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1.  Monocyte Subpopulations in Angiogenesis 
Cancer research  2014;74(5):1287-1293.
Growing understanding of the role of the tumor microenvironment in angiogenesis has brought monocyte-derived cells into focus. Monocyte subpopulations are an increasingly attractive therapeutic target in many pathologic states, including cancer. Before monocyte-directed therapies can be fully harnessed for clinical use, understanding of monocyte-driven angiogenesis in tissue development and homeostasis, as well as malignancy, is required. Here, we provide an overview of the mechanisms by which monocytic subpopulations contribute to angiogenesis in tissue and tumor development, highlight gaps in our existing knowledge, and discuss opportunities to exploit these cells for clinical benefit.
doi:10.1158/0008-5472.CAN-13-2825
PMCID: PMC4040005  PMID: 24556724
2.  Targeting Src in Mucinous Ovarian Carcinoma 
PURPOSE
Mucinous ovarian carcinomas have a distinct clinical pattern compared to other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of src kinase in pre-clinical models of mucinous ovarian carcinoma.
EXPERIMENTAL DESIGN
1302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of src kinase inhibition were tested in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2) using dasatinib-based therapy.
RESULTS
Patients with advanced-stage mucinous ovarian cancer had significantly worse survival compared to those with serous histology: median overall survival, 1.67 versus 3.41 years, p=0.002; and median survival time after recurrence of 0.53 versus 1.66 years, p<0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting src with dasatinib in vivo showed significant anti-tumor effects in the RMUG-S-ip2 model, but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further demonstrated significant effects on reducing cell viability, increasing apoptosis, and in vivo anti-tumor effects in the RMUG-S-ip2 model.
CONCLUSIONS
Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting src kinase with combination of dasatinib and oxaliplatin may be an attractive approach in this disease.
doi:10.1158/1078-0432.CCR-10-3176
PMCID: PMC4028171  PMID: 21737505
ovarian cancer; mucinous; oxaliplatin; dasatinib; src kinase
3.  Therapeutic synergy between microRNA and siRNA in ovarian cancer treatment 
Cancer discovery  2013;3(11):10.1158/2159-8290.CD-13-0159.
Development of improved RNA interference based strategies is of utmost clinical importance. While siRNA-mediated silencing of EphA2, an ovarian cancer oncogene, results in reduction of tumor growth, we present evidence that additional inhibition of EphA2 by a microRNA further ‘boosts’ its anti-tumor effects. We identified miR-520d-3p as a tumor suppressor upstream of EphA2, whose expression correlated with favorable outcomes in two independent patient cohorts comprising of 647 patients. Restoration of miR-520d-3p prominently decreased EphA2 protein levels, and suppressed tumor growth and migration/invasion both in vitro and in vivo. Dual inhibition of EphA2 in vivo using DOPC nano-liposomes loaded with miR-520d-3p and EphA2-siRNA showed synergistic anti-tumor efficiency and greater therapeutic efficacy than either monotherapy alone. This synergy is atleast in part due to miR-520d-3p targeting EphB2, another Eph receptor. Our data emphasize the feasibility of combined miRNA-siRNA therapy, and will have broad implications for innovative gene silencing therapies for cancer and other diseases.
doi:10.1158/2159-8290.CD-13-0159
PMCID: PMC3855315  PMID: 24002999
miR-520d-3p; EphA2; EphB2; ovarian cancer; RNA interference
4.  EphA2 Targeted Chemotherapy Using an Antibody Drug Conjugate in Endometrial Carcinoma 
Purpose
EphA2 overexpression is frequently observed in endometrial cancers, and is predictive of poor clinical outcome. Here, we utilize an antibody drug conjugate (MEDI-547) composed of a fully human monoclonal antibody against both human and murine EphA2 (1C1) and the tubulin polymerization inhibitor, monomethylauristatin F (MMAF).
Experimental design
EphA2 expression was examined in endometrial cancer cell lines by Western Blot. Specificity of MEDI-547 was examined by antibody degradation and internalization assays. Viability and apoptosis were investigated in endometrial cancer cell lines and orthotopic tumor models.
Results
EphA2 was expressed in the Hec-1A and Ishikawa cells, but was absent in the SPEC-2 cells. Antibody degradation and internalization assays showed that the antibody drug conjugate decreased EphA2 protein levels and was internalized in EphA2 positive cells (Hec-1A and Ishikawa). Moreover, in vitro cytotoxicity and apoptosis assays demonstrated that the antibody drug conjugate decreased viability and increased apoptosis of Hec-1A and Ishikawa cells. In vivo therapy experiments in mouse orthotopic models with this antibody drug conjugate resulted in 86 to 88% growth inhibition (P < 0.001) in the orthotopic Hec-1A and Ishikawa models compared to controls. Moreover, the mice treated with this antibody drug conjugate had a lower incidence of distant metastasis compared with controls. The anti-tumor effects of the therapy were related to decreased proliferation and increased apoptosis of tumor and associated endothelial cells.
Conclusions
The preclinical data for endometrial cancer treatment using MEDI-547 demonstrate substantial anti-tumor activity.
doi:10.1158/1078-0432.CCR-10-0017
PMCID: PMC3955167  PMID: 20388851
EphA2 Receptor; Antibody Drug Conjugates; Targeted Therapy; Endometrial Cancer
5.  Neuroendocrine influences on cancer progression 
Brain, behavior, and immunity  2012;30(Suppl):S19-S25.
During the past decade, new studies have continued to shed light on the role of neuroendocrine regulation of downstream physiological and biological pathways relevant to cancer growth and progression. More specifically, our knowledge of the effects of the sympathetic nervous system (SNS) on cancer biology has been greatly expanded by new data demonstrating how the cellular immune response, inflammatory processes, tumor-associated angiogenesis, and tumor cell invasion and survival converge to promote tumor growth. This review will summarize these studies, while synthesizing clinical, cellular and molecular research that has continued to unearth the biological events mediating the interplay between SNS-related processes and cancer progression.
doi:10.1016/j.bbi.2012.06.005
PMCID: PMC3467346  PMID: 22728325
behavioral stress; adrenergic receptors; metastasis; catecholamines; cancer
6.  Comprehensive epigenetic analysis of Notch pathway in high-grade serous ovarian cancer 
Gynecologic oncology  2012;128(3):506-511.
Objectives
Gene methylation and other epigenetic modifications of gene regulation have been implicated in the growth of ovarian cancer, but the clinical significance of such modifications in the Notch pathway in high-grade serous ovarian cancer (HGS-OvCa) is not well understood. We used The Cancer Genome Atlas (TCGA) data to study the clinical relevance of epigenetic modifications of Notch pathway genes.
Methods
We analyzed the interaction of DNA methylation and miRNAs with gene expression data for Notch family members with the Spearman rank correlation test and explored potential relationships with overall survival (OS) with the log-rank test. We downloaded clinical data, level 3 gene expression data, and level 3 DNA methylation data for 480 patients with stage II-IV HGS-OvCa from TCGA data portal. Patients were randomly divided into training and validation cohorts for survival analyses. In each set, patients were grouped into percentiles according to methylation and microRNA (miRNA) or messenger RNA (mRNA) levels. We used several algorithms to predict miRNA-mRNA interaction.
Results
There were significant inverse relationships between methylation status and mRNA expression for PPARG, CCND1, and RUNX1. For each of these genes, patients with a lower methylation level and higher expression level had significantly poorer OS than did patients with a higher methylation level and lower expression level. We also found a significant inverse relationship between miRNAs and mRNA expression for CCND1, PPARG, and RUNX1. By further analyzing the effect of miRNAs on gene expression and OS, we found that patients with higher levels of CCND1, PPARG, and RUNX1 expression and lower expression levels of their respective miRNAs (502-5p, 128, and 215/625) had significantly poorer OS.
Conclusions
Epigenetic alterations of multiple Notch target genes and pathway interacting genes (PPARG, CCND1, and RUNX1) may relate to activation of this pathway and poor survival of patients with HGS-OvCa.
doi:10.1016/j.ygyno.2012.11.029
PMCID: PMC3645276  PMID: 23200915
Notch pathway; high-grade serous ovarian carcinoma; epigenetic alterations; High-grade serous ovarian cancer; The Cancer Genome Atlas; Epigenetic modifications of gene regulation
7.  Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer 
Cancer cell  2013;23(2):186-199.
Summary
Integrated genomic analyses revealed a miRNA-regulatory network, which further defined a robust integrated mesenchymal subtype associated with poor overall survival in 459 cases of serous ovarian cancer (OvCa) from The Cancer Genome Atlas and 560 cases from independent cohorts. Eight key miRNAs, including miR-506, miR-141 and miR-200a, were predicted to regulate 89% of the targets in this network. Follow-up functional experiments illustrate that miR-506 augmented E-cadherin expression, inhibited cell migration and invasion, and prevented TGFβ-induced epithelial-mesenchymal transition (EMT) by targeting SNAI2, a transcriptional repressor of E-cadherin. In human OvCa, miR-506 expression was correlated with decreased SNAI2 and VIM, elevated E-cadherin, and beneficial prognosis. Nanoparticle delivery of miR-506 in orthotopic OvCa mouse models led to E-cadherin induction and reduced tumor growth.
doi:10.1016/j.ccr.2012.12.020
PMCID: PMC3603369  PMID: 23410973
8.  Why stress is BAD for cancer patients 
Behavioral stress is known to promote tumor progression in experimental models, but the role of behavioral stress in cancer initiation is less clear. In this issue, Hassan et al. focus on the signaling and biological effects induced by stress hormones that lead to tumor cell evasion from apoptosis, resulting in prostate cancer progression.
doi:10.1172/JCI67887
PMCID: PMC3561841  PMID: 23348736
9.  Resistance and Escape From Antiangiogenesis Therapy: Clinical Implications and Future Strategies 
Journal of Clinical Oncology  2012;30(32):4026-4034.
Angiogenesis has long been considered an important target for cancer therapy. Initial efforts have primarily focused on targeting of endothelial and tumor-derived vascular endothelial growth factor signaling. As evidence emerges that angiogenesis has significant mechanistic complexity, therapeutic resistance and escape have become practical limitations to drug development. Here, we review the mechanisms by which dynamic changes occur in the tumor microenvironment in response to antiangiogenic therapy, leading to drug resistance. These mechanisms include direct selection of clonal cell populations with the capacity to rapidly upregulate alternative proangiogenic pathways, increased invasive capacity, and intrinsic resistance to hypoxia. The implications of normalization of vasculature with subsequently improved vascular function as a result of antiangiogenic therapy are explored, as are the implications of the ability to incorporate and co-opt otherwise normal vasculature. Finally, we consider the extent to which a better understanding of the biology of hypoxia and reoxygenation, as well as the depth and breadth of systems invested in angiogenesis, may offer putative biomarkers and novel therapeutic targets. Insights gained through this work may offer solutions for personalizing antiangiogenesis approaches and improving the outcome of patients with cancer.
doi:10.1200/JCO.2012.41.9242
PMCID: PMC3488272  PMID: 23008289
10.  Autocrine Effects of Tumor-Derived Complement 
Cell reports  2014;6(6):1085-1095.
SUMMARY
We describe a role for the complement system in enhancing cancer growth. Cancer cells secrete complement proteins that stimulate tumor growth upon activation. Complement promotes tumor growth via a direct autocrine effect that is partially independent of tumor-infiltrating cytotoxic T cells. Activated C5aR and C3aR signal through the PI3K/AKT pathway in cancer cells, and silencing the PI3K or AKT gene in cancer cells eliminates the progrowth effects of C5aR and C3aR stimulation. In patients with ovarian or lung cancer, higher tumoral C3 or C5aR mRNA levels were associated with decreased overall survival. These data identify a role for tumor-derived complement proteins in promoting tumor growth, and they therefore have substantial clinical and therapeutic implications.
doi:10.1016/j.celrep.2014.02.014
PMCID: PMC4084868  PMID: 24613353
11.  TARDBP regulates glycolysis in hepatocellular carcinoma by regulating PFKP through miR-520 
Hepatology (Baltimore, Md.)  2013;58(1):182-191.
Metabolic changes are common features of many cancer cells and are frequently associated with the clinical outcome of patients with various cancers including hepatocellular carcinoma (HCC). Thus, aberrant metabolic pathways in cancer cells are attractive targets for cancer therapy. However, our understanding of cancer-specific regulatory mechanisms of cell metabolism is still very limited. We found that Tat activating regulatory DNA-binding protein (TARDBP) is a novel regulator of glycolysis in HCC cells. TARDBP regulates expression of the platelet isoform of phosphofructokinase (PFKP), the rate-limiting enzyme of glycolysis that catalyzes the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Silencing of TARDBP expression in multiple HCC cell lines leads to impaired glucose metabolism and inhibition of in vitro and in vivo growth of HCC cells. Notably, the miR-520 family is an intermediate regulator of TARDBP-mediated regulation of glycolysis. Mechanistically, TARDBP suppressed expression of the miR-520 family, which in turn inhibited expression of PFKP. We further showed that expression of TARDBP is significantly associated with the overall survival of patients with HCC.
Conclusion
Our study provides new mechanistic insights into the regulation of glycolysis in HCC cells and reveals TARDBP as a potential therapeutic target for HCC.
doi:10.1002/hep.26310
PMCID: PMC3923572  PMID: 23389994
TARDBP; PFKP; Glycolysis; miR-520; Hepatocellular carcinoma
12.  Social Influences on Clinical Outcomes of Patients With Ovarian Cancer  
Journal of Clinical Oncology  2012;30(23):2885-2890.
Purpose
Previous research has demonstrated relationships of social support with disease-related biomarkers in patients with ovarian cancer. However, the clinical relevance of these findings to patient outcomes has not been established. This prospective study examined how social support relates to long-term survival among consecutive patients with ovarian cancer. We focused on two types of social support: social attachment, a type of emotional social support reflecting connections with others, and instrumental social support reflecting the availability of tangible assistance.
Patients and Methods
Patients were prospectively recruited during a presurgical clinic visit and completed surveys before surgery. One hundred sixty-eight patients with histologically confirmed epithelial ovarian cancer were observed from the date of surgery until death or December 2010. Clinical information was obtained from medical records.
Results
In a Cox regression model, adjusting for disease stage, grade, histology, residual disease, and age, greater social attachment was associated with a lower likelihood of death (hazard ratio [HR], 0.87; 95% CI, 0.77 to 0.98; P = .018). The median survival time for patients with low social attachment categorized on a median split of 15 was 3.35 years (95% CI, 2.56 to 4.15 years). In contrast, by study completion, 59% of patients with high social attachment were still alive after 4.70 years. No significant association was found between instrumental social support and survival, even after adjustment for covariates.
Conclusion
Social attachment is associated with a survival advantage for patients with ovarian cancer. Clinical implications include the importance of screening for deficits in the social environment and consideration of support activities during adjuvant treatment.
doi:10.1200/JCO.2011.39.4411
PMCID: PMC3410403  PMID: 22802321
13.  Poor survival with wild-type TP53 ovarian cancer? 
Gynecologic oncology  2013;130(3):565-569.
Objective
To investigate whether wild-type TP53 status in high-grade serous ovarian carcinoma is associated with poorer survival.
Methods
Clinical and genomic data of 316 sequenced samples from The Cancer Genome Atlas (TCGA) ovarian high-grade serous carcinoma (HGOSC) study were downloaded from TCGA data portal. Association between wild-type TP53 and survival was analyzed with Kaplan Meier method and Cox regression. The diagnosis of HGOSC was evaluated by reviewing pathological reports and high-resolution hematoxylin and eosin (H&E) images from frozen sections. The authenticity of wild-type TP53 in these tumor samples was assessed by analyzing SNP array data with ASCAT algorithm, reverse phase protein array (RPPA) data and RNAseq data.
Results
Fifteen patients with HGOSCs were identified to have wild-type TP53, which had significantly shorter survival and higher chemoresistance than those with mutated TP53. The authenticity of wild-type TP53 status in these fifteen patients was supported by SNP array, RPPA, and RNAseq data. Except four cases with mixed histology, the classification as high grade serous carcinomas was supported by pathological reports and H&E images. Using RNAseq data, it was found that EDA2R gene, a direct target of wild-type TP53, was highly up-regulated in samples with wild-type TP53 in comparison to samples with either nonsense or missense TP53 mutations.
Conclusion
Patients with wild-type TP53 high grade ovarian serous carcinomas appeared to have a poorer survival and were more chemoresistant than those with mutated TP53. Differentially expressed genes in these TP53 wild-type tumors may provide insight in the molecular mechanism in chemotherapy resistance.
doi:10.1016/j.ygyno.2013.06.016
PMCID: PMC4059202  PMID: 23800698
Ovarian Cancer; p53 mutation; wild-type p53; EDA2R; Survival Statistics; Collagen VI
14.  Metronomic Activity of CD44-Targeted Hyaluronic Acid-Paclitaxel in Ovarian Carcinoma 
Purpose
Most primary human ovarian tumors and peritoneal implants, as well as tumor vascular endothelial cells, express the CD44 family of cell surface proteoglycans, the natural ligand for which is hyaluronic acid (HA). Metronomic (MET) dosing, the frequent administration of chemotherapeutics at substantially lower than maximum tolerated doses (MTD), has been shown to result in reduced normal tissue toxicity and to minimize “off-treatment” exposure resulting in an improved therapeutic ratio.
Experimental Design
We tested the hypothesis that HA conjugates of paclitaxel (TXL; HA-TXL) would exert strong anti-tumor effects with MET dosing and induce anti-angiogenic effects superior to those achieved with MTD administration or with free TXL. Female nude mice bearing SKOV3ip1 or HeyA8 ovarian cancer cells were treated intraperitoneally (ip) with MET HA-TXL regimens (or MTD administration to determine therapeutic and biological effects.
Results
All MET HA-TXL-treated mice and the MTD group revealed significantly reduced tumor weights and nodules compared to controls (all p values < 0.05) in the chemotherapy-sensitive models. However, the MTD HA-TXL-treated mice showed significant weight loss compared to control mice, whereas body weights were not affected in the MET groups in HeyA8-MDR model, reflecting reduced toxicity. In the taxane-resistant HeyA8-MDR model, significant reduction in tumor weight and nodule counts was noted in the MET groups, whereas the response of the MTD group did not achieve significance. While both MTD and MET regimens reduced proliferation (Ki-67) and increased apoptosis (TUNEL), only MET treatment resulted in significant reductions in angiogenesis (CD31, microvessel density). Moreover, MET treatment resulted in substantial increases in thrombospondin-1 (Tsp-1), an inhibitor of angiogenesis.
Conclusions
This study demonstrated that MET HA-TXL regimens have substantial antitumor activity in ovarian carcinoma, likely via a predominant anti-angiogenic mechanism.
doi:10.1158/1078-0432.CCR-11-3250
PMCID: PMC3638880  PMID: 22693353
Ovarian carcinoma; metronomic chemotherapy; and CD44
15.  NANOTECHNOLOGY IN CANCER THERAPY 
Journal of drug targeting  2013;21(10):904-913.
Cancer is one of the major causes of mortality worldwide and advanced techniques for therapy are urgently needed. The development of novel nanomaterials and nanocarriers has allowed a major drive to improve drug delivery in cancer. The major aim of most nanocarrier applications has been to protect the drug from rapid degradation after systemic delivery and allowing it to reach tumor site at therapeutic concentrations, meanwhile avoiding drug delivery to normal sites as much as possible to reduce adverse effects. These nanocarriers are formulated to deliver drugs either by passive targeting, taking advantage of leaky tumor vasculature or by active targeting using ligands that increase tumoral uptake potentially resulting in enhanced antitumor efficacy, thus achieving a net improvement in therapeutic index. The rational design of nanoparticles plays a critical role since structural and physical characteristics, such as size, charge, shape, and surface characteristics determine the biodistribution, pharmacokinetics, internalization and safety of the drugs. In this review, we focus on several novel and improved strategies in nanocarrier design for cancer therapy.
doi:10.3109/1061186X.2013.837469
PMCID: PMC4057038  PMID: 24079419
nanoparticles; nanomedicine; drug delivery; cancer therapy
16.  JNK-1 Inhibition Leads to Antitumor Activity in Ovarian Cancer 
Purpose
To demonstrate the functional, clinical and biological significance of JNK-1 in ovarian carcinoma.
Experimental Design
Analysis of the impact of JNK on 116 epithelial ovarian cancers was conducted. The role of JNK in vitro and in experimental models of ovarian cancer was assessed. We studied the role of WBZ_4, a novel JNK inhibitor redesigned from imatinib based on targeting wrapping defects, in cell lines and in experimental models of ovarian cancer.
Results
We found a significant association of pJNK with progression free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose dependent fashion in four ovarian cancer cell lines. In vivo, while imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The anti-tumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights as compared to non-silencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition.
Conclusions
These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the re-designed WBZ_4 compound should be considered for further clinical development.
doi:10.1158/1078-0432.CCR-09-1180
PMCID: PMC3716580  PMID: 20028751
JNK-1; Ovarian Cancer; Wrapping defects; Tyrosine Kinase inhibitor; Dehydrons
17.  Neighborhood matters: Response to EZH2 methyltransferase inhibitors 
Cell Cycle  2013;12(15):2345.
doi:10.4161/cc.25775
PMCID: PMC3841310  PMID: 23887388
18.  CA-125 Level as a Prognostic Indicator in Type I and Type II Epithelial Ovarian Cancer 
Objective
The majority of patients with epithelial ovarian cancer achieved a complete clinical remission with normal CA-125 will still relapse and die from their disease. The present study was to determine whether CA-125 levels before, during and after primary treatment provided prognostic information for both Type I and Type II ovarian cancer.
Methods
In this retrospective study, we identified 410 epithelial ovarian cancer patients who had achieved a CCR between 1984 and 2011. A Cox proportional hazards model and log-rank test were used to assess associations between the nadir CA-125, histotype, and prognosis.
Results
The baseline serum CA-125 concentration was higher in patients with type II ovarian cancer than in those with type I (p < 0.001). The nadir CA-125 was an independent predictor of PFS (p < 0.001) and OS (p = 0.035) duration. The PFS and OS durations were 21.7 and 79.4 months in patients with CA-125 ≤ 10 U/ml and 13.6 and 64.6 months in those with 11-35 U/ml (p = 0.01 and 0.002, respectively). Histotype was an independent predictor of PFS (p = 0.041): the PFS and OS durations of type I patients were longer than those in type II (p < 0.001 and < 0.001, respectively).
Conclusions
The nadir CA-125 and the histotype are predictive of PFS and OS duration in ovarian cancers experienced a CCR. PFS and OS durations were shorter in patients with CA-125 levels of 11-35 U/ml and type II disease than in those with ≤ 10 U/ml and type I.
doi:10.1097/IGC.0b013e31828f7a24
PMCID: PMC3760786  PMID: 23669443
ovarian cancer; CA-125; prognosis factors; tumor marker; pathological type
19.  Targeting Angiogenesis in Gynecologic Cancers 
doi:10.1016/j.hoc.2012.01.009
PMCID: PMC3334841  PMID: 22520979
20.  ATP11B mediates platinum resistance in ovarian cancer 
The Journal of Clinical Investigation  2013;123(5):2119-2130.
Platinum compounds display clinical activity against a wide variety of solid tumors; however, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. We found that ATP11B expression was correlated with higher tumor grade in human ovarian cancer samples and with cisplatin resistance in human ovarian cancer cell lines. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-targeted siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux kinetics indicated that ATP11B enhances the export of cisplatin from cells. The colocalization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins, such as syntaxin-6 (STX6) and vesicular-associated membrane protein 4 (VAMP4), strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, inhibition of ATP11B expression could serve as a therapeutic strategy to overcome cisplatin resistance.
doi:10.1172/JCI65425
PMCID: PMC3635722  PMID: 23585472
21.  Biological Significance of HORM-A Domain Containing Protein 1 (HORMAD1) in Epithelial Ovarian Carcinoma 
Cancer letters  2012;330(2):123-129.
The present study was undertaken to determine the expression and biological significance of HORMAD1 in human epithelial ovarian carcinoma. We found that a substantial proportion of human epithelial ovarian cancers expressed HORMAD1. In vitro, HORMAD1 siRNA enhanced docetaxel induced apoptosis and substantially reduced the invasive and migratory potential of ovarian cancer cells (2774). In vivo, HORMAD1 siRNA-DOPC treatment resulted in reduced tumor weight, which was further enhanced in combination with cisplatin. HORMAD1 gene silencing resulted in significantly reduced VEGF protein levels and microvessel density compared to controls. Our data suggest that HOMRAD1 may be an important therapeutic target.
doi:10.1016/j.canlet.2012.07.001
PMCID: PMC3498611  PMID: 22776561
HORMAD1; ovarian cancer; angiogenesis; VEGF; xenograft
22.  Silencing of p130Cas in Ovarian Carcinoma: A Novel Mechanism for Tumor Cell Death 
Background
We investigated the clinical and biological significance of p130cas, an important cell signaling molecule, in ovarian carcinoma.
Methods
Expression of p130cas in ovarian tumors, as assessed by immunohistochemistry, was associated with tumor characteristics and patient survival. The effects of p130cas gene silencing with small interfering RNAs incorporated into neutral nanoliposomes (siRNA-DOPC), alone and in combination with docetaxel, on in vivo tumor growth and on tumor cell proliferation (proliferating cell nuclear antigen) and apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling) were examined in mice bearing orthotopic taxane-sensitive (HeyA8 and SKOV3ip1) or taxane-resistant (HeyA8-MDR) ovarian tumors (n = 10 per group). To determine the specific mechanisms by which p130cas gene silencing abrogates tumor growth, we measured cell viability (MTT assay), apoptosis (fluorescence-activated cell sorting), autophagy (immunoblotting, fluorescence, and transmission electron microscopy), and cell signaling (immunoblotting) in vitro. All statistical tests were two-sided.
Results
Of 91 ovarian cancer specimens, 70 (76%) had high p130cas expression; and 21 (24%) had low p130cas expression. High p130cas expression was associated with advanced tumor stage (P < .001) and higher residual disease (>1 cm) following primary cytoreduction surgery (P = .007) and inversely associated with overall survival and progression-free survival (median overall survival: high p130cas expression vs low expression, 2.14 vs 9.1 years, difference = 6.96 years, 95% confidence interval = 1.69 to 9.48 years, P < .001; median progression-free survival: high p130cas expression vs low expression, 1.04 vs 2.13 years, difference = 1.09 years, 95% confidence interval = 0.47 to 2.60 years, P = .01). In mice bearing orthotopically implanted HeyA8 or SKOV3ip1 ovarian tumors, treatment with p130cas siRNA-DOPC in combination with docetaxel chemotherapy resulted in the greatest reduction in tumor growth compared with control siRNA therapy (92%–95% reduction in tumor growth; P < .001 for all). Compared with control siRNA therapy, p130cas siRNA-DOPC reduced SKOV3ip1 cell proliferation (31% reduction, P < .001) and increased apoptosis (143% increase, P < .001) in vivo. Increased tumor cell apoptosis may have persisted despite pan-caspase inhibition by the induction of autophagy and related signaling pathways.
Conclusions
Increased p130cas expression is associated with poor clinical outcome in human ovarian carcinoma, and p130cas gene silencing decreases tumor growth through stimulation of apoptotic and autophagic cell death.
doi:10.1093/jnci/djr372
PMCID: PMC3206039  PMID: 21957230
23.  Enhancing chemotherapy response with sustained EphA2 silencing using multistage vector delivery 
Purpose
RNA interference has the potential to specifically knock down the expression of target genes, and thereby transform cancer therapy. However, lack of effective delivery of small inhibitory RNA (siRNA) has dramatically limited its in vivo applications. We have developed a multistage vector (MSV) system, composed of discoidal porous silicon particles loaded with nanotherapeutics, that directs effective delivery and sustained release of siRNA in tumor tissues. In this study, we evaluated therapeutic efficacy of MSV-loaded EphA2 siRNA (MSV/EphA2) with murine orthotopic models of metastatic ovarian cancers as a first step towards development of a new class of nanotherapeutics for the treatment of ovarian cancer.
Experimental design
Tumor accumulation of MSV/EphA2 and sustained release of siRNA from MSV were analyzed after i.v. administration of MSV/siRNA. Nude mice with metastatic SKOV3ip2 tumors were treated with MSV/EphA2 and paclitaxel, and therapeutic efficacy was assessed. Mice with chemotherapy-resistant HeyA8 ovarian tumors were treated with a combination of MSV/EphA2 and docetaxel, and enhanced therapeutic efficacy was evaluated.
Results
Treatment of SKOV3ip2 tumor mice with MSV/EphA2 biweekly for 6 weeks resulted in dose-dependent (5, 10 and 15 μg/mice) reduction of tumor weight (36%, 64%, and 83%) and number of tumor nodules compared with the control groups. In addition, tumor growth was completely inhibited when mice were treated with MSV/EphA2 in combination with paclitaxel. Furthermore, combination treatment with MSV/EphA2 and docetaxel inhibited growth of HeyA8-MDR tumors, which were otherwise resistant to docetaxel treatment.
Conclusion
These findings indicate that MSV/EphA2 merits further development as a novel therapeutic agent for ovarian cancer.
doi:10.1158/1078-0432.CCR-12-2764
PMCID: PMC3618564  PMID: 23386691
ovarian cancer; siRNA; nanoliposome; porous silicon; multistage vector; sustained release
24.  Latest research and clinical treatment of advanced-stage epithelial ovarian cancer 
Nature reviews. Clinical oncology  2013;10(4):211-224.
The natural history of ovarian cancer continues to be characterized by late-stage presentation, metastatic bulky disease burden and stagnant mortality statistics despite prolific drug development. Robust clinical investigation, particularly with modifications to primary treatment surgical goals and adjuvant therapy are increasing median progression-free and overall survival, although the cure rates have only modestly been affected. Maintenance therapy holds promise, but studies have yet to identify an agent and/or strategy that can affect survival. Recurrent disease is largely an incurable state; however, current intervention with selected surgery, combination and targeted therapy and investigational protocols are impacting progression-free survival. Ovarian cancer is a diverse and genomically complex disease, which commands global attention. Rational investigation must balance the high rate of discovery with lagging clinical investigation and limited patient resources. Nevertheless, armamentarium growth offers unprecedented opportunities for patients suffering with this disease. This Review presents and reviews the contemporary management of the disease spectrum termed epithelial ‘ovarian’ cancer and introduces the direction and early results of clinical investigation.
doi:10.1038/nrclinonc.2013.5
PMCID: PMC3786558  PMID: 23381004
25.  miR-101 suppresses the epithelial-to-mesenchymal transition by targeting ZEB1 and ZEB2 in ovarian carcinoma 
Oncology Reports  2014;31(5):2021-2028.
Ovarian carcinoma is the most lethal gynecologic malignancy; the majority of patients succumb to the disease within 5 years of diagnosis. The poor survival rate is attributed to diagnosis at advanced stage, when the tumor has metastasized. The epithelial-to-mesenchymal transition (EMT) is a necessary step toward metastatic tumor progression. Through integrated computational analysis, we recently identified a master microRNA (miRNA) network that includes miR-101 and regulates EMT in ovarian carcinoma. In the present study, we characterized the functions of miR-101. Using reporter gene assays, we demonstrated that miR-101 suppressed the expression of the E-cadherin repressors ZEB1 and ZEB2 by directly targeting the 3′-untranslated region (3′UTR) of both ZEB1 and ZEB2. Introduction of miR-101 significantly inhibited EMT and cell migration and invasion. Introducing cDNAs of ZEB1 and ZEB2 without 3′UTR abrogated miR-101-induced EMT alteration, respectively. Our findings showed that miR-101 represents a redundant mechanism for the miR-200 family that regulates EMT through two major E-cadherin transcriptional repressors.
doi:10.3892/or.2014.3106
PMCID: PMC4020617  PMID: 24677166
ovarian carcinoma; epithelial-to-mesenchymal transition; miR-101; ZEB1; ZEB2

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