Investigational New Drugs

, Volume 31, Issue 1, pp 213–229 | Cite as

Investigational agents in development for the treatment of ovarian cancer

  • Shannon N. Westin
  • Thomas J. Herzog
  • Robert L. Coleman


Although significant success has been achieved in the treatment of advanced and recurrent ovarian cancer, there is clearly room for improvement. The use of targeted agents in this patient population has the promise to provide improved survival and quality of life. There are a myriad of relevant pathways under exploration in all settings of ovarian cancer. Clinical trial data are accumulating for antiangiogenic therapy, including vascular endothelial growth factor (VEGF)-specific inhibitors and multiple angiogenic signaling target inhibitors, as well as poly-ADP-ribose polymerase (PARP) inhibitors. Other types of tumorigenic pathway inhibitors, including those that target phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR), protein kinase B (AKT), Src, folate receptor alpha, and insulin-like growth factor-1 receptor (IGF-1R) pathways are in earlier phases of development for ovarian cancer. Attempts to target the epidermal growth factor receptor (EGFR) of ovarian tumors have been met with limited success; however, newer agents that inhibit this pathway show promise. Finally, with recognition of the role of Wee-1 in p53-deficient tumors, an inhibitor of this tyrosine kinase is being evaluated in recurrent ovarian cancer. The logistical challenge is to determine the optimal timing and proper combinations of novel agents independently as well as concomitantly with conventional chemotherapeutics. Reported results have been modest; however, our growing understanding of these pathways will be potentially reflected in greater impact on response and survival.


Ovarian cancer Targeted therapy Personalized therapy Resistance Angiogenesis 


  1. 1.
    American Cancer Society (2012) Cancer facts & figures, 2012. American Cancer Society, AtlantaGoogle Scholar
  2. 2.
    Guarneri V, Piacentini F, Barbieri E, Conte PF (2010) Achievements and unmet needs in the management of advanced ovarian cancer. Gynecol Oncol 117:152–158PubMedCrossRefGoogle Scholar
  3. 3.
    McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M (1996) Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1–6PubMedCrossRefGoogle Scholar
  4. 4.
    Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA (2006) Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354:34–43PubMedCrossRefGoogle Scholar
  5. 5.
    Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, Tsuda H, Sugiyama T, Kodama S, Kimura E, Ochiai K, Noda K (2009) Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised controlled trial. Lancet 374:1331–1338PubMedCrossRefGoogle Scholar
  6. 6.
    National Comprehensive Cancer Network (2012) NCCN Clinical Practice Guidelines in Oncology™. Ovarian Cancer. Including Fallopian Tube Cancer and Primary Peritoneal Cancer. V.2.2012. Accessed 8 February 2012Google Scholar
  7. 7.
    Brown MR, Blanchette JO, Kohn EC (2000) Angiogenesis in ovarian cancer. Baillieres Best Pract Res Clin Obstet Gynaecol 14:901–918PubMedCrossRefGoogle Scholar
  8. 8.
    Ramakrishnan S, Subramanian IV, Yokoyama Y, Geller M (2005) Angiogenesis in normal and neoplastic ovaries. Angiogenesis 8:169–182PubMedCrossRefGoogle Scholar
  9. 9.
    Chen H, Ye D, Xie X, Chen B, Lu W (2004) VEGF, VEGFRs expressions and activated STATs in ovarian epithelial carcinoma. Gynecol Oncol 94:630–635PubMedCrossRefGoogle Scholar
  10. 10.
    Delli Carpini J, Karam AK, Montgomery L (2010) Vascular endothelial growth factor and its relationship to the prognosis and treatment of breast, ovarian, and cervical cancer. Angiogenesis 13:43–58PubMedCrossRefGoogle Scholar
  11. 11.
    Kamat AA, Merritt WM, Coffey D, Lin YG, Patel PR, Broaddus R, Nugent E, Han LY, Landen CN Jr, Spannuth WA, Lu C, Coleman RL, Gershenson DM, Sood AK (2007) Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. Clin Cancer Res 13:7487–7495PubMedCrossRefGoogle Scholar
  12. 12.
    Zebrowski BK, Liu W, Ramirez K, Akagi Y, Mills GB, Ellis LM (1999) Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol 6:373–378PubMedCrossRefGoogle Scholar
  13. 13.
    Kaye SB (2007) Bevacizumab for the treatment of epithelial ovarian cancer: will this be its finest hour? J Clin Oncol 25:5150–5152PubMedCrossRefGoogle Scholar
  14. 14.
    Kumaran GC, Jayson GC, Clamp AR (2009) Antiangiogenic drugs in ovarian cancer. Br J Cancer 100:1–7PubMedCrossRefGoogle Scholar
  15. 15.
    Cannistra SA, Matulonis UA, Penson RT, Hambleton J, Dupont J, Mackey H, Douglas J, Burger RA, Armstrong D, Wenham R, McGuire W (2007) Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25:5180–5186PubMedCrossRefGoogle Scholar
  16. 16.
    Burger RA, Sill MW, Monk BJ, Greer BE, Sorosky JI (2007) Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol 25:5165–5171PubMedCrossRefGoogle Scholar
  17. 17.
    Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, Groshen S, Swenson S, Markland F, Gandara D, Scudder S, Morgan R, Chen H, Lenz HJ, Oza AM (2008) 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 26:76–82PubMedCrossRefGoogle Scholar
  18. 18.
    del Carmen MG, Micha JP, Small LA, Street DG, Londhe A, McGowan T (2011) Pegylated liposomal doxorubicin and carboplatin plus bevacizumab in patients with platinum sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancers: Results of a phase II study. J Clin Oncol 29: Abstract 5061Google Scholar
  19. 19.
    Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR (2012) 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 OncolGoogle Scholar
  20. 20.
    Sanchez-Munoz A, Mendiola C, Perez-Ruiz E, Rodriguez-Sanchez CA, Jurado JM, Alonso-Carrion L, Ghanem I, de Velasco G, Quero-Blanco C, Alba E (2010) Bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. Oncology 79:98–104PubMedCrossRefGoogle Scholar
  21. 21.
    McGonigle KF, Muntz HG, Vuky J, Paley PJ, Veljovich DS, Greer BE, Goff BA, Gray HJ, Malpass TW (2011) Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a Phase 2 Study. Cancer 117:3731–3740PubMedCrossRefGoogle Scholar
  22. 22.
    Kudoh K, Takano M, Kouta H, Kikuchi R, Kita T, Miyamoto M, Watanabe A, Kato M, Goto T, Kikuchi Y (2011) Effects of bevacizumab and pegylated liposomal doxorubicin for the patients with recurrent or refractory ovarian cancers. Gynecol Oncol 122:233–237PubMedCrossRefGoogle Scholar
  23. 23.
    Tillmanns TD, Lowe MP, Schwartzberg LS, Walker MS, Stepanski EJ (2010) A phase II study of bevacizumab with nab-paclitaxel in patients with recurrent, platinum-resistant primary epithelial ovarian or primary peritoneal carcinoma. J Clin Oncol 28: Abstract 5009Google Scholar
  24. 24.
    Wenham R, LaPolla J, Lin H, Apte S, Roberts W, Lancaster J, Theodore S, Fabri D, Havrilesky L, Alvarez-Secord A (2010) A phase II trial of docetaxel and bevacizumab in recurrent ovarian cancer within 12 months of prior platinum-based chemotherapy. Gynecol Oncol 116:S61–S62, Abstract 155CrossRefGoogle Scholar
  25. 25.
    Nimeiri HS, Oza AM, Morgan RJ, Friberg G, Kasza K, Faoro L, Salgia R, Stadler WM, Vokes EE, Fleming GF (2008) 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 110:49–55PubMedCrossRefGoogle Scholar
  26. 26.
    Micha JP, Goldstein BH, Rettenmaier MA, Genesen M, Graham C, Bader K, Lopez KL, Nickle M, Brown JV III (2007) A phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advanced-stage epithelial ovarian, peritoneal, and fallopian tube cancer. Int J Gynecol Cancer 17:771–776PubMedCrossRefGoogle Scholar
  27. 27.
    Penson RT, Dizon DS, Cannistra SA, Roche MR, Krasner CN, Berlin ST, Horowitz NS, Disilvestro PA, Matulonis UA, Lee H, King MA, Campos SM (2010) Phase II study of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab as first-line chemotherapy for advanced mullerian tumors. J Clin Oncol 28:154–159PubMedCrossRefGoogle Scholar
  28. 28.
    Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, Mannel RS, Homesley HD, Fowler J, Greer BE, Boente M, Birrer MJ, Liang SX (2011) Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 365:2473–2483PubMedCrossRefGoogle Scholar
  29. 29.
    Perren TJ, Swart AM, Pfisterer J, Ledermann JA, 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 (2011) A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med 365:2484–2496PubMedCrossRefGoogle Scholar
  30. 30.
    Perren T, Swart AM, Pfisterer J, Ledermann J, Lortholary A, Kristensen G, Carey M, Beale P, Cervantes A, Oza A, on behalf of GCIG ICON7 collaborators (2010) ICON7: a phase III randomised gynaecologic cancer intergroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab, versus chemotherapy alone in women with newly diagnosed epithelial ovarian (EOC), primary peritoneal (PPC) or fallopian tube cancer (FTC). Ann Oncol 21:viii2–3, Abstract LBA4Google Scholar
  31. 31.
    Lockhart AC, Rothenberg ML, Dupont J, Cooper W, Chevalier P, Sternas L, Buzenet G, Koehler E, Sosman JA, Schwartz LH, Gultekin DH, Koutcher JA, Donnelly EF, Andal R, Dancy I, Spriggs DR, Tew WP (2010) Phase I study of intravenous vascular endothelial growth factor trap, aflibercept, in patients with advanced solid tumors. J Clin Oncol 28:207–214PubMedCrossRefGoogle Scholar
  32. 32.
    Gotlieb WH, Amant F, Advani S, Goswami C, Hirte H, Provencher D, Somani N, Yamada SD, Tamby JF, Vergote I (2012) Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol 13:154–162PubMedCrossRefGoogle Scholar
  33. 33.
    Tew WP, Colombo N, Ray-Coquard I, Oza A, del Campo J, Scambia G, Spriggs D (2007) 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: Abstract 5508Google Scholar
  34. 34.
    Coleman RL, Duska LR, Ramirez PT, Heymach JV, Kamat AA, Modesitt SC, Schmeler KM, Iyer RB, Garcia ME, Miller DL, Jackson EF, Ng CS, Kundra V, Jaffe R, Sood AK (2011) Phase 1-2 study of docetaxel plus aflibercept in patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer. Lancet Oncol 12:1109–1117PubMedCrossRefGoogle Scholar
  35. 35.
    Rapisarda A, Melillo G (2009) Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat 12:74–80PubMedCrossRefGoogle Scholar
  36. 36.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedCrossRefGoogle Scholar
  37. 37.
    Grepin R, Pages G (2010) Molecular mechanisms of resistance to tumour anti-angiogenic strategies. J Oncol 2010:835680PubMedGoogle Scholar
  38. 38.
    Henriksen R, Funa K, Wilander E, Backstrom T, Ridderheim M, Oberg K (1993) Expression and prognostic significance of platelet-derived growth factor and its receptors in epithelial ovarian neoplasms. Cancer Res 53:4550–4554PubMedGoogle Scholar
  39. 39.
    Apte SM, Bucana CD, Killion JJ, Gershenson DM, Fidler IJ (2004) Expression of platelet-derived growth factor and activated receptor in clinical specimens of epithelial ovarian cancer and ovarian carcinoma cell lines. Gynecol Oncol 93:78–86PubMedCrossRefGoogle Scholar
  40. 40.
    Dabrow MB, Francesco MR, McBrearty FX, Caradonna S (1998) The effects of platelet-derived growth factor and receptor on normal and neoplastic human ovarian surface epithelium. Gynecol Oncol 71:29–37PubMedCrossRefGoogle Scholar
  41. 41.
    Lu C, Thaker PH, Lin YG, Spannuth W, Landen CN, Merritt WM, Jennings NB, Langley RR, Gershenson DM, Yancopoulos GD, Ellis LM, Jaffe RB, Coleman RL, Sood AK (2008) Impact of vessel maturation on antiangiogenic therapy in ovarian cancer. Am J Obstet Gynecol 198:477–479PubMedCrossRefGoogle Scholar
  42. 42.
    Matei D, Emerson RE, Lai YC, Baldridge LA, Rao J, Yiannoutsos C, Donner DD (2006) Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer. Oncogene 25:2060–2069PubMedCrossRefGoogle Scholar
  43. 43.
    Wilczynski SP, Chen YY, Chen W, Howell SB, Shively JE, Alberts DS (2005) Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers. Hum Pathol 36:242–249PubMedCrossRefGoogle Scholar
  44. 44.
    Matei D, Kelich S, Cao L, Menning N, Emerson RE, Rao J, Jeng MH, Sledge GW (2007) PDGF BB induces VEGF secretion in ovarian cancer. Cancer Biol Ther 6:1951–1959PubMedGoogle Scholar
  45. 45.
    Crickard K, Gross JL, Crickard U, Yoonessi M, Lele S, Herblin WF, Eidsvoog K (1994) Basic fibroblast growth factor and receptor expression in human ovarian cancer. Gynecol Oncol 55:277–284PubMedCrossRefGoogle Scholar
  46. 46.
    Di Blasio AM, Cremonesi L, Vigano P, Ferrari M, Gospodarowicz D, Vignali M, Jaffe RB (1993) Basic fibroblast growth factor and its receptor messenger ribonucleic acids are expressed in human ovarian epithelial neoplasms. Am J Obstet Gynecol 169:1517–1523PubMedGoogle Scholar
  47. 47.
    Fujimoto J, Ichigo S, Hori M, Hirose R, Sakaguchi H, Tamaya T (1997) Expression of basic fibroblast growth factor and its mRNA in advanced ovarian cancers. Eur J Gynaecol Oncol 18:349–352PubMedGoogle Scholar
  48. 48.
    Steele IA, Edmondson RJ, Bulmer JN, Bolger BS, Leung HY, Davies BR (2001) Induction of FGF receptor 2-IIIb expression and response to its ligands in epithelial ovarian cancer. Oncogene 20:5878–5887PubMedCrossRefGoogle Scholar
  49. 49.
    Whitworth MK, Backen AC, Clamp AR, Wilson G, McVey R, Friedl A, Rapraeger AC, David G, McGown A, Slade RJ, Gallagher JT, Jayson GC (2005) Regulation of fibroblast growth factor-2 activity by human ovarian cancer tumor endothelium. Clin Cancer Res 11:4282–4288PubMedCrossRefGoogle Scholar
  50. 50.
    Valve E, Martikainen P, Seppanen J, Oksjoki S, Hinkka S, Anttila L, Grenman S, Klemi P, Harkonen P (2000) Expression of fibroblast growth factor (FGF)-8 isoforms and FGF receptors in human ovarian tumors. Int J Cancer 88:718–725PubMedCrossRefGoogle Scholar
  51. 51.
    Benjamin LE, Hemo I, Keshet E (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125:1591–1598PubMedGoogle Scholar
  52. 52.
    Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A, Vajkoczy P (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18:338–340PubMedGoogle Scholar
  53. 53.
    Casanovas O, Hicklin DJ, Bergers G, Hanahan D (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309PubMedCrossRefGoogle Scholar
  54. 54.
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95PubMedCrossRefGoogle Scholar
  55. 55.
    Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295PubMedGoogle Scholar
  56. 56.
    Lu C, Kamat AA, Lin YG, Merritt WM, Landen CN, Kim TJ, Spannuth W, Arumugam T, Han LY, Jennings NB, Logsdon C, Jaffe RB, Coleman RL, Sood AK (2007) Dual targeting of endothelial cells and pericytes in antivascular therapy for ovarian carcinoma. Clin Cancer Res 13:4209–4217PubMedCrossRefGoogle Scholar
  57. 57.
    Laschke MW, Elitzsch A, Vollmar B, Vajkoczy P, Menger MD (2006) Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic lesions. Hum Reprod 21:262–268PubMedCrossRefGoogle Scholar
  58. 58.
    Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, Smith NR, James NH, Dukes M, Curwen JO, Chester R, Jackson JA, Boffey SJ, Kilburn LL, Barnett S, Richmond GH, Wadsworth PF, Walker M, Bigley AL, Taylor ST, Cooper L, Beck S, Jurgensmeier JM, Ogilvie DJ (2005) AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res 65:4389–4400PubMedCrossRefGoogle Scholar
  59. 59.
    Matulonis UA, Berlin S, Ivy P, Tyburski K, Krasner C, Zarwan C, Berkenblit A, Campos S, Horowitz N, Cannistra SA, Lee H, Lee J, Roche M, Hill M, Whalen C, Sullivan L, Tran C, Humphreys BD, Penson RT (2009) 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 27:5601–5606PubMedCrossRefGoogle Scholar
  60. 60.
    Hirte HW, Vidal L, Fleming GF, Sugimoto AK, Morgan RJ, Biagi JJ, Wang L, McGill S, Ivy SP, Oza AM (2008) A phase II study of cediranib (AZD2171) in recurrent or persistent ovarian, peritoneal or fallopian tube cancer: final results of a PMH, Chicago and California consortia trial. J Clin Oncol 26: Abstract 5521Google Scholar
  61. 61.
    Raja FA, Griffin CL, Qian W, Hirte H, Parmar MK, Swart AM, Ledermann JA (2011) Initial toxicity assessment of ICON6: a randomised trial of cediranib plus chemotherapy in platinum-sensitive relapsed ovarian cancer. Br J CancerGoogle Scholar
  62. 62.
    Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ (2008) BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res 68:4774–4782PubMedCrossRefGoogle Scholar
  63. 63.
    du Bois A, Huober J, Stopfer P, Pfisterer J, Wimberger P, Loibl S, Reichardt VL, Harter P (2010) A phase I open-label dose-escalation study of oral BIBF 1120 combined with standard paclitaxel and carboplatin in patients with advanced gynecological malignancies. Ann Oncol 21:370–375PubMedCrossRefGoogle Scholar
  64. 64.
    Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I, Earl H, Perren T, Gore M, Persic M, Adams M, James L, Temple G, Merger M, Rustin G (2011) 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 29:3798–3804PubMedCrossRefGoogle Scholar
  65. 65.
    Sloan B, Scheinfeld NS (2008) Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Investig Drugs 9:1324–1335PubMedGoogle Scholar
  66. 66.
    Kumar R, Knick VB, Rudolph SK, Johnson JH, Crosby RM, Crouthamel MC, Hopper TM, Miller CG, Harrington LE, Onori JA, Mullin RJ, Gilmer TM, Truesdale AT, Epperly AH, Boloor A, Stafford JA, Luttrell DK, Cheung M (2007) Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther 6:2012–2021PubMedCrossRefGoogle Scholar
  67. 67.
    Friedlander M, Hancock KC, Rischin D, Messing MJ, Stringer CA, Matthys GM, Ma B, Hodge JP, Lager JJ (2010) A phase II, open-label study evaluating pazopanib in patients with recurrent ovarian cancer. Gynecol Oncol 119:32–37PubMedCrossRefGoogle Scholar
  68. 68.
    Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, Cao Y, Shujath J, Gawlak S, Eveleigh D, Rowley B, Liu L, Adnane L, Lynch M, Auclair D, Taylor I, Gedrich R, Voznesensky A, Riedl B, Post LE, Bollag G, Trail PA (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099–7109PubMedCrossRefGoogle Scholar
  69. 69.
    Matei D, Sill MW, Lankes HA, DeGeest K, Bristow RE, Mutch D, Yamada SD, Cohn D, Calvert V, Farley J, Petricoin EF, Birrer MJ (2011) Activity of sorafenib in recurrent ovarian cancer and primary peritoneal carcinomatosis: a Gynecologic Oncology Group trial. J Clin Oncol 29:69–75PubMedCrossRefGoogle Scholar
  70. 70.
    Azad NS, Posadas EM, Kwitkowski VE, Steinberg SM, Jain L, Annunziata CM, Minasian L, Sarosy G, Kotz HL, Premkumar A, Cao L, McNally D, Chow C, Chen HX, Wright JJ, Figg WD, Kohn EC (2008) Combination targeted therapy with sorafenib and bevacizumab results in enhanced toxicity and antitumor activity. J Clin Oncol 26:3709–3714PubMedCrossRefGoogle Scholar
  71. 71.
    Kohn EC, Lee J, Annunziata CM, Minasian LM, Zujewski J, Prindiville SA, Kotz HL, Squires J, Houston ND, Chen HX, Wright JJ (2011) A phase II study of intermittent sorafenib with bevacizumab in bevacizumab-naïve epithelial ovarian cancer (EOC) patients. J Clin Oncol 29: Abstract 5019Google Scholar
  72. 72.
    Ramasubbaiah R, Perkins SM, Schilder J, Whalen C, Johnson CS, Callahan M, Jones T, Sutton G, Matei D (2011) Sorafenib in combination with weekly topotecan in recurrent ovarian cancer, a phase I/II study of the Hoosier Oncology Group. Gynecol Oncol 123:499–504PubMedCrossRefGoogle Scholar
  73. 73.
    Welch SA, Hirte HW, Elit L, Schilder RJ, Wang L, Macalpine K, Wright JJ, Oza AM (2010) Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer: a study of the Princess Margaret Hospital Phase II Consortium. Int J Gynecol Cancer 20:787–793PubMedCrossRefGoogle Scholar
  74. 74.
    Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, Fukuda JY, Chu JY, Nematalla A, Wang X, Chen H, Sistla A, Luu TC, Tang F, Wei J, Tang C (2003) Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 46:1116–1119PubMedCrossRefGoogle Scholar
  75. 75.
    Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM (2003) SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2:471–478PubMedGoogle Scholar
  76. 76.
    Kim DW, Jo YS, Jung HS, Chung HK, Song JH, Park KC, Park SH, Hwang JH, Rha SY, Kweon GR, Lee SJ, Jo KW, Shong M (2006) An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 91:4070–4076PubMedCrossRefGoogle Scholar
  77. 77.
    Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9:327–337PubMedGoogle Scholar
  78. 78.
    O’Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD, Manning WC, Murray LJ, Heinrich MC, Cherrington JM (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101:3597–3605PubMedCrossRefGoogle Scholar
  79. 79.
    Baumann KH, du Bois A, Meier W, Rau J, Wimberger P, Sehouli J, Kurzeder C, Hilpert F, Hasenburg A, Canzler U, Hanker LC, Hillemanns P, Richter B, Wollschlaeger K, Dewitz T, Bauerschlag D, Wagner U (2012) A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: a randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy. Ann OncolGoogle Scholar
  80. 80.
    Biagi JJ, Oza AM, Chalchal HI, Grimshaw R, Ellard SL, Lee U, Hirte H, Sederias J, Ivy SP, Eisenhauer EA (2011) A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: an NCIC Clinical Trials Group Study. Ann Oncol 22:335–340PubMedCrossRefGoogle Scholar
  81. 81.
    Campos S, Penson R, Berlin S, Matulonis U, Horowitz N (2010) A phase II trial of sunitinib in recurrent and refractory ovarian, fallopian tube, and peritoneal carcinoma. Gynecol Oncol 116:S119-S120. Abstract 306Google Scholar
  82. 82.
    Buckanovich RJ, Berger R, Sella A, Sikic BI, Shen X, Ramies DA, Smith DC, Vergote IB (2011) Activity of cabozantinib (XL184) in advanced ovarian cancer patients (pts): Results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 29: Abstract 5008Google Scholar
  83. 83.
    Schreiber V, Dantzer F, Ame JC, de Murcia G (2006) Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol 7:517–528PubMedCrossRefGoogle Scholar
  84. 84.
    Schultz N, Lopez E, Saleh-Gohari N, Helleday T (2003) Poly(ADP-ribose) polymerase (PARP-1) has a controlling role in homologous recombination. Nucleic Acids Res 31:4959–4964PubMedCrossRefGoogle Scholar
  85. 85.
    Ashworth A (2008) A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 26:3785–3790PubMedCrossRefGoogle Scholar
  86. 86.
    Iglehart JD, Silver DP (2009) Synthetic lethality–a new direction in cancer-drug development. N Engl J Med 361:189–191PubMedCrossRefGoogle Scholar
  87. 87.
    Ledermann JA, Raja FA (2010) Targeted trials in ovarian cancer. Gynecol Oncol 119:151–156PubMedCrossRefGoogle Scholar
  88. 88.
    Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA (2001) Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet 68:700–710PubMedCrossRefGoogle Scholar
  89. 89.
    Lux MP, Fasching PA, Beckmann MW (2006) Hereditary breast and ovarian cancer: review and future perspectives. J Mol Med (Berl ) 84:16–28CrossRefGoogle Scholar
  90. 90.
    Hennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD, Abkevich V, Potter J, Pruss D, Glenn P, Li Y, Li J, Gonzalez-Angulo AM, McCune KS, Markman M, Broaddus RR, Lanchbury JS, Lu KH, Mills GB (2010) Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 28:3570–3576PubMedCrossRefGoogle Scholar
  91. 91.
    Baldwin RL, Nemeth E, Tran H, Shvartsman H, Cass I, Narod S, Karlan BY (2000) BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res 60:5329–5333PubMedGoogle Scholar
  92. 92.
    Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N, Levine DA, Cannistra SA (2010) Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol 28:3555–3561PubMedCrossRefGoogle Scholar
  93. 93.
    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 (2010) Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 376:245–251PubMedCrossRefGoogle Scholar
  94. 94.
    Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A (2011) Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol 12:852–861PubMedCrossRefGoogle Scholar
  95. 95.
    Ang J, Yap TA, Fong P, et al (2010) Preliminary experience with use of chemotherapy (CT) following treatment with olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), in patients with BRCA1/2-deficient ovarian cancer (BDOC). J Clin Oncol 28: Abstract 5041Google Scholar
  96. 96.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134PubMedCrossRefGoogle Scholar
  97. 97.
    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 (2012) Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer. J Clin Oncol 30:372–379PubMedCrossRefGoogle Scholar
  98. 98.
    Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U (2012) Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 366:1382–1392PubMedCrossRefGoogle Scholar
  99. 99.
    Penson RT, Whalen C, Lasonde B, et al (2011) A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GC) in patients with platinum-sensitive recurrent ovarian cancer. J Clin Oncol 29: Abstract 5004Google Scholar
  100. 100.
    Birrer MJ, Konstantinopoulos P, Penson RT, Roche M, Ambrosio A, Stallings TE, Matulonis U, Bradley CR (2011) A phase II trial of iniparib (BSI-201) in combination with gemcitabine/carboplatin (GC) in patients with platinum-resistant recurrent ovarian cancer. J Clin Oncol 29: Abstract 5005Google Scholar
  101. 101.
    Patel AG, De Lorenzo SB, Flatten KS, Poirier GG, Kaufmann SH (2012) Failure of iniparib to inhibit poly(ADP-Ribose) polymerase in vitro. Clin Cancer Res 18:1655–1662PubMedCrossRefGoogle Scholar
  102. 102.
    Liu X, Shi Y, Maag DX, Palma JP, Patterson MJ, Ellis PA, Surber BW, Ready DB, Soni NB, Ladror US, Xu AJ, Iyer R, Harlan JE, Solomon LR, Donawho CK, Penning TD, Johnson EF, Shoemaker AR (2012) Iniparib nonselectively modifies cysteine-containing proteins in tumor cells and is not a Bona Fide PARP inhibitor. Clin Cancer Res 18:510–523PubMedCrossRefGoogle Scholar
  103. 103.
    Liu X, Han EK, Anderson M, Shi Y, Semizarov D, Wang G, McGonigal T, Roberts L, Lasko L, Palma J, Zhu GD, Penning T, Rosenberg S, Giranda VL, Luo Y, Leverson J, Johnson EF, Shoemaker AR (2009) Acquired resistance to combination treatment with temozolomide and ABT-888 is mediated by both base excision repair and homologous recombination DNA repair pathways. Mol Cancer Res 7:1686–1692PubMedCrossRefGoogle Scholar
  104. 104.
    Edwards SL, Brough R, Lord CJ, Natrajan R, Vatcheva R, Levine DA, Boyd J, Reis-Filho JS, Ashworth A (2008) Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451:1111–1115PubMedCrossRefGoogle Scholar
  105. 105.
    Ashworth A (2008) Drug resistance caused by reversion mutation. Cancer Res 68:10021–10023PubMedCrossRefGoogle Scholar
  106. 106.
    Mazzoletti M, Broggini M (2010) PI3K/AKT/mTOR inhibitors in ovarian cancer. Curr Med Chem 17:4433–4447PubMedCrossRefGoogle Scholar
  107. 107.
    Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4:988–1004PubMedCrossRefGoogle Scholar
  108. 108.
    Meric-Bernstam F, Gonzalez-Angulo AM (2009) Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27:2278–2287PubMedCrossRefGoogle Scholar
  109. 109.
    Altomare DA, Wang HQ, Skele KL, De RA, Klein-Szanto AJ, Godwin AK, Testa JR (2004) AKT and mTOR phosphorylation is frequently detected in ovarian cancer and can be targeted to disrupt ovarian tumor cell growth. Oncogene 23:5853–5857PubMedCrossRefGoogle Scholar
  110. 110.
    Kolasa IK, Rembiszewska A, Felisiak A, Ziolkowska-Seta I, Murawska M, Moes J, Timorek A, Dansonka-Mieszkowska A, Kupryjanczyk J (2009) PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients. Cancer Biol Ther 8:21–26PubMedCrossRefGoogle Scholar
  111. 111.
    Romero I, Bast RC Jr (2012) Minireview: human ovarian cancer: biology, current management, and paths to personalizing therapy. Endocrinology 153:1593–1602PubMedCrossRefGoogle Scholar
  112. 112.
    Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix-Trench G, Thomas EJ, Campbell IG (1998) Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res 58:2095–2097PubMedGoogle Scholar
  113. 113.
    Edelman G, Bedell C, Shapiro G, Pandya SS, Kwak EL, Scheffold C, Nguyen LT, Laird A, Baselga J, Rodon J (2010) A phase I dose-escalation study of XL147 (SAR245408), a PI3K inhibitor administered orally to patients (pts) with advanced solid tumors. J Clin Oncol 28: Abstract 3004Google Scholar
  114. 114.
    Traynor AM, Kurzrock R, Bailey HH, Attia S, Scheffold C, van Leeuwen B, Wu B, Falchook GS, Moulder SL, Wheler J (2010) A phase I safety and pharmacokinetic (PK) study of PI3K inhibitor XL147 (SAR245408) in combination with paclitaxel (P) and carboplatin (C) in patients (pts) with advanced solid tumors. J Clin Oncol 28: Abstract 3078Google Scholar
  115. 115.
    Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, Minion DJ, Halter RJ, Wipf P, Abraham R, Kirkpatrick L, Powis G (2004) Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther 3:763–772PubMedGoogle Scholar
  116. 116.
    Jimeno A, Herbst RS, Falchook GS, Messersmith WA, Hecker S, Peterson S, Hausman DF, Kurzrock R, Eckhardt SG, Hong DS (2010) Final results from a phase I, dose-escalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase. J Clin Oncol 28: Abstract 3089Google Scholar
  117. 117.
    Mabuchi S, Altomare DA, Connolly DC, Klein-Szanto A, Litwin S, Hoelzle MK, Hensley HH, Hamilton TC, Testa JR (2007) RAD001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Res 67:2408–2413PubMedCrossRefGoogle Scholar
  118. 118.
    Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, Schilder RJ, Ozols RF, Testa JR (2007) RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 13:4261–4270PubMedCrossRefGoogle Scholar
  119. 119.
    Mabuchi S, Kawase C, Altomare DA, Morishige K, Sawada K, Hayashi M, Tsujimoto M, Yamoto M, Klein-Szanto AJ, Schilder RJ, Ohmichi M, Testa JR, Kimura T (2009) mTOR is a promising therapeutic target both in cisplatin-sensitive and cisplatin-resistant clear cell carcinoma of the ovary. Clin Cancer Res 15:5404–5413PubMedCrossRefGoogle Scholar
  120. 120.
    Temkin SM, Yamada SD, Fleming GF (2010) A phase I study of weekly temsirolimus and topotecan in the treatment of advanced and/or recurrent gynecologic malignancies. Gynecol Oncol 117:473–476PubMedCrossRefGoogle Scholar
  121. 121.
    Morgan R, Oza AM, Qin R, Laumann KM, Mackay H, Strevel EL, Welch S, Sullivan D, Wenham RM, Chen HX, Doyle LA, Gandara DR, Erlichman C (2011) 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: Abstract 5015Google Scholar
  122. 122.
    Behbakht K, Sill MW, Darcy KM, Rubin SC, Mannel RS, Waggoner S, Schilder RJ, Cai KQ, Godwin AK, Alpaugh RK (2011) Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study. Gynecol Oncol 123:19–26PubMedCrossRefGoogle Scholar
  123. 123.
    O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508PubMedCrossRefGoogle Scholar
  124. 124.
    Van Ummersen L, Binger K, Volkman J, Marnocha R, Tutsch K, Kolesar J, Arzoomanian R, Alberti D, Wilding G (2004) A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res 10:7450–7456PubMedCrossRefGoogle Scholar
  125. 125.
    Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK (2003) Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2:1093–1103PubMedGoogle Scholar
  126. 126.
    Engel JB, Schonhals T, Hausler S, Krockenberger M, Schmidt M, Horn E, Koster F, Dietl J, Wischhusen J, Honig A (2010) Induction of programmed cell death by inhibition of AKT with the alkylphosphocholine perifosine in in vitro models of platinum sensitive and resistant ovarian cancers. Arch Gynecol Obstet 283:603–610PubMedCrossRefGoogle Scholar
  127. 127.
    Fu S, Hennessy BT, Ng CS, Ju Z, Coombes KR, Wolf JK, Sood AK, Levenback CF, Coleman RL, Kavanagh JJ, Gershenson DM, Markman M, Dice K, Howard A, Li J, Li Y, Stemke-Hale K, Dyer M, Atkinson E, Jackson E, Kundra V, Kurzrock R, Bast RC, Jr., Mills GB (2012) Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer. Gynecol Oncol. doi:10.1016/j.ygyno.2012.04.006
  128. 128.
    Abrams SL, Steelman LS, Shelton JG, Wong EW, Chappell WH, Basecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA (2010) The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle 9:1781–1791PubMedCrossRefGoogle Scholar
  129. 129.
    Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, Russo M, Cancelliere C, Zecchin D, Mazzucchelli L, Sasazuki T, Shirasawa S, Geuna M, Frattini M, Baselga J, Gallicchio M, Biffo S, Bardelli A (2010) Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest 120:2858–2866PubMedCrossRefGoogle Scholar
  130. 130.
    Kinross KM, Brown DV, Kleinschmidt M, Jackson S, Christensen J, Cullinane C, Hicks RJ, Johnstone RW, McArthur GA (2011) In vivo activity of combined PI3K/mTOR and MEK-inhibition in a KrasG12D;Pten deletion mouse model of ovarian cancer. Mol Cancer Ther 10:1440–1449PubMedCrossRefGoogle Scholar
  131. 131.
    Farley J, Brady W, Birrer M, Lankes H, Coleman R, Morgan M, Mannel R, Yamada D, Mutch D, Gershenson D (2011) A phase II trial of AZD6244 in women with recurrent low-grade serous carcinoma of the ovary or peritoneum. Int J Gynaecol Cancer 21:38Google Scholar
  132. 132.
    Blagden S, Gabra H (2009) Promising molecular targets in ovarian cancer. Curr Opin Oncol 21:412–419PubMedCrossRefGoogle Scholar
  133. 133.
    Wiener JR, Nakano K, Kruzelock RP, Bucana CD, Bast RC Jr, Gallick GE (1999) Decreased Src tyrosine kinase activity inhibits malignant human ovarian cancer tumor growth in a nude mouse model. Clin Cancer Res 5:2164–2170PubMedGoogle Scholar
  134. 134.
    Wiener JR, Windham TC, Estrella VC, Parikh NU, Thall PF, Deavers MT, Bast RC, Mills GB, Gallick GE (2003) Activated SRC protein tyrosine kinase is overexpressed in late-stage human ovarian cancers. Gynecol Oncol 88:73–79PubMedCrossRefGoogle Scholar
  135. 135.
    Chen T, Pengetnze Y, Taylor CC (2005) Src inhibition enhances paclitaxel cytotoxicity in ovarian cancer cells by caspase-9-independent activation of caspase-3. Mol Cancer Ther 4:217–224PubMedGoogle Scholar
  136. 136.
    Pengetnze Y, Steed M, Roby KF, Terranova PF, Taylor CC (2003) Src tyrosine kinase promotes survival and resistance to chemotherapeutics in a mouse ovarian cancer cell line. Biochem Biophys Res Commun 309:377–383PubMedCrossRefGoogle Scholar
  137. 137.
    Konecny GE, Glas R, Dering J, Manivong K, Qi J, Finn RS, Yang GR, Hong KL, Ginther C, Winterhoff B, Gao G, Brugge J, Slamon DJ (2009) Activity of the multikinase inhibitor dasatinib against ovarian cancer cells. Br J Cancer 101:1699–1708PubMedCrossRefGoogle Scholar
  138. 138.
    Teoh D, Ayeni TA, Rubatt JM, Adams DJ, Grace L, Starr MD, Barry WT, Berchuck A, Murphy SK, Secord AA (2011) Dasatinib (BMS-35482) has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells. Gynecol Oncol 121(1):187–192Google Scholar
  139. 139.
    Poole C, Lisyanskaya A, Rodenhuis S, Kristensen G, Pujade-Lauraine E, Cantarini M, Emeribe U, Stuart M, Ray-Coquard I (2010) A randomized phase II clinical trial of the Src inhibitor saracatinib (AZD0530) and carboplatin + paclitaxel (C + P) versus C + P in patients (pts) with advanced platinum-sensitive epithelial ovarian cancer (EOC). Ann Oncol 21:viii304. doi:Abstract9720 CrossRefGoogle Scholar
  140. 140.
    Lafky JM, Wilken JA, Baron AT, Maihle NJ (2008) Clinical implications of the ErbB/epidermal growth factor (EGF) receptor family and its ligands in ovarian cancer. Biochim Biophys Acta 1785:232–265PubMedGoogle Scholar
  141. 141.
    Mendelsohn J, Baselga J (2000) The EGF receptor family as targets for cancer therapy. Oncogene 19:6550–6565PubMedCrossRefGoogle Scholar
  142. 142.
    Normanno N, De LA, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De FG, Caponigro F, Salomon DS (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366:2–16PubMedCrossRefGoogle Scholar
  143. 143.
    Posadas EM, Liel MS, Kwitkowski V, Minasian L, Godwin AK, Hussain MM, Espina V, Wood BJ, Steinberg SM, Kohn EC (2007) A phase II and pharmacodynamic study of gefitinib in patients with refractory or recurrent epithelial ovarian cancer. Cancer 109:1323–1330PubMedCrossRefGoogle Scholar
  144. 144.
    Gordon AN, Finkler N, Edwards RP, Garcia AA, Crozier M, Irwin DH, Barrett E (2005) Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. Int J Gynecol Cancer 15:785–792PubMedCrossRefGoogle Scholar
  145. 145.
    Mavroudis D, Efstathiou E, Polyzos A, Athanasiadis A, Milaki G, Kastritis E, Kalykaki A, Saridaki Z, Dimopoulos A, Georgoulias V (2004) A phase I-II trial of gefitinib in combination with vinorelbine and oxaliplatin as salvage therapy in women with advanced ovarian cancer (AOC). J Clin Oncol 22: Abstract 5020Google Scholar
  146. 146.
    Pautier P, Joly F, Kerbrat P, Bougnoux P, Fumoleau P, Petit T, Rixe O, Ringeisen F, Carrasco AT, Lhomme C (2010) Phase II study of gefitinib in combination with paclitaxel (P) and carboplatin (C) as second-line therapy for ovarian, tubal or peritoneal adenocarcinoma (1839IL/0074). Gynecol Oncol 116:157–162PubMedCrossRefGoogle Scholar
  147. 147.
    Vasey PA, Gore M, Wilson R, Rustin G, Gabra H, Guastalla JP, Lauraine EP, Paul J, Carty K, Kaye S (2008) A phase Ib trial of docetaxel, carboplatin and erlotinib in ovarian, fallopian tube and primary peritoneal cancers. Br J Cancer 98:1774–1780PubMedCrossRefGoogle Scholar
  148. 148.
    Bookman MA, Darcy KM, Clarke-Pearson D, Boothby RA, Horowitz IR (2003) Evaluation of monoclonal humanized anti-HER2 antibody, trastuzumab, in patients with recurrent or refractory ovarian or primary peritoneal carcinoma with overexpression of HER2: a phase II trial of the Gynecologic Oncology Group. J Clin Oncol 21:283–290PubMedCrossRefGoogle Scholar
  149. 149.
    Kimball KJ, Numnum TM, Kirby TO, Zamboni WC, Estes JM, Barnes MN, Matei DE, Koch KM, Alvarez RD (2008) A phase I study of lapatinib in combination with carboplatin in women with platinum sensitive recurrent ovarian carcinoma. Gynecol Oncol 111:95–101PubMedCrossRefGoogle Scholar
  150. 150.
    Joly F, Weber B, Pautier P, Fabbro M, Selle F, Krieger S, Leconte A, Bourgeois H, Henry-Amar M (2009) Combined topotecan and lapatinib in patients with early recurrent ovarian and peritoneal cancer after first line of platinum-based chemotherapy: a French FEDEGYN-FNCLCC Phase II trial. J Clin Oncol 27: Abstract 5555Google Scholar
  151. 151.
    Schilder RJ, Pathak HB, Lokshin AE, Holloway RW, Alvarez RD, Aghajanian C, Min H, Devarajan K, Ross E, Drescher CW, Godwin AK (2009) Phase II trial of single agent cetuximab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with the potential for dose escalation to rash. Gynecol Oncol 113:21–27PubMedCrossRefGoogle Scholar
  152. 152.
    Konner J, Schilder RJ, DeRosa FA, Gerst SR, Tew WP, Sabbatini PJ, Hensley ML, Spriggs DR, Aghajanian CA (2008) A phase II study of cetuximab/paclitaxel/carboplatin for the initial treatment of advanced-stage ovarian, primary peritoneal, or fallopian tube cancer. Gynecol Oncol 110:140–145PubMedCrossRefGoogle Scholar
  153. 153.
    Secord AA, Blessing JA, Armstrong DK, Rodgers WH, Miner Z, Barnes MN, Lewandowski G, Mannel RS (2008) Phase II trial of cetuximab and carboplatin in relapsed platinum-sensitive ovarian cancer and evaluation of epidermal growth factor receptor expression: a Gynecologic Oncology Group study. Gynecol Oncol 108:493–499PubMedCrossRefGoogle Scholar
  154. 154.
    Gordon MS, Matei D, Aghajanian C, Matulonis UA, Brewer M, Fleming GF, Hainsworth JD, Garcia AA, Pegram MD, Schilder RJ, Cohn DE, Roman L, Derynck MK, Ng K, Lyons B, Allison DE, Eberhard DA, Pham TQ, Dere RC, Karlan BY (2006) Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J Clin Oncol 24:4324–4332PubMedCrossRefGoogle Scholar
  155. 155.
    Kaye SB, Poole CJ, Bidzinksi M, Gianni L, Gorbunova V, Novikova E, Strauss A, McNally VA, Ross G, Vergote I (2008) A randomized phase II study evaluating the combination of carboplatin-based chemotherapy with pertuzumab (P) versus carboplatin-based therapy alone in patients with relapsed, platinum sensitive ovarian cancer. J Clin Oncol 26: Abstract 5520Google Scholar
  156. 156.
    Makhija S, Amler LC, Glenn D, Ueland FR, Gold MA, Dizon DS, Paton V, Lin CY, Januario T, Ng K, Strauss A, Kelsey S, Sliwkowski MX, Matulonis U (2010) Clinical activity of gemcitabine plus pertuzumab in platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. J Clin Oncol 28:1215–1223PubMedCrossRefGoogle Scholar
  157. 157.
    Cheng L, Zhang S, Alexander R, Yao Y, Maclennan GT, Pan CX, Huang J, Wang M, Montironi R, Lopez-Beltran A (2011) The landscape of EGFR pathways and personalized management of non-small-cell lung cancer. Future Oncol 7:519–541PubMedCrossRefGoogle Scholar
  158. 158.
    Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, Burenkova O, Pace E, Walton Z, Nie L, Fulgham A, Song Y, Nielsen UB, Engelman JA, Wong KK (2010) An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res 70:2485–2494PubMedCrossRefGoogle Scholar
  159. 159.
    Annunziata CM, Walker AJ, Minasian L, Yu M, Kotz H, Wood BJ, Calvo K, Choyke P, Kimm D, Steinberg SM, Kohn EC (2010) Vandetanib, designed to inhibit VEGFR2 and EGFR signaling, had no clinical activity as monotherapy for recurrent ovarian cancer and no detectable modulation of VEGFR2. Clin Cancer Res 16:664–672PubMedCrossRefGoogle Scholar
  160. 160.
    Kamat AA, Kim TJ, Landen CN Jr, Lu C, Han LY, Lin YG, Merritt WM, Thaker PH, Gershenson DM, Bischoff FZ, Heymach JV, Jaffe RB, Coleman RL, Sood AK (2007) Metronomic chemotherapy enhances the efficacy of antivascular therapy in ovarian cancer. Cancer Res 67:281–288PubMedCrossRefGoogle Scholar
  161. 161.
    Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, Hartmann LC (2008) Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol 108:619–626PubMedCrossRefGoogle Scholar
  162. 162.
    Konner JA, Bell-McGuinn KM, Sabbatini P, Hensley ML, Tew WP, Pandit-Taskar N, Vander EN, Phillips MD, Schweizer C, Weil SC, Larson SM, Old LJ (2010) Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer: a phase I study. Clin Cancer Res 16:5288–5295PubMedCrossRefGoogle Scholar
  163. 163.
    White AJ, Coleman RL, Armstrong DK, Glenn D, Bicher A, Richards DA, Schneeweiss A, Old LJ, Schweizer C, Weil S (2010) Efficacy and safety of farletuzumab, a humanized monoclonal antibody to folate receptor alpha, in platinum-sensitive relapsed ovarian cancer subjects: final data from a multicenter phase II study. J Clin Oncol 28: Abstract 5001Google Scholar
  164. 164.
    Elit L, Konner JA, Armstrong DK, Buck M, Dean A, Finkler NJ, Hulstine A, Schweizer C, Phillips M, Weil S (2010) A randomized, double-blind, placebo-controlled phase II study of the efficacy and safety of farletuzumab (MORAb-003) in combination with weekly paclitaxel in subjects with platinum-resistant or refractory relapsed ovarian cancer. J Clin Oncol 28: Abstract TPS255Google Scholar
  165. 165.
    Naumann RW et al (2011) PRECEDENT: A randomized phase II trial comparing EC145 and pegylated liposomal doxorubicin (PLD) in combination, versus PLD alone, in subjects with platinumresistant ovarian cancer. J Clin Oncol 29:343s, Abstract 5045Google Scholar
  166. 166.
    Furstenberger G, Senn HJ (2002) Insulin-like growth factors and cancer. Lancet Oncol 3:298–302PubMedCrossRefGoogle Scholar
  167. 167.
    Kalli KR, Falowo OI, Bale LK, Zschunke MA, Roche PC, Conover CA (2002) Functional insulin receptors on human epithelial ovarian carcinoma cells: implications for IGF-II mitogenic signaling. Endocrinology 143:3259–3267PubMedCrossRefGoogle Scholar
  168. 168.
    Spentzos D, Cannistra SA, Grall F, Levine DA, Pillay K, Libermann TA, Mantzoros CS (2007) IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer. Endocr Relat Cancer 14:781–790PubMedCrossRefGoogle Scholar
  169. 169.
    Cancer Genome Atlas Research Network (2011) Integrated genomic analyses of ovarian carcinoma. Nature 474:609–615CrossRefGoogle Scholar
  170. 170.
    Leijen S, Beijnen JH, Schellens JH (2010) Abrogation of the G2 checkpoint by inhibition of Wee-1 kinase results in sensitization of p53-deficient tumor cells to DNA-damaging agents. Curr Clin Pharmacol 5:186–191PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Shannon N. Westin
    • 1
  • Thomas J. Herzog
    • 2
  • Robert L. Coleman
    • 1
  1. 1.Department of Gynecologic Oncology and Reproductive MedicineUniversity of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Division of Gynecologic Oncology, Department of OB/GYNColumbia University College of Physicians and SurgeonsNew YorkUSA

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