Frontiers of Medicine in China

, Volume 3, Issue 3, pp 256–264

Molecular targeted therapy of gynecological malignant tumors: the development and challenge, from laboratory to clinic



More and more molecular drugs based on targeted therapy have been utilized in the treatment of gynecologic cancer, especially in ovarian cancer. In this article, we systematically review the current targeted therapeutic trials running in clinic. Large, randomized trials have been conducted in the treatment of ovarian cancer, endometrial cancer and cervical cancer by usingsmall molecule, antisense, mutational gene as well as antibodies. Other planned or ongoing trials currently targeted at molecular markers which may play important roles in gynecological carcinogenesis and progression suggest that combination chemotherapy with molecular targeted therapy will ultimately be an important option.


target therapy gynecologic malignant tumors clinical trail molecular medicine 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Rosner B A, Colditz G A, Webb P M, Hankinson S E. Mathematical models of ovarian cancer incidence. Epidemiology, 2005, 16(4): 508–515PubMedCrossRefGoogle Scholar
  2. 2.
    Novac L, Grigore T, Cernea N, Niculescu M, Cotarcea S. Incidence of endometrial carcinoma in patients with endometrial hyperplasia. Eur J Gynaecol Oncol, 2005, 26(5): 561–563PubMedGoogle Scholar
  3. 3.
    Katz I T, Wright A A. Preventing cervical cancer in the developing world. N Engl J Med, 2006, 354(11): 1110PubMedCrossRefGoogle Scholar
  4. 4.
    Farley J H, Birrer M J. Biologic directed therapies in gynecologic oncology. Curr Oncol Rep, 2003, 5(6): 459–467PubMedCrossRefGoogle Scholar
  5. 5.
    Qian C, Prieto J. Gene therapy of cancer: induction of anti-tumor immunity. Cell Mol Immunol, 2004, 1(2): 105–111PubMedGoogle Scholar
  6. 6.
    Copland M, Jorgensen H G, Holyoake T L. Evolving molecular therapy for chronic myeloid leukaemia-are we on target? Hematology, 2005, 10(5): 349–359PubMedCrossRefGoogle Scholar
  7. 7.
    Stipsanelli E, Valsamaki P. Monoclonal antibodies: old and new trends in breast cancer imaging and therapeutic approach. Hell J Nucl Med, 2005, 8(2): 103–108PubMedGoogle Scholar
  8. 8.
    Zhang Z, Li M, Rayburn E R, Hill D L, Zhang R, Wang H. Oncogenes as novel targets for cancer therapy (part II): Intermediate signaling molecules. Am J Pharmacogenomics, 2005, 5(6): 247–257PubMedCrossRefGoogle Scholar
  9. 9.
    Sharma S, Odunsi K. Targeted therapy for epithelial ovarian cancer. Expert Opin Ther Targets, 2005, 9(3): 501–513PubMedCrossRefGoogle Scholar
  10. 10.
    Hyde J, McMeekin D S. Targeted therapies for gynecologic malignancies. Curr Treat Options Oncol, 2005, 6(2): 121–132PubMedCrossRefGoogle Scholar
  11. 11.
    Kumar R, Hung M C. Signaling intricacies take center stage in cancer cells. Cancer Res, 2005, 65(7): 2511–2515PubMedCrossRefGoogle Scholar
  12. 12.
    Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis-the p53 network. J Cell Sci, 2003, 116(20): 4077–4085PubMedCrossRefGoogle Scholar
  13. 13.
    Hanahan D, Weinberg R A. The hallmarks of cancer. Cell, 2000, 100(1): 57–70PubMedCrossRefGoogle Scholar
  14. 14.
    Sanseverino F, Torricelli M, Petraglia F, Giordano A. Role of the retinoblastoma family in gynecological cancer. Cancer Biol Ther, 2003, 2(6): 636–641PubMedGoogle Scholar
  15. 15.
    Crowe D L, Kim R, Chandraratna R A. Retinoic acid differentially regulates cancer cell proliferation via dose-dependent modulation of the mitogen-activated protein kinase pathway. Mol Cancer Res, 2003, 1(7): 532–540PubMedGoogle Scholar
  16. 16.
    Katayama K, Dobashi Y, Kitagawa M, Kawai M, Kadoya Y, Kameya T. Cdk4/cyclin D1 kinase, a universal and critical regulator of apoptosis. Anticancer Res, 2003, 23(1A): 235–243PubMedGoogle Scholar
  17. 17.
    Mammas I N, Zafiropoulos A, Spandidos D A. Involvement of the ras genes in female genital tract cancer. Int J Oncol, 2005, 26(5): 1241–1255PubMedGoogle Scholar
  18. 18.
    Wang Y, Kristensen G B, Helland A, Nesland JM, Borresen-Dale A L, Holm R. Protein expression and prognostic value of genes in the erb-b signaling pathway in advanced ovarian carcinomas. Am J Clin Pathol, 2005, 124(3): 392–401PubMedCrossRefGoogle Scholar
  19. 19.
    Hennessy B T, Smith D L, Ram P T, Lu Y, Mills G B. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov, 2005, 4(12): 988–1004PubMedCrossRefGoogle Scholar
  20. 20.
    Thomas G V. mTOR and cancer: reason for dancing at the crossroads? Curr Opin Genet Dev, 2006, 16(1): 78–84PubMedCrossRefGoogle Scholar
  21. 21.
    Choo A Y, Blenis J. TORgeting oncogene addiction for cancer therapy. Cancer Cell, 2006, 9(2): 77–79PubMedCrossRefGoogle Scholar
  22. 22.
    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): 630–635PubMedCrossRefGoogle Scholar
  23. 23.
    Hirano T, Shino Y, Saito T, Komoda F, Okutomi Y, Takeda A, Ishihara T, Yamaguchi T, Saisho H, Shirasawa H. Dominant negative MEKK1 inhibits survival of pancreatic cancer cells. Oncogene, 2002, 21(38): 5923–5928PubMedCrossRefGoogle Scholar
  24. 24.
    Silver D L, Naora H, Liu J, Cheng W, Montell D J. Activated signal transducer and activator of transcription (STAT) 3: localization in focal adhesions and function in ovarian cancer cell motility. Cancer Res, 2004, 64(10): 3550–3558PubMedCrossRefGoogle Scholar
  25. 25.
    Wang S C, Hung M C. HER2 overexpression and cancer targeting. Semin Oncol, 2001, 28(5 Suppl 16): 115–124PubMedCrossRefGoogle Scholar
  26. 26.
    Mizuki M, Ueda S, Matsumura I, Ishiko J, Schwable J, Serve H, Kanakura Y. Oncogenic receptor tyrosine kinase in leukemia. Cell Mol Biol (Noisy-le-grand), 2003, 49(6): 907–922Google Scholar
  27. 27.
    Hu W, Kavanagh J J. Anticancer therapy targeting the apoptotic pathway. Lancet Oncol, 2003, 4(12): 721–729PubMedCrossRefGoogle Scholar
  28. 28.
    Leonard J V, Schapira A H. Mitochondrial respiratory chain disorders I: mitochondrial DNA defects. Lancet, 2000, 355(9200): 299–304PubMedCrossRefGoogle Scholar
  29. 29.
    Sherbet G V, Patil D. Genetic abnormalities of cell proliferation, invasion and metastasis, with special reference to gynaecological cancers. Anticancer Res, 2003, 23(2B): 1357–1371PubMedGoogle Scholar
  30. 30.
    Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer, 2005, 5(4): 275–284PubMedCrossRefGoogle Scholar
  31. 31.
    Sirotnak F M, Zakowski M F, Miller V A, Scher H I, Kris M G. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res, 2000, 6(12): 4885–4892PubMedGoogle Scholar
  32. 32.
    Gadducci A, Cosio S, Genazzani A R. Old and new perspectives in the pharmacological treatment of advanced or recurrent endometrial cancer: Hormonal therapy, chemotherapy and molecularly targeted therapies. Crit Rev Oncol Hematol, 2006, 58(3): 242–256PubMedCrossRefGoogle Scholar
  33. 33.
    Sewell J M, Macleod K G, Ritchie A, Smyth J F, Langdon S P. Targeting the EGF receptor in ovarian cancer with the tyrosine kinase inhibitor ZD 1839 (“Iressa”). British J Cancer, 2002, 86(3): 456–462CrossRefGoogle Scholar
  34. 34.
    Schilder R J, Sill M W, Chen X, Darcy K M, Decesare S L, Lewandowski G, Lee R B, Arciero C A, Wu H, Godwin A K. Phase II study of gefitinib in patients with relapsed or persistent ovarian or primary peritoneal carcinoma and evaluation of epidermal growth factor receptor mutations and immunohistochemical expression: a Gynecologic Oncology Group Study. Clin Cancer Res, 2005, 11(15): 5539–5548PubMedCrossRefGoogle Scholar
  35. 35.
    Gordon A N, Finkler N, Edwards R P, Garcia A A, Crozier M, Irwin D H, Barrett E. 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, 2005, 15(5): 785–792PubMedCrossRefGoogle Scholar
  36. 36.
    Xiong H Q, Herbst R, Faria S C, Scholz C, Davis D, Jackson E F, Madden T, McConkey D, Hicks M, Hess K, Charnsangavej C A, Abbruzzese J L. A phase I surrogate endpoint study of SU6668 in patients with solid tumors. Invest New Drugs, 2004, 22(4): 459–466PubMedCrossRefGoogle Scholar
  37. 37.
    Del Carmen M G, Rizvi I, Chang Y, Moor A C, Oliva E, Sherwood M, Pogue B, Hasan T. Synergism of epidermal growth factor receptor-targeted immunotherapy with photodynamic treatment of ovarian cancer in vivo. J Natl Cancer Inst, 2005, 97(20): 1516–1524PubMedCrossRefGoogle Scholar
  38. 38.
    Cohn D E, Valmadre S, Resnick K E, Eaton L A, Copeland L J, Fowler J M. Bevacizumab and weekly taxane chemotherapy demonstrates activity in refractory ovarian cancer. Gynecol Oncol, 2006, 102(2): 131–133CrossRefGoogle Scholar
  39. 39.
    Bookman M A, Darcy K M, Clarke-Pearson D, Boothby R A, Horowitz I R. 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, 2003, 21(2): 283–290PubMedCrossRefGoogle Scholar
  40. 40.
    Santin A D, Bellone S, Gokden M, Palmieri M, Dunn D, Agha J, Roman J J, Hutchins L, Pecorelli S, O’Brien T, Cannon MJ, Parham G P. Overexpression of HER-2/neu in uterine serous papillary cancer. Clin Cancer Res, 2002, 8(5): 1271–1279PubMedGoogle Scholar
  41. 41.
    Oza A M, Elit L, Swenerton K, Faught W, Ghatage P, Carey M, McIntosh L, Dorr A, Holmlund J T, Eisenhauer E. Phase II study of CGP 69846A (ISIS 5132) in recurrent epithelial ovarian cancer: an NCIC clinical trials group study (NCIC IND.116). Gynecol Oncol, 2003, 89(1): 129–133PubMedCrossRefGoogle Scholar
  42. 42.
    Advani R, Peethambaram P, Lum B L, Fisher G A, Hartmann L, Long H J, Halsey J, Holmlund J T, Dorr A, Sikic B I. A Phase II trial of aprinocarsen, an antisense oligonucleotide inhibitor of protein kinase C alpha, administered as a 21-day infusion to patients with advanced ovarian carcinoma. Cancer, 2004, 100(2): 321–326PubMedCrossRefGoogle Scholar
  43. 43.
    Armstrong D K, Blessing J A, Look K Y, Schilder R, Nunez E R. A randomized phase II evaluation of bryostatin-1 (NSC #339555) in recurrent or persistent platinum-sensitive ovarian cancer: a Gynecologic Oncology Group Study. Invest New Drugs, 2003, 21(3): 373–377PubMedCrossRefGoogle Scholar
  44. 44.
    Smith V, Hobbs S, Court W, Eccles S, Workman P, Kelland L R. ErbB2 overexpression in an ovarian cancer cell line confers sensitivity to the HSP90 inhibitor geldanamycin. Anticancer Res, 2002, 22(4): 1993–1999PubMedGoogle Scholar
  45. 45.
    Aghajanian C, Dizon D S, Sabbatini P, Raizer J J, Dupont J, Spriggs D R. Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer. J Clin Oncol, 2005, 23(25): 5943–5949PubMedCrossRefGoogle Scholar
  46. 46.
    Siu L L, Awada A, Takimoto C H, Piccart M, Schwartz B, Giannaris T, Lathia C, Petrenciuc O, Moore M J. Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer. Clin Cancer Res, 2006, 12(1): 144–151PubMedCrossRefGoogle Scholar
  47. 47.
    Buller R E, Runnebaum I B, Karlan B Y, Horowitz J A, Shahin M, Buekers T, Petrauskas S, Kreienberg R, Slamon D, Pegram M. A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer. Cancer Gene Ther, 2002, 9(7): 553–566PubMedCrossRefGoogle Scholar
  48. 48.
    Hortobagyi G N, Ueno N T, Xia W, Zhang S, Wolf J K, Putnam J B, Weiden P L, Willey J S, Carey M, Branham D L, Payne J Y, Tucker S D, Bartholomeusz C, Kilbourn R G, De Jager R L, Sneige N, Katz R L, Anklesaria P, Ibrahim N K, Murray J L, Theriault R L, Valero V, Gershenson D M, Bevers M W, Huang L, Lopez-Berestein G, Hung M C. Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial. J Clin Oncol, 2001, 19 (14): 3422–3433PubMedGoogle Scholar
  49. 49.
    Kavanagh J J, Gershenson DM, Choi H, Lewis L, Patel K, Brown G L, Garcia A, Spriggs D R. Multi-institutional phase 2 study of TLK286 (TELCYTA, a glutathione S-transferase P1-1 activated glutathione analog prodrug) in patients with platinum and paclitaxel refractory or resistant ovarian cancer. Int J Gynecol Cancer, 2005, 15(4): 593–600PubMedCrossRefGoogle Scholar
  50. 50.
    Vasey P A, Shulman L N, Campos S, Davis J, Gore M, Johnston S, Kirn D H, O’Neill V, Siddiqui N, Seiden M V, Kaye S B. Phase I trial of intraperitoneal injection of the E1B-55-kd-gene-deleted adenovirus ONYX-015 (dl1520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol, 2002, 20(6): 1562–1569PubMedCrossRefGoogle Scholar
  51. 51.
    Geffen D B, Man S. New drugs for the treatment of cancer, 1990–2001. Isr Med Assoc J, 2002, 4(12): 1124–1131PubMedGoogle Scholar
  52. 52.
    Libermann T A, Zerbini L F. Targeting transcription factors for cancer gene therapy. Curr Gene Ther, 2006, 6(1): 17–33PubMedCrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH 2009

Authors and Affiliations

  1. 1.Institute of Gynecologic Oncology, Fujian Provincial Women and Children’s HospitalFujian Medical UniversityFuzhouChina
  2. 2.Department of GynecologyCampus Virchow KlinikumBerlinGermany
  3. 3.Department of GynecologyPeking University People’s HospitalBeijingChina

Personalised recommendations