Current status of molecular‑targeted drugs for endometrial cancer (Review)

Nogami,Yuya; Banno,Kouji; Kisu,Iori; Yanokura,Megumi; Umene,Kiyoko; Masuda,Kenta; Kobayashi,Yusuke; Yamagami,Wataru; Nomura,Hiroyuki; Tominaga,Eiichiro; Susumu,Nobuyuki; Aoki,Daisuke

doi:10.3892/mco.2013.140

Current status of molecular‑targeted drugs for endometrial cancer (Review)

Authors:
- Yuya Nogami
- Kouji Banno
- Iori Kisu
- Megumi Yanokura
- Kiyoko Umene
- Kenta Masuda
- Yusuke Kobayashi
- Wataru Yamagami
- Hiroyuki Nomura
- Eiichiro Tominaga
- Nobuyuki Susumu
- Daisuke Aoki
View Affiliations

Affiliations: Department of Obstetrics and Gynecology, School of Medicine, Keio University, Shinjuku‑ku, Tokyo 1608582, Japan
Published online on: June 26, 2013 https://doi.org/10.3892/mco.2013.140
Pages: 799-804

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Endometrial cancer is a common gynecological malignant tumor in Western countries and its incidence has also been on the increase in Asia. genetic abnormalities related to onset and progression of malignancy in the endometrial membrane and signaling system have been identified and the developmental mechanism of endometrial cancer is becoming elucidated. The identification of the molecules related to these abnormalities has led to new potential treatment regimens for endometrial cancer, using molecular‑targeted drugs. The current chemotherapy for endometrial cancer often causes systemic side effects that require discontinuation of the treatment. Furthermore, a treatment regimen for cancers of rare histological types has not been established. Recent studies on endometrial cancer revealed patterns of genetic disorders that differ among the histological types. genetic and molecular information that underlie pathological changes and is associated with DNA mismatch repair genes and epigenetic regulation was also identified. Targeting of these mechanisms with molecular‑targeted drugs has been performed with the aim of linking treatment to the carcinogenic mechanism at the molecular and genetic levels. however, the response rates with single‑agent therapy are generally low and several problems remain unresolved. Trials of combinations of molecular‑targeted drugs with currently available treatments and identification of factors determining sensitivity are required to overcome these difficulties.

View Figures

View References

1	Sorosky JI: Endometrial cancer. Obstet Gynecol. 120:383–397. 2012. View Article : Google Scholar
2	Matsuda T, Marugame T, Kamo K, et al: Cancer incidence and incidence rates in Japan in 2006: based on data from 15 population-based cancer registries in the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 42:139–147. 2012. View Article : Google Scholar
3	Aggarwal P and Kehoe S: Serum tumour markers in gynaecological cancers. Maturitas. 67:46–53. 2010. View Article : Google Scholar
4	Larson DM, Connor GP, Broste SK, Krawisz BR and Johnson KK: Prognostic significance of gross myometrial invasion with endometrial cancer. Obstet Gynecol. 88:394–398. 1996. View Article : Google Scholar : PubMed/NCBI
5	Nakao Y, Yokoyama M, Hara K, et al: MR imaging in endometrial carcinoma as a diagnostic tool for the absence of myometrial invasion. Gynecol Oncol. 102:343–347. 2006. View Article : Google Scholar : PubMed/NCBI
6	Randall ME, Filiaci VL, Muss H, et al: Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol. 24:36–44. 2006. View Article : Google Scholar
7	Aapro MS, van Wijk FH, Bolis G, et al: Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group. Ann Oncol. 14:441–448. 2003. View Article : Google Scholar
8	Akram T, Maseelall P and Fanning J: Carboplatin and paclitaxel for the treatment of advanced or recurrent endometrial cancer. Am J Obstet Gynecol. 192:1365–1367. 2005. View Article : Google Scholar : PubMed/NCBI
9	Michener CM, Peterson G, Kulp B, Webster KD and Markman M: Carboplatin plus paclitaxel in the treatment of advanced or recurrent endometrial carcinoma. J Cancer Res Clin Oncol. 131:581–584. 2005. View Article : Google Scholar : PubMed/NCBI
10	Yamada K, Tanabe H, Imai M, et al: Feasibility study of paclitaxel plus carboplatin in patients with endometrial cancer: a Japan Kanto Tumor Board study (JKTB trial). J Obstet Gynaecol Res. 39:311–316. 2013. View Article : Google Scholar : PubMed/NCBI
11	Lax SF, Kendall B, Tashiro H, Slebos RJ and Hedrick L: The frequency of p53, K-ras mutations, and microsatellite instability differs in uterine endometrioid and serous carcinoma: evidence of distinct molecular genetic pathways. Cancer. 88:814–824. 2000. View Article : Google Scholar
12	Lax SF, Pizer ES, Ronnett BM and Kurman RJ: Clear cell carcinoma of the endometrium is characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor expression. Hum Pathol. 29:551–558. 1998. View Article : Google Scholar : PubMed/NCBI
13	Catasus L, Machin P, Matias-Guiu X and Prat J: Microsatellite instability in endometrial carcinomas: clinicopathologic correlations in a series of 42 cases. Hum Pathol. 29:1160–1164. 1998. View Article : Google Scholar
14	Kobayashi K, Matsushima M, Koi S, et al: Mutational analysis of mismatch repair genes, hMLH1 and hMSH2, in sporadic endometrial carcinomas with microsatellite instability. Jpn J Cancer Res. 87:141–145. 1996. View Article : Google Scholar : PubMed/NCBI
15	Simpkins SB, Bocker T, Swisher EM, et al: MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum Mol Genet. 8:661–666. 1999. View Article : Google Scholar : PubMed/NCBI
16	Kanaya T, Kyo S, Maida Y, et al: Frequent hypermethylation of MLH1 promoter in normal endometrium of patients with endometrial cancers. Oncogene. 22:2352–2360. 2003. View Article : Google Scholar : PubMed/NCBI
17	King SA, Adas AA, LiVolsi VA, et al: Expression and mutation analysis of the p53 gene in uterine papillary serous carcinoma. Cancer. 75:2700–2705. 1995. View Article : Google Scholar : PubMed/NCBI
18	Peyssonnaux C and Eychene A: The Raf/MEK/ERK pathway: new concepts of activation. Biol Cell. 93:53–62. 2001. View Article : Google Scholar : PubMed/NCBI
19	Saegusa M, Hashimura M, Yoshida T and Okayasu I: Beta-catenin mutations and aberrant nuclear expression during endometrial tumorigenesis. Br J Cancer. 84:209–217. 2001. View Article : Google Scholar : PubMed/NCBI
20	Zysman M, Saka A, Millar A, Knight J, Chapman W and Bapat B: Methylation of adenomatous polyposis coli in endometrial cancer occurs more frequently in tumors with microsatellite instability phenotype. Cancer Res. 62:3663–3666. 2002.PubMed/NCBI
21	Kamat AA, Merritt WM, Coffey D, et al: Clinical and biological significance of vascular endothelial growth factor in endometrial cancer. Clin Cancer Res. 13:7487–7495. 2007. View Article : Google Scholar : PubMed/NCBI
22	Aghajanian C, Sill MW, Darcy KM, et al: Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 29:2259–2265. 2011. View Article : Google Scholar : PubMed/NCBI
23	Zagouri F, Bozas G, Kafantari E, et al: Endometrial cancer: what is new in adjuvant and molecularly targeted therapy? Obstet Gynecol Int. 2010:7495792010. View Article : Google Scholar : PubMed/NCBI
24	Coleman RL, Sill MW, Lankes HA, et al: A phase II evaluation of aflibercept in the treatment of recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. Gynecol Oncol. 127:538–543. 2012. View Article : Google Scholar : PubMed/NCBI
25	McMeekin DS, Sill MW, Benbrook D, et al: A phase II trial of thalidomide in patients with refractory endometrial cancer and correlation with angiogenesis biomarkers: a Gynecologic Oncology Group study. Gynecol Oncol. 105:508–516. 2007. View Article : Google Scholar : PubMed/NCBI
26	Leslie KK, Sill MW, Darcy KM, et al: Efficacy and safety of gefitinib and potential prognostic value of soluble EGFR, EGFR mutations, and tumor markers in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer. J Clin Oncol. 27:e165422009.
27	Jasas KV, Fyles A, Elit L, et al: Phase II study of erlotinib (OSI 774) in women with recurrent or metastatic endometrial cancer: NCIC CTG IND-1. J Clin Oncol. 22:e50192004.
28	Takahashi K, Saga Y, Mizukami H, et al: Cetuximab inhibits growth, peritoneal dissemination, and lymph node and lung metastasis of endometrial cancer, and prolongs host survival. Int J Oncol. 35:725–729. 2009.PubMed/NCBI
29	Fleming GF, Sill MW, Darcy KM, et al: Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 116:15–20. 2010. View Article : Google Scholar
30	Santin AD: Letter to the Editor referring to the manuscript entitled: ‘Phase II trial of trastuzumab in women with advanced or recurrent HER2-positive endometrial carcinoma: a Gynecologic Oncology Group Study’ recently reported by Fleming et al, (Gynecol Oncol., 116; 15–20;2010). Gynecol Oncol. 118:95–96; author reply 96–97. 2010.
31	Elsahwi KS and Santin AD: erbB2 overexpression in uterine serous cancer: a molecular target for trastuzumab therapy. Obstet Gynecol Int. 2011:1282952011. View Article : Google Scholar : PubMed/NCBI
32	Oza AM, Elit L, Biagi J, et al: Molecular correlates associated with a phase II study of temsirolimus (CCI-779) in patients with metastatic or recurrent endometrial cancer - NCIC IND 160. J Clin Oncol. 24:e30032006.
33	Oza AM, Elit L, Provencher D, et al: A phase II study of temsirolimus (CCI-779) in patients with metastatic and/or locally advanced recurrent endometrial cancer previously treated with chemotherapy: NCIC CTG IND 160 b. J Clin Oncol. 26:e55162008.
34	Colombo N, McMeekin S, Schwartz P, et al: A phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer. J Clin Oncol. 25:e55162007.
35	Trope C, Johnsson JE, Simonsen E, Christiansen H, Cavallin-Stahl E and Horvath G: Treatment of recurrent endometrial adenocarcinoma with a combination of doxorubicin and cisplatin. Am J Obstet Gynecol. 149:379–381. 1984. View Article : Google Scholar : PubMed/NCBI
36	Nimeiri HS, Oza AM, Morgan RJ, et al: A phase II study of sorafenib in advanced uterine carcinoma/carcinosarcoma: a trial of the Chicago, PMH, and California Phase II Consortia. Gynecol Oncol. 117:37–40. 2010. View Article : Google Scholar : PubMed/NCBI
37	Takai N, Desmond JC, Kumagai T, et al: Histone deacetylase inhibitors have a profound antigrowth activity in endometrial cancer cells. Clin Cancer Res. 10:1141–1149. 2004. View Article : Google Scholar : PubMed/NCBI
38	Tsuruta T, Kozaki K, Uesugi A, et al: miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. Cancer Res. 71:6450–6462. 2011. View Article : Google Scholar : PubMed/NCBI
39	Karaayvaz M, Zhang C, Liang S, Shroyer KR and Ju J: Prognostic significance of miR-205 in endometrial cancer. PLoS One. 7:e351582012. View Article : Google Scholar : PubMed/NCBI