The target therapy of ovarian clear cell carcinoma

Tan et al 19 reported that HER2 gene amplification and protein overexpression were observed in 14% of CCCs using hierarchical cluster analysis. Using an immunohistochemical method, Fujimura et al reported that HER2 was frequently overexpressed in 42.9% of CCC patients compared with 20.8% of ovarian serous adenocarcinoma, 23.1% of ovarian endometrioid adenocarcinoma, and 30.0% of mucinous adenocarcinoma specimens. Trastuzumab, a humanized recombinant monoclonal antibody against HER2, significantly and dose-dependently reduced the growth of CCC cell lines in vitro. Trastuzumab also dose-dependently inhibited the growth of xenografted RMG-1 (CCC cell line) tumor. The survival period of trastuzumab-treated mice was longer than that of the control group. 47 Thus, trastuzumab appears to be a candidate treatment modality for HER2 overexpressing CCC. A clinical trial was conducted to use single-agent trastuzumab to treat HER2-overexpression ovarian and primary peritoneal carcinoma (documented by an immunohistochemical method). 48 An overall response rate of only 7% was observed. However, patient selection (41 patients of which seven were CCCs) was based only on HER2 immunohistochemical expression levels, without assessment of HER2 copy number status. Future studies are warranted to assess the predictive value of HER2 amplification and overexpression in CCCs. The distinct molecular features of CCC and serous ovarian cancer serve to emphasize the need to develop subtype-specific therapeutic approaches in the management of EOC. Patients with CCC have poor prognosis and short survival due to lack of effective therapy. Despite displaying histologically uniform features, CCCs do not constitute a single entity and may be classified into distinct molecular genetic subtypes that also appear to be associated with clinical outcome. Future research is expected to help better understand the pathogenesis of CCC and identify new compounds to block important signaling pathways.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. A majority of cases (61%) are diagnosed at an advanced stage, with a corresponding 5-year survival rate of only 27%. 1 Clear cell adenocarcinoma (CCC) accounts for 10% of EOC 2 and is a distinct entity from other epithelial ovarian carcinomas. Unlike serous EOC, which is thought to originate in the distal fallopian tube, 3 the CCCs and endometrioid carcinoma were thought to arise from the endometriosis. A large epidemiological pooled analysis of 13 case-control studies, including 13,226 controls and 7,911 women with invasive ovarian cancer, investigated the frequency of self-reported endometriosis and found significantly increased risks for ovarian cancer in women with a history of endometriosis, with an odds ratio of 1.46 (95% confidence interval [CI] 1.31–1.63, P ,0.0001). Importantly, a significant association of the histological subtypes of clear cell (odds ratio [OR] 3.05, 95% CI 2.43–3.84, P <0.0001), endometrioid (OR 2.04, 95% CI 1.67–2.48, P <0.0001), and low-grade serous ovarian carcinomas (OR 2.11, 95% CI 1.39–3.20, P <0.0001) was found with endometriosis in this study. In contrast, there was no association of endometriosis with mucinous and high-grade serous cancer as well as borderline tumors. 4 CCC has specific biological and clinical behavior. Compared with other histological types, CCC has been recognized to show a chemoresistant phenotype, leading to poorer prognosis. The response rate by paclitaxel plus carboplatin was lower than the other histologic type, ranging from 22% to 56%. Thus, development of new target-based therapies remains an unmet need for these patients. This review discusses molecular characteristics of CCC, frequent mutations and pathways involved, and potential implications of these factors on choice of therapy.

Met protooncogene (also called hepatocyte growth factor receptor or MET ) encodes MET kinase, which is composed of three functional domains including the ligand-binding domain, regulatory juxtamembrane domain, and the receptor tyrosine kinase domain. When its ligand, hepatocyte growth factor, binds, the Ras-mitogen-activated protein kinase pathway is activated as well as the phosphatidylinositol 3-kinase-AKT-mTOR signaling pathway and several other pathways. 38 , 39 In tumor cells, MET can be activated in a ligand-independent manner through amplification and overexpression of the MET gene. MET amplification was identified in 4%–10% of gastric cancers, esophageal cancers, lung cancers, and colorectal cancers. 40 – 43 MET overexpression and gene amplification were commonly detected in CCC with their frequencies at 22% and 24%, respectively. Such alterations were extremely rare in the other histological subtypes of ovarian carcinoma (ie, serous, endometrioid, and mucinous adenocarcinomas). MET overexpression was associated with a worse prognosis in the CCC patients. 44 Furthermore, in the case with synchronous endometriosis and with adjacent CCC components, the overall incidence of MET overexpression gradually increased from the precursors of nonatypical form (0%), through those of atypical form (67%) and the relatively differentiated carcinoma components (92%), to the poorly differentiated carcinoma components (100%). The results indicated that MET alterations occur as an early event in carcinogenesis of the MET amplification-positive CCC, and these alterations might drive the development and progression in a subset of CCC. 45 Furthermore, Yamashita et al 46 also revealed MET gene amplification in four out of 13 CCC primary tumors and two out of eight CCC cell lines using an array-based comparative genomic hybridization analysis. A total of 37% demonstrated MET gene amplifications (more than four copies) were confirmed in 73 CCC cases using real-time quantitative polymerase chain reaction. In the meantime, amplification of the AKT2 gene was also observed in five out of 21 samples by array-based comparative genomic hybridization analysis. MET knockdown in CCC cell lines with MET amplification showed both increased apoptosis and senescence in vitro, which suggested that MET -amplified CCC cells primarily depend on activation of the MET/PI3K/AKT pathway for cell proliferation and survival. Targeted therapy inhibiting the MET/PI3K/AKT pathway may be promising for CCC treatment.