Murat ÖZ, İlker SELÇUK, Zafer ARIK, Tayfun GÜNGÖR

Targeted Agents in Ovarian Carcinoma

Gynecologic malignancies take an important part in female cancers. Ovarian cancer is the second most common gynecologic cancer with the highest mortality rate in developed countries. Most of the patients need an adjuvant chemotherapy regimen after the initial surgery. Despite their suppressive effect on tumor cells, much toxicity on healthy cells could be seen with these standard chemotherapeutics. In that manner a new way of tumor cell disruption with less toxicity and cancer selective effect is needed, which is called targeted therapy. Moreover this approach could prevent chemo-resistance and increase chemosensitivity of the disease. Primary cytoreductive surgery with platinum based chemotherapy shape the initial management of these tumors. However, recently we are on the edge of molecular therapy for this cancer. In this setting we need to identify a dominant biological pathway for tumor progression and discover a functional and structural molecule within this pathway. The new therapeutic modalities with targeted molecules should build up new perspectives insight tumor cell behaviour. Agents against angiogenesis and receptors of growth factors in addition to signalling cascades and intracellular enzymes could shape the individual treatment protocols for cancer survivors.

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Siegel R, Naishadham D, Jemal A. Cancer statistics, CA Cancer Clin. 2013;63(l):ll-- 30.

Oz M, Ozgu E, Korkmaz E, Bayramoglu H, Erkaya S, Gungor T. Utility of frozen section pathology with endometrial pre-- malignant lesions. Asian Pac Cancer Prev. 2014;15(15):6053--7.

Han-Chung Wu D--KC, Chia--Ting Huang. Targeted Therapy for Cancer. Cancer. 2006;2(2):57--66.

Gerber DE. Targeted therapies: new generation of cancer treatments. Am Fam Physician. 2008;77(3):3 1--9.

Kohler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. l975;256(5517):495--7.

Maatta JA, Sundvall M, Junttila TT, Peri L, Laine VJ, Isola J, Egeblad M, Elenius K. Proteolytic cleavage and phosphorylation of tumor--associated ErbB4 isoform promote ligand--independent survival and cancer cell growth. Mol Biol Cell. 2006;l7(l):67--79.

Knight ZA, Shokat KM. Features of selective kinase inhibitors. Chem biol. 2005;12(6):621--37.

Sapra P, Moase EH, Ma J, Allen TM. Improved therapeutic responses in xenograft model of human lymphoma (Namalwa) for liposomal Vincristine versus liposomal doxorubicin targeted via anti--CDl9 IgG2a or Fab' fragments. Clin Cancer Res. 2004;lO(3):llOO--ll.

Bast RC, Jr., Hennessy B, Mills GB. The biology of ovarian cancer: new opportunities for translation. Nat Rev Cancer. 2009;9(6):415--28.

Folkman J. Tumor angiogenesis: therapeutic implications. Engl Med. 1971;285(21):1182--6.

Blume--Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001;41 l(6835):355--65.

Willmott LJ, Fruehauf JP. Targeted therapy in ovarian cancer. Oncol. 2010;20102740472.

Mitri Z, Constantine T, O'Regan R. The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy. Chemother Res Pract. 2012;2012:743193.

Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. Trastuzumab treatment in patients With advanced or recurrent endometrial carcinoma overeXpressing HER2/neu. Int Gynaecol Obstet. 2008;102(2):128--3l.

Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nature Med. 2003;9(6):669--76.

Banerjee S, Kaye S. The role of targeted therapy in ovarian cancer. Eur Cancer. 2011;47(Suppl 3):S116--30.

Ramakrishnan S, Subramanian IV, Yokoyama Y, Geller M. Angiogenesis in normal and neoplastic ovaries. Angiogenesis. 2005 ;8(2):l69--82.

Chen H, Ye D, Xie X, Chen B, Lu W. VEGF, VEGFRs expressions and activated STATs in ovarian epithelial carcinoma. Gynecol Oncol. 2004;94(3):630--5.

Monk BJ, Dalton H, Farley JH, Chase DM, Benjamin 1. Antiangiogenic agents as maintenance strategy for advanced epithelial ovarian cancer. Crit Rev Oncol Hematol. 2013;86(2):161--75.

Sendur MA, Aksoy S, Arik Z, Yaman S, Ozdemir NY, Uncu D, Zengin N. Bevacizumab: new potential therapeutic option in sinusoidal obstruction syndrome. Asian Pac Cancer Prev. 2011;12(8):2l47--8.

Mabuchi S, Terai Y, Morishige K, Tanabe--Kimura A, Sasaki H, Kanemura M, Tsunetoh

S, Tanaka Y, Sakata M, Burger RA, Kimura T, Ohmichi M. Maintenance treatment with bevacizumab prolongs survival in an in Vivo ovarian cancer model. Clin Res. 2008;14(23):7781--9.

Walters CL, Arend RC, Armstrong DK,Naumann RW, Alvarez RD. Folate and folate receptor alpha antagonists mechanism of action in ovarian cancer. Gynecol Oncol. 2013;l3l(2):493-8.

Perren TJ, Swart AM, Pfisterer J, Ledermann A, Pujade--Lauraine E, Kristensen G, Carey MS, Beale P, Cervantes A, Kurzeder C, du Bois A, Sehouli J, Kimmig R, Stahle A,

Collinson F, Essapen S, Gourley C, Lortholary A, Selle F, Mirza MR, Leminen A, Plante M, Stark D, Qian W, Parmar MK, Oza AM; ICON7 Investigators. phase trial of bevacizumab in ovarian cancer. Engl Med. 2011;365(26):2484--96.

Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycurn LR. OCEANS: 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. Clin Oncol. 2012;30(17):2039--45.

EK Hill MS, Raker, PA DiSilvestro. Tumor microvessel density does not correlate with bevacizumab response in recurrent ovarian cancer (abstract). Gynecol Oncol. Poster No: 209. 2014;133(Sl):86.

Burger RA. Experience with bevacizumab in the management of epithelial ovarian cancer. Clin Oncol. 2007;25(20):2902--8.

Byme AT, Ross L, Holash J, Nakanishi M, Hu L, Hofmann JI, Yancopoulos GD, Jaffe RB. Vascular endothelial growth factor--trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res. 2003;9(15):5721--8.

Becker G, Blum HE. VEGF Trap for the treatment of malignant ascites. The Lancet Oncology. 2012;13(2):115--6.

Gomez-Raposo C, Mendiola M, Barriuso J, Casado E, Hardisson D, Redondo A. Angiogenesis and ovarian cancer. Clin Transl Oncol. 2009;11(9):564--71.

Masoumi Moghaddam S, Amini A, Morris DL, Pourgholami MH. Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer. Cancer Metastasis Rev. 2012;3l(l--2):l43--62.

Bogdan S, Klambt C. Epidermal growth factor receptor signaling. Current Biol. 2001;11(8):R292--5.

Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298(5600):1912-34.

Matei D, Sill MW, Lankes HA, DeGeest K, Bristow RE, Mutch D, Yamada SD, Cohn D, Calvert V, Farley J, Petricoin EF, Birrer MJ. Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: gynecologic oncology group trial. Clin Oncol. 2011;29(1):69--75.

Morotti M, Becker CM, Menada MV, Ferrero S. Targeting tyrosine--kinases in ovarian cancer. Expert Opin Investig Drugs. 2013;22(10):1265 --79.

Alberts DS, Liu PY, Wilczynski SP, Jang A, Moon J, Ward JH, Beck JT, Clouser M, Markman M. Phase II trial of imatinib mesylate in recurrent, biomarker positive, ovarian cancer (Southwest Oncology Group Protocol $0211). Int Gynecol Cancer. 2007;17(4):784--8.

Eichbaum M, Mayer C, Eickhoff R, Bischofs E, Gebauer G, Fehm T, Lenz F, Fricke HC, Solomayer E, Fersis N, Schmidt M, Wallwiener M, Schneeweiss A, Sohn C. The PACOVAR--trial: phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum--resistant recurrent, pre--treated ovarian cancer. BMC Cancer. 2011;11:453.

Friedlander M, Hancock KC, Rischin D, Messing MJ, Stringer CA, Matthys GM, Ma B, Hodge JP, Lager JJ. Phase II, open--label study evaluating pazopanib in patients With recurrent ovarian cancer. Gynecol Oncol. 2010;l l9(l):32--7.

Schmid BC, Oehler MK. New perspectives in ovarian cancer treatment. Maturitas. 2014;77(2):128--36.

Visentin M, Zhao R, Goldman ID. The antifolates. Hematol Oncol Clin North Am. 2012;26(3):629--48.

Gonen N, Assaraf YG. Antifolates in cancer therapy: structure, activity and mechanisms of drug resistance. Drug Resist Updat. 2012;15(4):l83--210.

Reddy JA, Haneline LS, Srour EF, Antony AC, Clapp DW, Low PS. Expression and functional characterization of the beta--isoform of the folate receptor on CD34(+) cells. Blood. l999;93(ll):3940--8.

Markert S, Lassmann S, Gabriel B, Klar M, Werner M, Gitsch G, Kratz F, Hasenburg A. Alpha--folate receptor expression in epithelial ovarian carcinoma and non--neoplastic ovarian tissue. Anticancer Research. 2008;28(6A):3567--72.

Elnakat H, Ratnam M. Role of folate receptor genes in reproduction and related cancers. Front Biosci. 2006;11:506--19.

Toffoli G, Cemigoi C, Russo A, Gallo A, Bagnoli M, Boiocchi M. Overexpression of folate binding protein in ovarian cancers. Int Cancer. l997;74(2):l93 --8.

Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, Hartmann LC. Folate receptor alpha as tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008;108(3):6l9--26.

Sehouli J, Alvarez AM, Manouchehrpour S, Ghatage P, Szczylik C, Zimmermann A, Bauknecht T, Look KY, Oskay-Oezcelik G. phase II trial of pemetrexed in combination With carboplatin in patients with recurrent ovarian or primary peritoneal cancer. Gynecol Oncol. 2012;124(2):205 --9.

Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as therapeutic strategy. Nature. 2005;434(7035):9l7--21.

Liu JF, Konstantinopoulos PA, Matulonis UA. PARP inhibitors in ovarian cancer: current status and future promise. Gynecol Oncol. 2014;l33(2):362--9.

Hennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD 2nd, Abkevich V, Potter J, Pruss D, Glenn P, Li Y, Li J, Gonzalez--Angulo AM, McCune KS, Markman M,

Broaddus RR, Lanchbury S, Lu KH, Mills GB. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. Clin Oncol. 2010;28(22):3570--6.

Campos SM, Ghosh S. current review of targeted therapeutics for ovarian cancer. Clin Oncol. 2010;2010:149362.

Cancer Genome Atlas Research N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609--15.

Kaye SB, Lubinski J, Matulonis U, Ang JE, Gourley C, Karlan BY, Amnon A, Bell-- McGuinn KM, Chen LM, Friedlander M, Safra T, Vergote I, Wickens M, Lowe ES, Carmichael J, Kaufman B. Phase ll, open--label, randomized, multicenter study comparing the efficacy and safety of olaparib, poly (ADP--ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCAl or BRCA2 mutations and recurrent ovarian cancer. Clin Oncol. 2012;30(4).372--9.

Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell--McGuinn KM, Scott C, Weitzel JN, Oaknin A, Loman N, Lu K, Schmutzler RK, Matulonis U, Wickens M, Tutt A. Oral poly(ADP--ribose) polymerase inhibitor olaparib in patients with BRCAl or BRCA2 mutations and recurrent ovarian cancer: proof--of--concept trial. Lancet. 2010;376(9737):245--51.

Fong PC, Yap TA, Boss DS, Carden CP, Mergui--Roelvink M, Gourley C, De Greve J, Lubinski J, Shanley S, Messiou C, A'Hem R, Tutt A, Ashworth A, Stone J, Carmichael J, Schellens JH, de Bono S, Kaye SB. Poly(ADP)--ribose polymerase inhibition. frequent durable responses in BRCA carrier ovarian cancer correlating with platinum--free interval. Clin Oncol. 2010;28(15):2512--9.

Keen N, Taylor S. Aurora--kinase inhibitors as anticancer agents. Nat Rev Cancer. 2004;4(12):927--36.

Fu S, Hu W, Kavanagh JJ, Bast RC, Jr. Targeting Aurora kinases in ovarian cancer. Expert Opin Ther Targets. 2006;10(1):77--85

Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, Brinkley BR, Sen S. Tumour amplified kinase STKlS/BTAK induces centrosome amplification, aneuploidy and transformation. Nature Genetics. l998;20(2):l89--93.

Katayama H, Brinkley WR, Sen S. The Aurora kinases: role in cell transfonnation and tumorigenesis. Cancer Metastasis Rev. 2003;22(4):451-64.

Dicioccio RA, Song H, Waterfall C, Kimura MT, Nagase H, McGuire V, Hogdall E, Shah MN, Luben RN, Easton DF, Jacobs IJ, Ponder BA, Whittemore AS, Gayther SA, Pharoah PD, Kruger--Kjaer S. STK15 polymorphisms and association with risk of invasive ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2004;l3(10):1589--94.

Ewart--Toland A, Dai Q, Gao YT, Nagase H, Dunlop MG, Farrington SM, Barnetson RA,

Anton--Culver H, Peel D, Ziogas A, Lin D, Miao X, Sun T, Ostrander EA, Stanford JL, Langlois M, Chan JM, Yuan J, Harris CC, Bowman ED, Clayman GL, Lippman SM, Lee

JJ Zheng W, Balmain A. Aurora--A/STKlS T+9lA is general low penetrance cancer susceptibility gene: meta--analysis of multiple cancer types. Carcinogenesis. 2005;26(8):l368--73.

Landen CN, Jr., Lin YG, Immaneni A, Deavers MT, Merritt WM, Spannuth WA, Bodurka DC, Gershenson DM, Brinkley WR, Sood AK. Overexpression of the centrosomal protein Aurora--A kinase is associated with poor prognosis in epithelial ovarian cancer patients. Clin Cancer Res. 2007;l3(l4):4098--104.

Umene K, Banno K, Kisu I, Yanokura M, Nogami Y, Tsuji K, Masuda K, Ueki A, Kobayashi Y, Yamagami W, Nomura H, Tominaga E, Susumu N, Aoki D. Aurora kinase inhibitors: Potential molecular--targeted drugs for gynecologic malignant tumors. Biomed Rep. 2013;1(3):335--340.

Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Develop. 2001;15(23):3059--87.

Chen Q, Gao G, Luo S. Hedgehog signaling pathway and ovarian cancer. Chin Cancer Res. 2013;25(3):346--53.

Liao X, Siu MK, Au CW, Wong ES, Chan HY, Ip PP, Ngan HY, Cheung AN. Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis. 2009;30(l):l3l-40.

Chen X, Horiuchi A, Kikuchi N, Osada R, Yoshida J, Shiozawa T, Konishi I. Hedgehog signal pathway is activated in ovarian carcinomas, correlating with cell proliferation: it's inhibition leads to growth suppression and apoptosis. Cancer Sci. 2007;98(l):68 --76.

Yang L, He J, Huang S, Zhang X, Bian Y, He N, Zhang H, Xie J. Activation of hedgehog signaling is not frequent event in ovarian cancers. Molecular Cancer. 2009;82112.

Vivanco I, Sawyers CL. The phosphatidylinositol 3--Kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2(7):489--501.

Hopkins BD, Hodakoski C, Barrows D, Mense SM, Parsons RE. PTEN function: the long and the short of it. Trends Biochem Sci. 2014;39(4):183--l90.

Sudo T. Molecular--targeted therapies for ovarian cancer: prospects for the future. Int Clin Oncol. 2012;l7(5):424--9.

Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6Kl and 4E--BPl/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2004;24(l):200-l6.

Husseinzadeh N, Husseinzadeh HD. mTOR inhibitors and their clinical application in cervical, endometrial and ovarian cancers: critical review. Gynecol Oncol. 2014;133(2):375--81.

Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs. 2002;3(2):295--304.

He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43:67--93.

Altomare DA, Wang HQ, Skele KL, De Rienzo A, Klein--Szanto AJ, Godwin AK, Testa JR. AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene. 2004;23(34):5853--7.

Yuan ZQ, Feldman RI, Sussman GE, Coppola D, Nicosia SV, Cheng Q. AKT2 inhibition of cisplatin--induced JNK/p38 and BaX activation by phosphorylation of ASKl: implication of AKT2 in chemoresistance. Biol Chem. 2003;278(26):23432--40.

Hu L, Hofmann J, Lu Y, Mills GB, affe RB. Inhibition of phosphatidylinositol 3'--kinase increases efficacy of paclitaxel in in vitro and in Vivo ovarian cancer models. Cancer Res. 2002;62(4):1087--92.