Top

International Journal of Clinical Oncology

Published in:

01-10-2012 | Review Article

Molecular-targeted therapies for ovarian cancer: prospects for the future

Author: Tamotsu Sudo

Published in: International Journal of Clinical Oncology | Issue 5/2012

Abstract

Ovarian cancer accounts for approximately 4 % of cancer deaths in women worldwide, with around 225,000 estimated new cases diagnosed each year and 140,000 related deaths. Prompt diagnosis is challenging because of the non-specific symptoms exhibited during the early stages of the disease; consequently, 50 % of cases present with advanced metastatic cancer, and 5-year survival rates are limited to 10–30 %. Furthermore, disease recurrence occurs in a high proportion of cases, and the survival rate is only 30 % even in patients who are sensitive to platinum-based chemotherapy. This review describes the increased characterization of the molecular mechanisms involved in the development and progression of ovarian cancer, and how this has resulted in improved therapeutic strategies with molecular-targeted agents. These include targeting BRCA mutations to affect DNA repair, inhibition of the mTOR and MAPK pathways, and anti-angiogenesis therapies. Ultimately, personalized therapy using novel biomarkers in parallel with improved early detection techniques could significantly enhance the prognosis of ovarian cancer patients.

Jemal A, Siegel R, Ward E et al (2008) Cancer statistics, 2008. CA Cancer J Clin 58(2):71–96PubMedCrossRef

Hoskins WJ, Bundy BN, Thigpen JT et al (1992) The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 47(2):159–166PubMedCrossRef

Hoskins WJ, McGuire WP, Brady MF et al (1994) The effect of diameter of largest residual disease on survival after primary cytoreductive surgery in patients with suboptimal residual epithelial ovarian carcinoma. Am J Obstet Gynecol 170(4): 974–979 (discussion 979–980)

Eisenkop SM, Friedman RL, Wang HJ (1998) Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 69(2):103–108PubMedCrossRef

Ozols RF, Bundy BN, Greer BE et al (2003) Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21(17):3194–3200PubMedCrossRef

du Bois A, Neijt JP, Thigpen JT (1999) First line chemotherapy with carboplatin plus paclitaxel in advanced ovarian cancer–a new standard of care? Ann Oncol 10(Suppl 1):35–41PubMedCrossRef

Biagi JJ, Eisenhauer EA (2003) Systemic treatment policies in ovarian cancer: the next 10 years. Int J Gynecol Cancer 13(Suppl 2):231–240PubMedCrossRef

Neijt JP, Engelholm SA, Tuxen MK (2000) Exploratory phase III study of paclitaxel and cisplatin versus paclitaxel and carboplatin in advanced ovarian cancer. J Clin Oncol 18(17):3084–3092PubMed

Sandercock J, Parmar MK, Torri V et al (2002) First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence. Br J Cancer 87(8):815–824PubMedCrossRef

10.

Greenlee RT, Hill-Harmon MB, Murray T et al (2001) Cancer statistics, 2001. CA Cancer J Clin 51(1):15–36

11.

Gore ME, Fryatt I, Wiltshaw E et al (1990) Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 36(2):207–211PubMedCrossRef

12.

Agarwal R, Kaye SB (2003) Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer 3(7):502–516PubMedCrossRef

13.

Sudo T, Ota Y, Kotani S (2001) Activation of Cdh1-dependent APC is required for G1 cell cycle arrest and DNA damage-induced G2 checkpoint in vertebrate cells. EMBO J 20(22):6499–6508PubMedCrossRef

14.

Bellacosa A, Kumar CC, Di Cristofano A et al (2005) Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94:29–86PubMedCrossRef

15.

Chiang JW, Karlan BY, Cass L et al (2006) BRCA1 promoter methylation predicts adverse ovarian cancer prognosis. Gynecol Oncol 101(3):403–410PubMedCrossRef

16.

Chan KY, Ozcelik H, Cheung AN et al (2002) Epigenetic factors controlling the BRCA1 and BRCA2 genes in sporadic ovarian cancer. Cancer Res 62(14):4151–4156PubMed

17.

Martin SA, Lord CJ, Ashworth A (2008) DNA repair deficiency as a therapeutic target in cancer. Curr Opin Genet Dev 18(1):80–86PubMedCrossRef

18.

Farmer H, McCabe N, Lord CJ et al (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434(7035):917–921PubMedCrossRef

19.

Bryant HE, Schultz N, Thomas HD et al (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917PubMedCrossRef

20.

Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361(2):123–134PubMedCrossRef

21.

Fong PC, Yap TA, Boss DS et al (2010) Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol 28(15): 2512–2519

22.

Turner N, Tutt A, Ashworth A (2004) Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer 4(10):814–819PubMedCrossRef

23.

McCabe N, Turner NC, Lord CJ et al (2006) Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66(16):8109–8115PubMedCrossRef

24.

Folkman J (1990) What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 82(1):4–6PubMedCrossRef

25.

Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70PubMedCrossRef

26.

Paley PJ, Staskus KA, Gebhard K (1997) Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer 80(1):98–106PubMedCrossRef

27.

Ishigami SI, Arii S, Furutani M (1998) Predictive value of vascular endothelial growth factor (VEGF) in metastasis and prognosis of human colorectal cancer. Br J Cancer 78(10):1379–1384PubMedCrossRef

28.

Mu J, Abe Y, Tsutsui T (1996) Inhibition of growth and metastasis of ovarian carcinoma by administering a drug capable of interfering with vascular endothelial growth factor activity. Jpn J Cancer Res 87(9):963–971PubMedCrossRef

29.

Hu L, Hofmann J, Zaloudek C et al (2002) Vascular endothelial growth factor immunoneutralization plus Paclitaxel markedly reduces tumor burden and ascites in athymic mouse model of ovarian cancer. Am J Pathol 161(5):1917–1924PubMedCrossRef

30.

Byrne AT, Ross L, Holash J (2003) Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 9(15):5721–5728PubMed

31.

O’Hanlon LH (2005) Taking down tumors: vascular disrupting agents entering clinical trials. J Natl Cancer Inst 97(17):1244–1245PubMedCrossRef

32.

Siemann DW, Chaplin DJ, Horsman MR (2004) Vascular-targeting therapies for treatment of malignant disease. Cancer 100(12):2491–2499PubMedCrossRef

33.

Gaya AM, Rustin GJ (2005) Vascular disrupting agents: a new class of drug in cancer therapy. Clin Oncol (R Coll Radiol) 17(4):277–290CrossRef

34.

Nathan P, Zweifel M, Padhani AR et al (2012) Phase I trial of combretastatin A4 phosphate (CA4P) in combination with bevacizumab in patients with advanced cancer. Clin Cancer Res; 18(12): 3428–3439

35.

Shaked Y, Ciarrocchi A, Franco M et al (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313(5794):1785–1787PubMedCrossRef

36.

McKeage MJ, Fong P, Jeffery M et al (2006) 5,6-Dimethylxanthenone-4-acetic acid in the treatment of refractory tumors: a phase I safety study of a vascular disrupting agent. Clin Cancer Res 12(6):1776–1784PubMedCrossRef

37.

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

38.

Shayesteh L, Lu Y, Kuo WL et al (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21(1):99–102PubMedCrossRef

39.

Levine DA, Bogomolniy F, Yee CJ et al (2005) Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 11(8):2875–2878PubMedCrossRef

40.

Obata K, Morland SJ, Watson RH et al (1998) Frequent PTEN/MMAC mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res 58(10):2095–2097PubMed

41.

Cheng JQ, Godwin AK, Bellacosa A et al (1992) AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci USA 89(19):9267–9271PubMedCrossRef

42.

Hu L, Hofmann J, Lu Y, Mills GB et al (2002) Inhibition of phosphatidylinositol 3’-kinase increases efficacy of paclitaxel in in vitro and in vivo ovarian cancer models. Cancer Res 62(4):1087–1092PubMed

43.

Yap TA, Garrett MD, Walton MI et al (2008) Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 8(4):393–412PubMedCrossRef

44.

Oza AM, Elit L, Tsao MS et al (2011) Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol; 29(24): 3278–3285

45.

Slomovitz BM, Lu KH, Johnston T et al (2010) A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 116(23): 5415–5419

46.

Singer G, Oldt R 3rd, Cohen Y et al (2003) Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 95(6):484–486PubMedCrossRef

47.

Sieben NL, Macropoulos P, Roemen GM et al (2004) In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol 202(3):336–340PubMedCrossRef

48.

Singer G, Stohr R, Cope L et al (2005) Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: a mutational analysis with immunohistochemical correlation. Am J Surg Pathol 29(2):218–224PubMedCrossRef

49.

Soda M, Choi YL, Enomoto M et al (2007) Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448(7153):561–566PubMedCrossRef

50.

Shaw AT, Yeap BY, Solomon BJ et al (2011) Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol 12(11):1004–1012

51.

Barker SD, Casado E, Gomez-Navarro J et al (2001) An immunomagnetic-based method for the purification of ovarian cancer cells from patient-derived ascites. Gynecol Oncol 82(1):57–63PubMedCrossRef

52.

Chan JK, Hamilton CA, Anderson EM et al (2007) A novel technique for the enrichment of primary ovarian cancer cells. Am J Obstet Gynecol 197(5):507 e1–5

53.

Poveda A, Kaye SB, McCormack R et al (2011) Circulating tumor cells predict progression free survival and overall survival in patients with relapsed/recurrent advanced ovarian cancer. Gynecol Oncol 122(3): 567–72

54.

Marth C, Kisic J, Kaern J et al (2002) Circulating tumor cells in the peripheral blood and bone marrow of patients with ovarian carcinoma do not predict prognosis. Cancer 94(3):707–712PubMedCrossRef

55.

Kindelberger DW, Lee Y, Miron A et al (2007) Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: evidence for a causal relationship. Am J Surg Pathol 31(2):161–169PubMedCrossRef

56.

Visvanathan K, Vang R, Shaw P et al (2011) Diagnosis of serous tubal intraepithelial carcinoma based on morphologic and immunohistochemical features: a reproducibility study. Am J Surg Pathol; 35(12):1766–1775

57.

Przybycin CG, Kurman RJ, Ronnett BM (2010) Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol 34(10):1407–1416

Title: Molecular-targeted therapies for ovarian cancer: prospects for the future
Author: Tamotsu Sudo
Publication date: 01-10-2012
Publisher: Springer Japan
Published in: International Journal of Clinical Oncology / Issue 5/2012
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-012-0461-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2012

Detailed dosimetric evaluation of intensity-modulated radiation therapy plans created for stage C prostate cancer based on a planning protocol

Combined modality therapy for laryngeal cancer with superselective intra-arterial cisplatin infusion and concomitant radiotherapy

Bleomycin-induced pulmonary fibrosis after tumor lysis syndrome in a case of advanced yolk sac tumor treated with bleomycin, etoposide and cisplatin (BEP) chemotherapy

Molecular-targeted therapies for ovarian cancer

Clinical characteristics of Japanese lung cancer patients with human immunodeficiency virus infection

Prognostic significance of breast cancer subtype and p53 overexpression in patients with locally advanced or high-risk breast cancer treated using upfront modified radical mastectomy with or without post-mastectomy radiation therapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer