013. View Article : Google Scholar : PubMed/NCBI
41.	Millimaggi D, Mari M, D’Ascenzo S, Carosa E, Jannini EA, Zucker S, Carta G, et al: Tumor vesicle-associated CD147 modulates the angiogenic capability of endothelial cells. Neoplasia. 9:349–357. 2007. View Article : Google Scholar : PubMed/NCBI
42.	Zaffryar-Eilot S, Marshall D, Voloshin T, Bar-Zion A, Spangler R, Kessler O, Ghermazien H, et al: Lysyl oxidase-like-2 promotes tumour angiogenesis and is a potential therapeutic target in angiogenic tumours. Carcinogenesis. 34:2370–2379. 2013. View Article : Google Scholar : PubMed/NCBI
43.	Su Y, Gao L, Teng L, Wang Y, Cui J, Peng S and Fu S: Id1 enhances human ovarian cancer endothelial progenitor cell angiogenesis via PI3K/Akt and NF-κB/MMP-2 signaling pathways. J Transl Med. 11:1322013.PubMed/NCBI
44.	Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH, Kim JW, et al: MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res. 14:2690–2695. 2008. View Article : Google Scholar
45.	He J, Jing Y, Li W, Qian X, Xu Q, Li FS, Liu LZ, et al: Roles and mechanism of miR-199a and miR-125b in tumor angiogenesis. PLoS One. 8:e566472013. View Article : Google Scholar : PubMed/NCBI
46.	Bamias A, Pignata S and Pujade-Lauraine E: Angiogenesis: A promising therapeutic target for ovarian cancer. Crit Rev Oncol Hematol. 84:314–326. 2012. View Article : Google Scholar : PubMed/NCBI
47.	Ziogas, Gavalas N, Tsiatas M, Tsitsilonis O, Politi E, Terpos E, Rodolakis A, et al: VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor type 2. Int J Cancer. 130:857–864. 2012. View Article : Google Scholar : PubMed/NCBI
48.	Wang X, Zhao X, Wang K, Wu L and Duan T: Interaction of monocytes/macrophages with ovarian cancer cells promotes angiogenesis in vitro. Cancer Sci. 104:516–523. 2013. View Article : Google Scholar : PubMed/NCBI
49.	Lin YS, Nguyen C, Mendoza JL, Escandon E, Fei D, Meng YG and Modi NB: Preclinical pharmacokinetics, interspecies scaling, and tissue distribution of a humanized monoclonal antibody against vascular endothelial growth factor. J Pharmacol Exp Ther. 288:371–378. 1999.
50.	Jain R: Antiangiogenic therapy for cancer: current and emerging concepts. Oncology (Williston Park). 19:7–16. 2005.PubMed/NCBI
51.	Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, et al: Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 365:2473–2483. 2011. View Article : Google Scholar : PubMed/NCBI
52.	Perren TJ, Swart AM, Pfisterer J, Ledermann JA, Pujade- Lauraine E, Kristensen G, Carey MS, et al: A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 365:2484–2496. 2011. View Article : Google Scholar : PubMed/NCBI
53.	Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, et al: OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 30:2039–2045. 2012. View Article : Google Scholar
54.	Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, et al: AURELIA: a randomised phase III trial evaluating bevacizumab combined with chemotherapy for platinum resistant recurrent ovarian cancer. J Clin Oncol. 30:(abst, LBA5002),. 2012.
55.	Garcia A, Hirte H, Fleming G, Yang D, Tsao- Wei D, Roman L, Groshen S, et al: Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol. 26:76–82. 2008. View Article : Google Scholar : PubMed/NCBI
56.	McGonigle K, Muntz H, Vuky J, Paley P, Veljovich D, Greer B, Goff BA, et al: Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study. Cancer. 117:3731–3740. 2011. View Article : Google Scholar : PubMed/NCBI
57.	Kudoh K, Takano M, Kouta H, Kikuchi R, Kita T, Miyamoto M, Watanabe A, et al: Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers. Gynecol Oncol. 122:233–237. 2011. View Article : Google Scholar : PubMed/NCBI
58.	O’Malley DM, Richardson DL, Rheaume PS, Salani R, Eisenhauer EL, McCann GA, Fowler JM, et al: Addition of bevacizumab to weekly paclitaxel significantly improves progression-free survival in heavily pretreated recurrent epithelial ovarian cancer. Gynecol Oncol. 121:269–272. 2011.
59.	Verschraegen CF, Czok S, Muller CY, Boyd L, Lee SJ, Rutledge T, Blank S, et al: Phase II study of bevacizumab with liposomal doxorubicin for patients with platinum- and taxane-resistant ovarian cancer. Ann Oncol. 23:3104–3110. 2012. View Article : Google Scholar : PubMed/NCBI
60.	Tillmanns TD, Lowe MP, Walker MS, Stepanski EJ and Schwartzberg LS: Phase II clinical trial of bevacizumab with albumin-bound paclitaxel in patients with recurrent, platinum-resistant primary epithelial ovarian or primary peritoneal carcinoma. Gynecol Oncol. 128:221–228. 2013. View Article : Google Scholar
61.	Del Carmen MG, Micha J, Small L, Street DG, Londhe A and McGowan T: A phase II clinical trial of pegylated liposomal doxorubicin and carboplatin plus bevacizumab in patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer. Gynecol Oncol. 126:369–374. 2012.
62.	Burger R, Sill M, Monk B, Greer B and Sorosky J: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J Clin Oncol. 25:5165–5171. 2007. View Article : Google Scholar : PubMed/NCBI
63.	Cannistra S, Matulonis U, Penson R, Hambleton J, Dupont J, Mackey H, Douglas J, et al: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 25:5180–5186. 2007. View Article : Google Scholar
64.	Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, Salgia R, et al: Efficacy and safety of bevacizumab plus erlotinib for patients with recurrent ovarian, primary peritoneal, and fallopian tube cancer: a trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol. 110:49–55. 2008. View Article : Google Scholar
65.	Chambers SK, Clouser MC, Baker AF, Roe DJ, Cui H, Brewer MA, Hatch KD, et al: Overexpression of tumor vascular endothelial growth factor A may portend an increased likelihood of progression in a phase II trial of bevacizumab and erlotinib in resistant ovarian cancer. Clin Cancer Res. 16:5320–5328. 2010. View Article : Google Scholar
66.	Morgan R, Oza AM, Qin R, Laumann KM, Mackay H, Strevel EL, Welch S, et al: A phase II trial of temsirolimus and bevacizumab in patients with endometrial, ovarian, hepatocellular carcinoma, carcinoid, or islet cell cancer: ovarian cancer (OC) subset - a study of the Princess Margaret, Mayo, Southeast phase II, and California Cancer (CCCP) N01 Consortia NCI#8233. J Clin Oncol. 29:50152011.
67.	Kohn EC, Lee J, Annunziata CM, Minasian LM, Zujewski J, Prindiville SA, Kotz HL, et al: A phase II study of intermittent sorafenib with bevacizumab in bevacizumab-naive epithelial ovarian cancer (EOC) patients. J Clin Oncol. 29:50192011.
68.	Tew WP, Colombo N, Ray-Coquard I, Oza A, del Campo J, Scambia G and Spriggs D: VEGF-Trap for patients (pts) with recurrent platinum-resistant epithelial ovarian cancer (EOC): Preliminary results of a randomized, multicenter phase II study. J Clin Oncol. 25:55082007.
69.	Colombo N, Mangili G, Mammoliti S, Kalling M, Tholander B, Sternas L, Buzenet G, et al: A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites. Gynecol Oncol. 125:42–47. 2012. View Article : Google Scholar : PubMed/NCBI
70.	Friedlander M, Hancock KC, Rischin D, Ma B, et al: A phase II open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol. 119:32–37. 2010. View Article : Google Scholar : PubMed/NCBI
71.	Matulonis UA, Berlin S, Ivy P, Tyburski K, Krasner C, Zarwan C, Berkenblit A, et al: Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer. J Clin Oncol. 27:5601–5606. 2009. View Article : Google Scholar
72.	Biagi JJ, Oza AM, ChalCha HI, Grimshaw R, Ellard SL, Lee U, Hirte H, et al: A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. Ann Oncol. 22:335–340. 2011. View Article : Google Scholar : PubMed/NCBI
73.	Matei D, Sill MW, Lankes HA, DeGeest K, Bristow RE, Mutch D, Yamada SD, et al: Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a gynecologic oncology group trial. J Clin Oncol. 29:69–75. 2011. View Article : Google Scholar : PubMed/NCBI
74.	Welch SA, Hirte WHMD, Elit L, Schilder RJ, Wang L, Macalpine K, Wright JJ, et al: Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer. A study of the Princess Margaret Hospital Phase II Consortium. Int J Gynecol Cancer. 20:787–793. 2010. View Article : Google Scholar : PubMed/NCBI
75.	Pölcher M, Eckhardt M, Coch C, Wolfgarten M, Kübler K, Hartmann G, Kuhn W, et al: Sorafenib in combination with carboplatin and paclitaxel as neoadjuvant chemotherapy in patients with advanced ovarian cancer. Cancer Chemother Pharmacol. 66:203–207. 2010.PubMed/NCBI
76.	Matei D, Ramasubbaiah R, Schilder J, Perkins S, Whalen C, Breen T, Johnson CS, et al: A phase I/II study of topotecan and sorafenib in recurrent, platinum-resistant ovarian cancer: HOG GYN-111. J Clin Oncol. 28:51082010.
77.	Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I, Earl H, et al: Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer. J Clin Oncol. 29:3798–3804. 2011. View Article : Google Scholar
78.	Buckanovich RJ, Berger R, Sella A, Sikic BI, Shen X, Ramies DA, Smith DC, et al: Activity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): results from a phase II randomized discontinuation trial (RDT). J Clin Oncol. 29:50082011.
79.	Schilder RJ, Sill MW, Lee RB, Shaw TJ, Senterman MK, Klein-Szanto AJ, Miner Z, et al: Phase II evaluation of imatinib mesylate in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: a gynecologic oncology group study. J Clin Oncol. 26:3418–3425. 2008. View Article : Google Scholar
80.	Karlan BY, Oza AM, Richardson GE, Provencher DM, Hansen VL, Buck M, Chambers SK, et al: Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol. 30:362–371. 2012. View Article : Google Scholar : PubMed/NCBI
81.	Downs LS Jr, Judson PL, Argenta PA, Ghebre R, Geller MA, Bliss RL, Boente MP, et al: A prospective randomized trial of thalidomide with topotecan compared with topotecan alone in women with recurrent epithelial ovarian carcinoma. Cancer. 112:331–339. 2008. View Article : Google Scholar : PubMed/NCBI
82.	Hurteau JA, Brady MF, Darcy KM, McGuire WP, Edmonds P, Pearl ML, Ivanov I, et al: Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrent-only epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to first-line platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor (VEGF): A Gynecologic Oncology Group Study. Gynecol Oncol. 119:444–450. 2010.
83.	Bell-McGuinn KM, Matthews CM, Ho SN, Barve M, Gilbert L, Penson RT, LengYel E, et al: A phase II, single-arm study of the anti-α5β1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer. Gynecol Oncol. 121:273–279. 2011.