Summary Background Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits ...angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. Methods For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m2 ) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , NCT01204749 , and is no longer accruing patients. Findings 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months 5·8–7·4 vs 5·4 months 95% CI 4·3–5·5, respectively, hazard ratio 0·66, 95% CI 0·57–0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 54% of 452 patients in the placebo group vs 258 56% of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 17% patients vs 27 6%, respectively) and higher incidences of oedema (294 64% patients had any-grade oedema in the trebananib group vs 127 28% patients in the placebo group). Grade 3 or higher adverse events included ascites (34 8% in the placebo group vs 52 11% in the trebananib group), neutropenia (40 9% vs 26 6%), and abdominal pain (21 5% vs 22 5%). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 17% vs 46 10%). Interpretation Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. Funding Amgen.
This study compared the efficacy and safety of patupilone with those of pegylated liposomal doxorubicin (PLD) in patients with platinum-refractory or -resistant epithelial ovarian, primary fallopian ...tube, or primary peritoneal cancer.
Patients with three or fewer prior regimens were eligible if they had received first-line taxane/platinum-based combination chemotherapy and were platinum refractory or resistant. Patients were randomly assigned to receive patupilone (10 mg/m(2) intravenously every 3 weeks) or PLD (50 mg/m(2) intravenously every 4 weeks).
A total of 829 patients were randomly assigned (patupilone, n = 412; PLD, n = 417). There was no statistically significant difference in overall survival (OS), the primary end point, between the patupilone and PLD arms (P = .195; hazard ratio, 0.93; 95% CI, 0.79 to 1.09), with median OS rates of 13.2 and 12.7 months, respectively. Median progression-free survival was 3.7 months for both arms. The overall response rate (all partial responses) was higher in the patupilone arm than in the PLD arm (15.5% v 7.9%; odds ratio, 2.11; 95% CI, 1.36 to 3.29), although disease control rates were similar (59.5% v 56.3%, respectively). Frequently observed adverse events (AEs) of any grade included diarrhea (85.3%) and peripheral neuropathy (39.3%) in the patupilone arm and mucositis/stomatitis (43%) and hand-foot syndrome (41.8%) in the PLD arm.
Patupilone did not demonstrate significant improvement in OS compared with the active control, PLD. No new or unexpected serious AEs were identified.
Sphingosine kinase 1 (SK1) is over‐expressed in multiple types of human cancer. SK1 has growth‐promoting effects and has been proposed as a potential therapeutic target. We investigated the ...therapeutic effects of SK1 inhibition in epithelial ovarian carcinoma (EOC). SK1 siRNA or inhibitors were tested in EOC cell lines, including A2780, SKOV3ip1, A2780‐CP20, SKOV3‐TR, ES2 and RMG2. Cells were treated with SK inhibitor or FTY720, and cell proliferation, apoptosis, angiogenesis and invasion were examined by MTT, FACS, ELISA and wound‐healing assays, respectively. In vivo experiments were performed to test the effects of FTY720 on tumor growth in orthotopic mouse xenografts of EOC cell lines A2780 or SKOV3ip1 and a patient‐derived xenograft (PDX) model of clear cell ovarian carcinoma (CCC). Blocking SK1 with siRNA or inhibitors significantly reduced proliferation, angiogenesis and invasion, and increased apoptosis in chemosensitive (A2780 and SKOV3ip1) and chemoresistant (A2780‐CP20, SKOV3‐TR, ES2 and RMG2) EOC cells. SK1 inhibitors also decreased the intracellular enzymatic activity of SK1. Furthermore, FTY720 treatment significantly decreased the in vivo tumor weight in xenograft models of established cell lines (A2780 and SKOV3ip1) and a PDX model for CCC compared to control (p < 0.05). These results support therapeutic targeting of SK1 as a potential new strategy for EOC.
What's new?
The products of sphingolipid metabolism regulate a variety of intracellular processes, and when altered, as in the case of sphingosine kinase 1 (SK1) overexpression, those products may contribute to cancer. The present study examined the effects of SK1 inhibition in epithelial ovarian carcinoma (EOC). In EOC cell lines, SK1 inhibition with the agent FTY720 significantly reduced angiogenesis, invasion, and proliferation and increased apoptosis. Administration of FTY720 in xenograft models of ovarian cancer cell lines and patient‐derived tumors yielded reductions in tumor weight. The results suggest that SK1 targeting is a potential therapeutic strategy in ovarian cancer.
Purpose: MicroRNAs (miRNA) are small noncoding RNAs that are 18 to 25 nucleotides in length; they regulate the stability or translational
efficiency of target mRNAs. Emerging evidence suggests that ...miRNAs might be involved in the pathogenesis of a variety of human
cancers.
Experimental Design: In this study, we profiled miRNA expression in 10 early stage invasive squamous cell carcinomas (ISCC) and 10 normal cervical
squamous epithelial specimens using TaqMan real-time quantitative PCR array methods. In order to evaluate the role of miR-199a , one of the most significantly overexpressed in ISCCs, we transfected cervical cancer cells (SiHa and ME-180) with anti– miR-199a oligonucleotides and assessed the cell viability.
Results: We found 70 genes (68 up-regulated, 2 down-regulated) with significantly different expression in the ISCCs compared with
normal samples ( P < 0.05). When we analyzed the expression of the 10 most significant miRNAs in 31 ISCCs, increased miR-127 expression was significantly associated with lymph node metastasis ( P = 0.006). Transfection of anti– miR-199a oligonucleotides to cervical cancer cells suppressed cell growth in vitro , which was potentiated with the anticancer agent cisplatin.
Conclusions: Our results show that miRNA deregulation may play an important role in the malignant transformation of cervical squamous
cells. In addition, they may offer new candidate targets to be exploited for both prognostic and therapeutic strategies in
patients with cervical cancer.
Although the concurrent use of a chemotherapeutic agent and radiotherapy improves survival in patients with locally advanced or recurrent cervical cancer, severe side effects related to chemotherapy ...are frequent and may result in a low quality of life for the patients. In this study, we investigated the effects of a combination of Wee1 inhibitor (AZD1775) and irradiation in cervical cancer. In vitro effects of AZD1775 with irradiation in human cervical cancer cells were assessed by clonogenic survival and apoptosis assays. The effects on DNA damage response signaling and the cell cycle were also explored. Tumor growth delay was evaluated to investigate the in vivo effects of AZD1775 with irradiation in cervical cancer mouse models, including xenografts and patient-derived xenografts (PDXs). The co-treatment of AZD1775 and irradiation significantly decreased clonogenic survival and increased apoptosis in cervical cancer cells. These effects were associated with G2 checkpoint abrogation which resulted in persistent DNA damage. Both in the xenografts and the PDXs, the co-treatment significantly decreased tumor growth compared tothe irradiation alone (p < 0.05). These results demonstrate that the Wee1 inhibitor (AZD1775) can be considered as a potential alternative as a radiosensitizer in cervical cancer instead of a chemotherapeutic agent such as cisplatin.
Abstract Objective. Recent reports suggest that targeting the unique miRNAs highly expressed in several cancers may be a promising approach in the development of new cancer therapeutic tools. The ...purpose of this study was to evaluate the roles of miRNAs as therapeutic targets in human endometrial endometrioid carcinomas (EECs). Methods. We evaluated the differential expressions of miRNAs in EECs and normal endometrial tissues using microarrays and cluster analysis. After validation of differentially expressed miRNAs in another set of EECs and normal endometrial tissues, we performed the in vitro experiment using endometrial cancer cells with anti-miRNA (anti-miR) to evaluate the roles of miRNAs that are highly expressed in EECs for cell proliferation and chemosensitivity. Results. A miRNA microarray showed that the miR-200 family, including hsa-miR-141 , hsa-miR-200a , hsa-miR-200b , hsa-miR-200c , and hsa-miR-429 , was up-regulated in EECs as compared with that in normal endometrial tissues. When we treated endometrial cancer cells with specific anti-miRs, including anti-miR-141, -200a, -200b, -200c, or -429, we found that anti-miR-200a, -200b, -200c, and -429 significantly inhibited the growth of HEC-1A cells and anti-miR-141, -200c, and -429 significantly inhibited the growth of Ishikawa cells. Moreover, transfection with anti-miR-429 enhanced the cytotoxic effect of cisplatin in HEC-1A cells. Conclusions. These results indicate that the miR-200 family is highly expressed in EECs compared with that of normal endometrial tissues and could play an important role in cancer growth. Specifically, anti-miR-429 could enhance the cytotoxic activity with cisplatin in EECs. Therefore, the miR-200 family may offer new candidate targets to be exploited in therapeutic strategies for patients with these carcinomas.
In this study, we investigated the therapeutic effects of c-MET inhibition in ovarian clear cell carcinoma (OCCC). Expression levels of c-MET in the epithelial ovarian cancers (EOCs) and normal ...ovarian tissues were evaluated using real-time PCR. To test the effects of c-MET inhibitors in OCCC cell lines, we performed MTT and apoptosis assays. We used Western blots to evaluate the expression of c-MET and its down-stream pathway. In vivo experiments were performed to test the effects of c-MET inhibitor on tumor growth in orthotopic mouse xenografts of OCCC cell line RMG1 and a patient-derived tumor xenograft (PDX) model of OCCC. c-MET expression was significantly greater in OCCCs compared with serous carcinomas and normal ovarian tissues (p < 0.001). In in vitro study, inhibition of c-MET using c-MET inhibitors (SU11274 or crizotinib) significantly decreased the proliferation, and increased the apoptosis of OCCC cells. SU11274 decreased expression of the p-c-MET proteins and blocked the phosphorylation of down-stream proteins Akt and Erk. Furthermore, SU11274 treatment significantly decreased the in vivo tumor weight in xenograft models of RMG1 cell and a PDX model for OCCC compared to control (p = 0.004 and p = 0.009, respectively).
Few studies have been conducted on the relationship between metabolic syndrome (MetS) and persistent human papillomavirus (HPV) infection. We investigated whether MetS and associated factors can ...predict the persistence of HPV infection.
We performed a retrospective cohort study of 80,993 female cases undergoing general medical screenings at Samsung Medical Center and 51,140 cases were included in final analysis. MetS and associated factors were used to develop a model predicting the persistence of HPV infection which was defined as HPV positivity for at least one year. The performance of the model was internally validated using bootstrapping and externally validated by testing the risk score against the test set.
Of the 51,140 cases, there were 5833 (11.4%) cases diagnosed with MetS and 7682 (15.0%) cases diagnosed with HPV infection at baseline. The 12- to 24-month persistence rates of HPV were 50.0% (2846/5691). MetS (OR 1.34, 95% CI 1.04–1.71), globulin (by quintile; OR 1.70, 95% CI 1.25–2.30), fibrinogen (x100 value by quintile; OR 1.07, 95% CI 1.02–1.14), total protein (by quintile; OR 0.91, 95% CI 0.84–0.99) and prothrombin time (by quintile; OR 0.94, 95% CI 0.89–0.99) were significantly associated with the persistence of HPV in multivariate analysis. For validation, a prediction model showed good performance for a range of risk scores and categorized cases into low-, intermediate- and high-risk, which were also correlated with HPV persistence (45.8%, 51.9%, and 60.2% respectively, P < 0.001).
MetS and associated factors were associated with an increased risk of persistent HPV infection.
•Metabolic syndrome was associated with an increased risk of persistent HPV infection.•Some of individual metabolic factors were associated with an increased risk of persistent HPV infection.•Our prediction model showed good performance for categorized cases with persistent HPV infection.
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