Uterine Cancer pp 259-271 | Cite as

Future Directions and New Targets in Endometrial Cancer

  • Jonathan D. Black
  • Dana M. Roque
  • Leslie I. Gold
  • Alessandro D. SantinEmail author
Part of the Current Clinical Oncology book series (CCO)


Recent advances in next generation sequencing (NRG) have provided compelling evidence that endometrial cancers result from heterogeneous somatic mutations. These findings argue that a catalog of molecular aberrations that cause endometrial cancer is critical for the proper classification of these tumors and for developing novel and more effective targeted therapies against this disease. This chapter summarizes the recent advances made toward the elucidation of underlying pathway aberrations and the development of targeted therapies that exploit the unique molecular characteristics of endometrial cancers.


Endometrial cancer Uterine serous carcinoma Targeted therapy Immunotherapy Novel therapies 


  1. 1.
    Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983;15:10–7.Google Scholar
  2. 2.
    Lax SF, Pizer ES, Ronnett BM, Kurman RJ. Comparison of estrogen and progesterone receptor, Ki-67, and p53 immunoreactivity in uterine endometrioid carcinoma and endometrioid carcinoma with squamous, mucinous, secretory, and ciliated cell differentiation. Hum Pathol. 1998;29:924–31.PubMedGoogle Scholar
  3. 3.
    Voss MA, et al. Should grade 3 endometrioid endometrial carcinoma be considered a type 2 cancer—a clinical and pathological evaluation. Gynecol Oncol. 2012;124:15–20.PubMedGoogle Scholar
  4. 4.
    Goff BA, et al. Uterine papillary serous carcinoma: patterns of metastatic spread. Gynecol Oncol. 1994;54:264–8.PubMedGoogle Scholar
  5. 5.
    Mutch DG. The more things change the more they stay the same. Gynecol Oncol. 2012;124:3–4.PubMedGoogle Scholar
  6. 6.
    Wilson TO, et al. Evaluation of unfavorable histologic subtypes in endometrial adenocarcinoma. Am J Obstet Gynecol. 1990;162:418–23. discussion 423–6.PubMedGoogle Scholar
  7. 7.
    Emons G, Fleckenstein G, Hinney B, Huschmand A, Heyl W. Hormonal interactions in endometrial cancer. Endocr Relat Cancer. 2000;7:227–42.PubMedGoogle Scholar
  8. 8.
    Hameed K, Morgan DA. Papillary adenocarcinoma of endometrium with psammoma bodies. Histology and fine structure. Cancer. 1972;29:1326–35.PubMedGoogle Scholar
  9. 9.
    Hamilton CA, et al. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Cancer. 2006;94:642–6.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Cancer Genome Atlas Research Network, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.Google Scholar
  11. 11.
    Albertson TM, et al. DNA polymerase epsilon and delta proofreading suppress discrete mutator and cancer phenotypes in mice. Proc Natl Acad Sci U S A. 2009;106:17101–4.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Palles C, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45:713.Google Scholar
  13. 13.
    Meng B, et al. POLE exonuclease domain mutation predicts long progression-free survival in grade 3 endometrioid carcinoma of the endometrium. Gynecol Oncol. 2014;134:15–9.PubMedGoogle Scholar
  14. 14.
    Santin AD, et al. Improved survival of patients with hypermutation in uterine serous carcinoma. Gynecol Oncol Report. 2015;12:3–4.Google Scholar
  15. 15.
    Boussiotis VA. Somatic Mutations and Immunotherapy Outcome with CTLA-4 Blockade in Melanoma. N Engl J Med. 2014. doi:10.1056/NEJMe1413061.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Loeb LA. Human cancers express mutator phenotypes: origin, consequences and targeting. Nat Rev Cancer. 2011;11:450–7.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Snyder A, et al. Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma. N Engl J Med. 2014. doi:10.1056/NEJMoa1406498.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Martin SA, et al. DNA polymerases as potential therapeutic targets for cancers deficient in the DNA mismatch repair proteins MSH2 or MLH1. Cancer Cell. 2010;17:235–48.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Hewish M, et al. Cytosine-based nucleoside analogs are selectively lethal to DNA mismatch repair-deficient tumour cells by enhancing levels of intracellular oxidative stress. Br J Cancer. 2013;108:983–92.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Risinger JI, Hayes AK, Berchuck A, Barrett JC. PTEN/MMAC1 mutations in endometrial cancers. Cancer Res. 1997;57:4736–8.PubMedGoogle Scholar
  21. 21.
    Tashiro H, et al. Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res. 1997;57:3935–40.PubMedGoogle Scholar
  22. 22.
    Samarnthai N, Hall K, Yeh I-T. Molecular profiling of endometrial malignancies. Obstet Gynecol Int. 2010;2010:162363.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Prat J, Gallardo A, Cuatrecasas M, Catasús L. Endometrial carcinoma: pathology and genetics. Pathology. 2007;39:72–87.PubMedGoogle Scholar
  24. 24.
    Mutter GL, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92:924–30.PubMedGoogle Scholar
  25. 25.
    Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010;11:329–41.PubMedGoogle Scholar
  26. 26.
    Matias-Guiu X, Prat J. Molecular pathology of endometrial carcinoma. Histopathology. 2013;62:111–23.PubMedGoogle Scholar
  27. 27.
    Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 2005;65:10669–73.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Doll A, et al. Novel molecular profiles of endometrial cancer—new light through old windows. J Steroid Biochem Mol Biol. 2008;108:221–9.Google Scholar
  29. 29.
    Pavlidou A, Vlahos NF. Molecular alterations of PI3K/Akt/mTOR pathway: a therapeutic target in endometrial cancer. ScientificWorldJournal. 2014;2014:709736.PubMedPubMedCentralGoogle Scholar
  30. 30.
    English DP, et al. Oncogenic PIK3CA gene mutations and HER2/neu gene amplifications determine the sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective inhibitor of Class I PI3 kinase and mTOR kinase (TORC1/2). Am J Obstet Gynecol. 2013;209:465.e1–9.Google Scholar
  31. 31.
    English DP, et al. HER2/neu gene amplification determines the sensitivity of uterine serous carcinoma cell lines to AZD8055, a novel dual mTORC1/2 inhibitor. Gynecol Oncol. 2013;131:753–8.PubMedGoogle Scholar
  32. 32.
    Chresta CM, et al. AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010;70:288–98.PubMedGoogle Scholar
  33. 33.
    Lopez S, et al. Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo. Gynecol Oncol. 2014. doi:10.1016/j.ygyno.2014.08.024.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Dancey JE. Therapeutic targets: MTOR and related pathways. Cancer Biol Ther. 2006;5:1065–73.PubMedGoogle Scholar
  35. 35.
    Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol. 2013;10:143–53.PubMedGoogle Scholar
  36. 36.
    Janku F, et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol. 2012;30:777–82.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Llauradó M, et al. Molecular bases of endometrial cancer: new roles for new actors in the diagnosis and the therapy of the disease. Mol Cell Endocrinol. 2012;358:244–55.PubMedGoogle Scholar
  38. 38.
    Konecny GE, et al. HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer. Br J Cancer. 2009;100:89–95.PubMedGoogle Scholar
  39. 39.
    Schwab CL, et al. Afatinib demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro and in vivo. Br J Cancer. 2014;111:1750–6.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Schwab CL, et al. Neratinib shows efficacy in the treatment of HER2/neu amplified uterine serous carcinoma in vitro and in vivo. Gynecol Oncol. 2014;135:142–8.PubMedGoogle Scholar
  41. 41.
    Kallioniemi OP, et al. ERBB2 amplification in breast cancer analyzed by fluorescence in situ hybridization. Proc Natl Acad Sci. 1992;89:5321–5.PubMedGoogle Scholar
  42. 42.
    Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J. 1997;16:1647–55.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Buza N, Roque DM, Santin AD. HER2/ neu in endometrial cancer: a promising therapeutic target with diagnostic challenges. Arch Pathol Lab Med. 2014;138:343–50.PubMedGoogle Scholar
  44. 44.
    Black JD, English DP, Roque DM, Santin AD. Targeted therapy in uterine serous carcinoma: an aggressive variant of endometrial cancer. Womens Health. 2014;10:45–57.Google Scholar
  45. 45.
    Piccart-Gebhart MJ, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.PubMedGoogle Scholar
  46. 46.
    Jewell E, Secord AA, Brotherton T, Berchuck A. Use of trastuzumab in the treatment of metastatic endometrial cancer. Int J Gynecol Cancer. 2006;16:1370–3.PubMedGoogle Scholar
  47. 47.
    Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int J Gynaecol Obstet. 2008;102:128–31.PubMedGoogle Scholar
  48. 48.
    Villella JA, Cohen S, Smith DH, Hibshoosh H, Hershman D. HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications. Int J Gynecol Cancer. 2006;16:1897–902.PubMedGoogle Scholar
  49. 49.
    Clinical trials. Evaluation of carboplatin/paclitaxel with and without Trastuzumab (Herceptin) in Uterine serous cancer.
  50. 50.
    Nagumo Y, et al. Trastuzumab and pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies. Clin Cancer Res. 2011;17:4451–61. at <>.PubMedGoogle Scholar
  51. 51.
    Bellone M, et al. In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma. Br J Cancer. 2010;102:134–43. at <>.PubMedGoogle Scholar
  52. 52.
    Mullen P, Cameron DA, Hasmann M, Smyth JF, Langdon SP. Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling. Mol Cancer Ther. 2007;6:93–100.PubMedGoogle Scholar
  53. 53.
    Kim JW, et al. The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett. 2008;272:296–306.PubMedGoogle Scholar
  54. 54.
    Lewis Phillips GD, et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008;68:9280–90.PubMedGoogle Scholar
  55. 55.
    Remillard S, Rebhun LI, Howie GA, Kupchan SM. Antimitotic activity of the potent tumor inhibitor maytansine. Science. 1975;189:1002–5.PubMedGoogle Scholar
  56. 56.
    Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347–56.PubMedGoogle Scholar
  57. 57.
    Wilken JA, Maihle NJ. Primary trastuzumab resistance: new tricks for an old drug. Ann N Y Acad Sci. 2010;1210:53–65.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Boyraz B, et al. Trastuzumab emtansine (T-DM1) for HER2-positive breast cancer. Curr Med Res Opin. 2013;29:405–14.PubMedGoogle Scholar
  59. 59.
    English DP, et al. T-DM1, a novel antibody-drug conjugate, is highly effective against primary HER2 overexpressing uterine serous carcinoma in vitro and in vivo. Cancer Med. 2014;3:1256–65.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.PubMedGoogle Scholar
  61. 61.
    Kamat AA, et al. Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. Clin Cancer Res. 2007;13:7487–95.PubMedGoogle Scholar
  62. 62.
    Hirai M, et al. Expression of vascular endothelial growth factors (VEGF-A/VEGF-1 and VEGF-C/VEGF-2) in postmenopausal uterine endometrial carcinoma. Gynecol Oncol. 2001;80:181–8.PubMedGoogle Scholar
  63. 63.
    Mazurek A, et al. Evaluation of angiogenesis, p-53 tissue protein expression and serum VEGF in patients with endometrial cancer. Neoplasma. 2004;51:193–7.PubMedGoogle Scholar
  64. 64.
    Aghajanian C, et al. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011;29:2259–65.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Alvarez EA, et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2013;129:22–7.PubMedGoogle Scholar
  66. 66.
    Paclitaxel, carboplatin, and bevacizumab or paclitaxel, carboplatin, and temsirolimus or ixabepilone, carboplatin, and bevacizumab in treating patients with stage III, stage IV, or recurrent endometrial cancer—full text view—
  67. 67.
    Coleman RL, et al. Corrigendum to “A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study” [Gynecol Oncol 127 (2012) 538–543]. Gynecol Oncol. 2013;130.Google Scholar
  68. 68.
    Fuchs CS, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31–9.PubMedGoogle Scholar
  69. 69.
    Powell MA, et al. A phase II trial of brivanib in recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group Study. Gynecologic. 2014;135:38–43. at <>.Google Scholar
  70. 70.
    Kuhn E, et al. Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses. J Natl Cancer Inst. 2012;104:1503–13.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008;8:83–93.PubMedGoogle Scholar
  72. 72.
    Mao J-H, et al. FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science. 2008;321:1499–502.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Cassia R, et al. Cyclin E gene (CCNE) amplification and hCDC4 mutations in endometrial carcinoma. J Pathol. 2003;201:589–95.PubMedGoogle Scholar
  74. 74.
    Shih I-M, et al. Somatic mutations of PPP2R1A in ovarian and uterine carcinomas. Am J Pathol. 2011;178:1442–7.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Nagendra DC, Burke 3rd J, Maxwell GL, Risinger JI. PPP2R1A mutations are common in the serous type of endometrial cancer. Mol Carcinog. 2012;51:826–31.PubMedGoogle Scholar
  76. 76.
    Zhao S, et al. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A. 2013;110:2916–21.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Lin CL, Lin JK. Curcumin: a potential cancer chemopreventive agent through suppressing NF-κB signaling. J Cancer Mol. 2008;4:11–6. at <>.Google Scholar
  78. 78.
    Bloom J, Pagano M. Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol. 2003;13.PubMedGoogle Scholar
  79. 79.
    Pagano M, et al. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995;269.Google Scholar
  80. 80.
    Sherr CJ, Roberts JM. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999;13.Google Scholar
  81. 81.
    Lahav-Baratz S. Decreased level of the cell cycle regulator p27 and increased level of its ubiquitin ligase Skp2 in endometrial carcinoma but not in normal secretory or in hyperstimulated endometrium. Mol Hum Reprod. 2004;10.Google Scholar
  82. 82.
    Miyamoto T, et al. Inverse correlation between Skp2 and p27Kip1 in normal endometrium and endometrial carcinoma. Gynecol Endocrinol. 2009. doi:10.1080/09513590903215482.CrossRefGoogle Scholar
  83. 83.
    Oshita T, Shigemasa K, Nagai N, Ohama K. p27, cyclin E, and CDK2 expression in normal and cancerous endometrium. Int J Oncol. 2002. doi:10.3892/ijo.21.4.737.CrossRefPubMedGoogle Scholar
  84. 84.
    Lecanda J, et al. Transforming growth factor-beta, estrogen, and progesterone converge on the regulation of p27Kip1 in the normal and malignant endometrium. Cancer Res. 2007;67:1007–18.PubMedGoogle Scholar
  85. 85.
    Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008;8.PubMedGoogle Scholar
  86. 86.
    Kamata Y, et al. High expression of skp2 correlates with poor prognosis in endometrial endometrioid adenocarcinoma. J Cancer Res Clin Oncol. 2005;131.PubMedGoogle Scholar
  87. 87.
    Wander SA, Zhao D, Slingerland JM. p27: a barometer of signaling deregulation and potential predictor of response to targeted therapies. Clin Cancer Res. 2010;17.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Davidovich S, Ben-Izhak O, Shapira M, Futerman B, Hershko DD. Over-expression of Skp2 is associated with resistance to preoperative doxorubicin-based chemotherapy in primary breast cancer. Breast Cancer Res. 2008;10.Google Scholar
  89. 89.
    Huang KT, Pavlides SC, Lecanda J, Blank SV, Mittal KR, Gold LI. Estrogen and progesterone regulate p27kip1 levels via the ubiquitin-proteasome system: pathogenic and therapeutic implications for endometrial cancer. PLoS One. 2012;7.PubMedPubMedCentralGoogle Scholar
  90. 90.
    Di Cristofano A, Ellenson LH. Endometrial carcinoma. Annu Rev Pathol Mech Dis. 2007;445:53–7. at <>.Google Scholar
  91. 91.
    Ellenson LH, Wu T-C. Focus on endometrial and cervical cancer. Cancer Cell. 2004;5.PubMedGoogle Scholar
  92. 92.
    Shiozawa T, et al. Up-regulation of p27Kip1 by progestins is involved in the growth suppression of the normal and malignant human endometrial glandular cells. Endocrinology. 2001;142:4182–8.PubMedGoogle Scholar
  93. 93.
    Watanabe J, et al. Significance of p27 as a predicting marker for medroxyprogesterone acetate therapy against endometrial endometrioid adenocarcinoma. Int J Gynecol Cancer. 2006;16 Suppl 1:452–7.PubMedGoogle Scholar
  94. 94.
    An H-J, et al. Alteration of PTEN expression in endometrial carcinoma is associated with down-regulation of cyclin-dependent kinase inhibitor, p27. Histopathology. 2002;41:437–45.PubMedGoogle Scholar
  95. 95.
    Mamillapalli R, et al. PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27(KIP1) through the ubiquitin E3 ligase SCF(SKP2). Curr Biol. 2001;11:263–7.PubMedGoogle Scholar
  96. 96.
    Mitsiades CS, Mitsiades N, Hideshima T, Richardson PG, Anderson KC. Proteasome inhibitors as therapeutics. Essays Biochem. 2005;41:205–18.PubMedGoogle Scholar
  97. 97.
    Kitagawa K, Kotake Y, Kitagawa M. Ubiquitin-mediated control of oncogene and tumor suppressor gene products. Cancer Sci. 2009;100:1374–81.PubMedGoogle Scholar
  98. 98.
    Hao B, et al. Structural basis of the Cks1-dependent recognition of p27(Kip1) by the SCF(Skp2) ubiquitin ligase. Mol Cell. 2005;20:9–19.PubMedGoogle Scholar
  99. 99.
    Cardozo T, Pagano M. Wrenches in the works: drug discovery targeting the SCF ubiquitin ligase and APC/C complexes. BMC Biochem. 2007;8 Suppl 1:S9.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Wu L, et al. Specific small molecule inhibitors of Skp2-mediated p27 degradation. Chem Biol. 2012;19:1515–24.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Denicourt C, Saenz CC, Datnow B, Cui X-S, Dowdy SF. Relocalized p27Kip1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma. Cancer Res. 2007;67:9238–43.PubMedGoogle Scholar
  102. 102.
    Larrea MD, Wander SA, Slingerland JM. p27 as Jekyll and Hyde: regulation of cell cycle and cell motility. Cell Cycle. 2009;8:3455–61.PubMedGoogle Scholar
  103. 103.
    Pavlides SC, et al. Inhibitors of SCF-Skp2/Cks1 E3 ligase block estrogen-induced growth stimulation and degradation of nuclear p27kip1: therapeutic potential for endometrial cancer. Endocrinology. 2013;154:4030–45.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Ungermannova D, et al. High-throughput screening AlphaScreen assay for identification of small-molecule inhibitors of ubiquitin E3 ligase SCFSkp2-Cks1. J Biomol Screen. 2013;18:910–20.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Rico-Bautista E, Wolf DA. Skipping cancer: small molecule inhibitors of SKP2-mediated p27 degradation. Chem Biol. 2012;19:1497–8.PubMedGoogle Scholar
  106. 106.
    Chan C-H, et al. Pharmacological inactivation of Skp2 SCF ubiquitin ligase restricts cancer stem cell traits and cancer progression. Cell. 2013;154:556–68.PubMedGoogle Scholar
  107. 107.
    Swift JG, Mukherjee TM, Rowland R. Intercellular junctions in hepatocellular carcinoma. J Submicrosc Cytol. 1983;15:799–810.PubMedGoogle Scholar
  108. 108.
    Morita K, Furuse M, Fujimoto K, Tsukita S. Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci U S A. 1999;96:511–6.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Santin AD, et al. Overexpression of claudin-3 and claudin-4 receptors in uterine serous papillary carcinoma: novel targets for a type-specific therapy using Clostridium perfringens enterotoxin (CPE). Cancer. 2007;109:1312–22.PubMedGoogle Scholar
  110. 110.
    Morin PJ. Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res. 2005;65:9603–6.PubMedGoogle Scholar
  111. 111.
    Hewitt KJ, Agarwal R, Morin PJ. The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer. 2006;6:186.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Kavallaris M, et al. Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J Clin Invest. 1997;100:1282–93.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Vitolo MI, et al. Loss of PTEN induces microtentacles through PI3K-independent activation of cofilin. Oncogene. 2013;32:2200–10.PubMedGoogle Scholar
  114. 114.
    Magnani M, et al. The betaI/betaIII-tubulin isoforms and their complexes with antimitotic agents. Docking and molecular dynamics studies. FEBS J. 2006;273:3301–10.PubMedGoogle Scholar
  115. 115.
    Hari M, Yang H, Zeng C, Canizales M, Cabral F. Expression of class III beta-tubulin reduces microtubule assembly and confers resistance to paclitaxel. Cell Motil Cytoskeleton. 2003;56:45–56.PubMedGoogle Scholar
  116. 116.
    Roque DM, et al. Class III β-tubulin overexpression in ovarian clear cell and serous carcinoma as a maker for poor overall survival after platinum/taxane chemotherapy and sensitivity to patupilone. Am J Obstet Gynecol. 2013;209:62.e1–9.Google Scholar
  117. 117.
    Roque DM, et al. Tubulin-β-III overexpression by uterine serous carcinomas is a marker for poor overall survival after platinum/taxane chemotherapy and sensitivity to epothilones. Cancer. 2013;119:2582–92.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Ferrandina G, et al. Class III beta-tubulin overexpression is a marker of poor clinical outcome in advanced ovarian cancer patients. Clin Cancer Res. 2006;12:2774–9.PubMedGoogle Scholar
  119. 119.
    Bollag DM, et al. Epothilones, a new class of microtubule-stabilizing agents with a taxol-like mechanism of action. Cancer Res. 1995;55:2325–33.PubMedGoogle Scholar
  120. 120.
    English DP, Roque DM, Santin AD. Class III b-tubulin overexpression in gynecologic tumors: implications for the choice of microtubule targeted agents? Expert Rev Anticancer Ther. 2013;13:63–74.PubMedGoogle Scholar
  121. 121.
    Carrara L, et al. Differential in vitro sensitivity to patupilone versus paclitaxel in uterine and ovarian carcinosarcoma cell lines is linked to tubulin-beta-III expression. Gynecol Oncol. 2012;125:231–6.PubMedGoogle Scholar
  122. 122.
    Paik D, et al. Higher sensitivity to patupilone versus paclitaxel chemotherapy in primary uterine serous papillary carcinoma cell lines with high versus low HER-2/neu expression in vitro. Gynecol Oncol. 2010;119:140–5.PubMedPubMedCentralGoogle Scholar
  123. 123.
    Dizon DS, et al. Phase II trial of ixabepilone as second-line treatment in advanced endometrial cancer: gynecologic oncology group trial 129-P. J Clin Oncol. 2009;27:3104–8.PubMedPubMedCentralGoogle Scholar
  124. 124.
    Duska LR, et al. A phase II evaluation of ixabepilone (IND #59699, NSC #710428) in the treatment of recurrent or persistent leiomyosarcoma of the uterus: an NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2014;135:44–8.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Jonathan D. Black
    • 1
  • Dana M. Roque
    • 2
  • Leslie I. Gold
    • 3
  • Alessandro D. Santin
    • 1
    Email author
  1. 1.Division of Gynecologic OncologyYale University, Yale School of MedicineNew HavenUSA
  2. 2.Department of ObstetricsUniversity of Maryland School of MedicineBaltimoreUSA
  3. 3.Gynecology & Reproductive SciencesNew York University School of MedicineNew YorkUSA

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