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1.  Targeting the undruggable: Advances and obstacles in current RNAi therapy 
Science translational medicine  2014;6(240):240ps7.
RNA interference (RNAi) therapeutics represents a rapidly emerging platform for personalized cancer treatment. Recent advances in delivery, target selection, and safety of RNAi cancer therapy provide unprecedented opportunities for clinical translation. Here, we discuss these advances and present strategies for making RNAi-based therapy a viable part of cancer management.
doi:10.1126/scitranslmed.3008362
PMCID: PMC4154139  PMID: 24920658
2.  Targeting Src and tubulin in mucinous ovarian carcinoma 
Purpose
To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma.
Experimental design
The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models.
Results
In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2/M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules.
Conclusion
Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma.
doi:10.1158/1078-0432.CCR-13-1305
PMCID: PMC3852199  PMID: 24100628
Ovarian carcinoma; Mucinous; Src kinase; Tubulin; KX-01
3.  Impact of cardiovascular comorbidity on ovarian cancer mortality 
BACKGROUND
A retrospective cohort study utilizing prospectively collected data was conducted from August 2003 until March 2008 at M. D. Anderson Cancer Center. It is unknown whether cardiovascular comorbidity and chronic stress impact ovarian cancer outcome, which remains poor despite advances in therapy. The purpose of this study was to determine whether cardiovascular disease and markers that may be associated with stress are also associated with survival in ovarian cancer patients.
METHODS
Participants with newly diagnosed epithelial ovarian cancer were followed until time of death or truncation of study period (median follow-up = 4.2 years; n=271). Tumor characteristics (stage, tumor grade, histology, debulking status), demographic variables, and cardiovascular comorbidity were documented and compared to overall survival.
RESULTS
Of the 9 cardiovascular events tracked during follow-up, venous thrombo embolism (VTE; Hazard Ratio= 3.2; 95%CI =1.8–5.5) and pulmonary hypertension (Hazard Ratio=8.5; 95%CI=3.9– 18.7) were associated with shorter survival in multivariate analysis. In addition, high tumor grade, suboptimal cytoreduction, and baseline heart rate (Hazard Ratio=1.02; 95%CI= 1.01– 1.04) were related to decreased survival.
CONCLUSION
Careful management of certain cardiovascular comorbidities may extend survival in patients with ovarian cancer. Our findings suggest that increased baseline heart rate and the development of VTE and pulmonary hypertension after cancer diagnosis may be significant predictors of survival in women with ovarian cancer.
IMPACT
Our study emphasizes the importance of identifying and optimally treating tachycardia, VTE and pulmonary hypertension in conjunction with cancer therapy.
doi:10.1158/1055-9965.EPI-13-0625
PMCID: PMC3830519  PMID: 24045927
Ovarian cancer; tachycardia; VTE; survival
4.  Role of Focal Adhesion Kinase in Regulating YB–1–Mediated Paclitaxel Resistance in Ovarian Cancer 
Background
We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood.
Methods
We characterized the biologic response of taxane-resistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). We used reverse-phase protein arrays (RPPA) to identify novel downstream targets in taxane-resistant cell lines. Furthermore, we correlated clinical and pathological data with nuclear and cytoplasmic expression of FAK and YB-1 in 105 ovarian cancer samples. Statistical tests were two-sided, and P values were calculated with Student t test or Fisher exact test.
Results
We found that VS-6063 inhibited FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. The combination of VS-6063 and paclitaxel markedly decreased proliferation and increased apoptosis, which resulted in 92.7% to 97.9% reductions in tumor weight. RPPA data showed that VS-6063 reduced levels of AKT and YB-1 in taxane-resistant cell lines. FAK inhibition enhanced chemosensitivity in taxane-resistant cells by decreasing YB-1 phosphorylation and subsequently CD44 in an AKT-dependent manner. In human ovarian cancer samples, nuclear FAK expression was associated with increased nuclear YB-1 expression (χ 2 = 37.7; P < .001). Coexpression of nuclear FAK and YB-1 was associated with statistically significantly worse median overall survival (24.9 vs 67.3 months; hazard ratio = 2.64; 95% confidence interval = 1.38 to 5.05; P = .006).
Conclusions
We have identified a novel pathway whereby FAK inhibition with VS-6063 overcomes YB-1–mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK.
doi:10.1093/jnci/djt210
PMCID: PMC3787907  PMID: 24062525
5.  2’f-OMe-phosphorodithioate modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity 
Nature communications  2014;5:3459.
Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2’-O-Methyl (2’-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2’-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM Domain Containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumors following MePS2-modified siRNA treatment, leading to a synergistic anti-tumor effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.
doi:10.1038/ncomms4459
PMCID: PMC4112501  PMID: 24619206
6.  Beta blockers: A new role in chemotherapy 
Beta-blockers are a class of drugs widely used to treat cardiac, respiratory and other ailments. They act by blocking beta-adrenergic receptor–mediated signalling. Studies in various cancers have shown that patients taking a beta-blocker have higher survival and lower recurrence and metastasis rates. This is supported by several preclinical and in vitro studies showing that adrenergic activation modulates apoptosis, promotes angiogenesis and other cancer hallmarks, and these effects can be abrogated by beta-blockers. These studies provide a rationale for the use of beta-blockers as adjuvants with cancer chemotherapy. However, all published studies so far are retrospective, and most do not take into account the specific beta-blocker used or address which is most likely to benefit cancer patients. The published epidemiological studies are correlative and have not examined the adrenergic receptor status of the tumours. Knowledge of the beta-adrenergic receptor status of tumour cells is essential in choosing the best beta-blocker for adjuvant therapy. A comprehensive, prospective study is necessary to prove definitively the utility of using beta-blockers with chemotherapy and to identify the specific betablocker most likely to benefit patients with cancer.
doi:10.1517/13543784.2013.825250
PMCID: PMC4143897  PMID: 23919278
Beta-blockers; beta-adrenergic receptor; catecholamines
7.  Prognostic Biomarkers in Ovarian Cancer 
Epithelial ovarian cancer (EOC) remains the most lethal gynecological malignancy despite several decades of progress in diagnosis and treatment. Taking advantage of the robust development of discovery and utility of prognostic biomarkers, clinicians and researchers are developing personalized and targeted treatment strategies. This review encompasses recently discovered biomarkers of ovarian cancer, the utility of published prognostic biomarkers for EOC (especially biomarkers related to angiogenesis and key signaling pathways), and their integration into clinical practice.
doi:10.3233/CBM-2011-0212
PMCID: PMC4143980  PMID: 22045356
biomarkers; ovarian carcinoma; prognosis
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  Neighborhood matters: Response to EZH2 methyltransferase inhibitors 
Cell Cycle  2013;12(15):2345.
doi:10.4161/cc.25775
PMCID: PMC3841310  PMID: 23887388
22.  Targeting Angiogenesis in Gynecologic Cancers 
doi:10.1016/j.hoc.2012.01.009
PMCID: PMC3334841  PMID: 22520979
23.  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
24.  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
25.  HLA Class I Antigen Processing Machinery Component Expression and Intratumoral T-Cell Infiltrate as Independent Prognostic Markers in Ovarian Carcinoma 
Purpose
Defects in the antigen processing machinery (APM) may provide tumor cells with a mechanism to escape immune recognition. The purpose of this study is to determine the clinical significance of APM component down-regulation and tumor-infiltrating T cells in ovarian carcinoma.
Experimental Design
After institutional review board approval, tumor samples from 150 patients with invasive epithelial ovarian cancers were examined for TAP1, TAP2, tapasin, HLA class I heavy chain (HLA-HC), β2 microglobulin, and T-cell (CD3+ and CD8+) tumor infiltration using immunohistochemistry.
Results
The majority of tumors had either heterogeneous or positive expression of TAP1, TAP2, HLA-HC, and β2 microglobulin (66.7%, 73.3%, 70.7%, and 63.3%, respectively), except tapasin for which 58% of the tumors lacked expression. Furthermore, 67% and 88% of the lesions possessed intratumoral and peritumoral CD3+ or CD8+ cells, respectively. The majority of APM component expression examined was significantly associated with both intratumoral and peritumoral T-cell infiltration (P < 0.05). The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival (all P ≤ 0.01); however, peritumoral T-cell infiltrates did not significantly affect survival (P = 0.33). APM component down-regulation (P < 0.001), lack of intratumoral T-cell infiltrates (P = 0.03), and suboptimal cytoreduction (P < 0.001) were independent prognostic markers for death from ovarian carcinoma.
Conclusion
The negative effectof APM component down-regulation by itself and in combination with absent intratumoral T-cell infiltration on the survival of patients with ovarian carcinoma implies a role for immune escape in addition to immunosurveillance in the clinical course of disease.
doi:10.1158/1078-0432.CCR-07-4433
PMCID: PMC3426216  PMID: 18519766

Results 1-25 (189)