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1.  Host Factors and Cancer Progression: Biobehavioral Signaling Pathways and Interventions 
Journal of Clinical Oncology  2010;28(26):4094-4099.
Whereas evidence for the role of psychosocial factors in cancer initiation has been equivocal, support continues to grow for links between psychological factors such as stress, depression, and social isolation and progression of cancer. In vitro, in vivo, and clinical studies show that stress- related processes can impact pathways implicated in cancer progression, including immuno-regulation, angiogenesis, and invasion. Contributions of systemic factors, such as stress hormones to the crosstalk between tumor and stromal cells, appear to be critical in modulating downstream signaling pathways with important implications for disease progression. Inflammatory pathways may also be implicated in fatigue and other factors related to quality of life. Although substantial evidence supports a positive effect of psychosocial interventions on quality of life in cancer, the clinical evidence for efficacy of stress-modulating psychosocial interventions in slowing cancer progression remains inconclusive, and the biobehavioral mechanisms that might explain such effects are still being established. This article reviews research findings to date and outlines future avenues of research in this area.
doi:10.1200/JCO.2009.26.9357
PMCID: PMC2940426  PMID: 20644093
2.  Interleukin-6, Cortisol, and Depressive Symptoms in Ovarian Cancer Patients 
Journal of Clinical Oncology  2008;26(29):4820-4827.
Purpose
Inflammatory processes have been implicated in the pathogenesis of both depression and cancer. Links between depressive symptoms, interleukin-6 (IL-6), and cortisol dysregulation have been demonstrated in cancer patients, but vegetative versus affective components of depression have been minimally examined. The objective of the current study was to examine associations between IL-6, diurnal cortisol rhythms, and facets of depression in epithelial ovarian cancer patients.
Patients and Methods
Patients awaiting surgery for a pelvic mass suspected for ovarian cancer completed questionnaires, collected salivary samples for 3 days presurgery, and gave a presurgical blood sample. Ascites was obtained during surgery. IL-6 was measured by enzyme-linked immunosorbent assay and cortisol by a chemiluminescence immunoassay. The final sample included 112 invasive ovarian cancer patients (86 advanced stage, 26 early stage) and 25 patients with tumors of low malignant potential (LMP).
Results
Advanced-stage ovarian cancer patients demonstrated elevations in vegetative and affective depressive symptoms, plasma IL-6, and the cortisol area under the curve (AUC) compared with patients with LMP tumors (all P < .05). Among invasive ovarian cancer patients, greater vegetative depression was related to elevated IL-6 in plasma (P = .008) and ascites (P = .024), but affective depression was unrelated to IL-6. Elevations in total depression (P = .026) and vegetative depression (P = .005) were also related to higher evening cortisol levels. Plasma IL-6 was related to greater afternoon and evening cortisol and cortisol AUC (all P values < .005).
Conclusion
These results demonstrate significant relationships between IL-6, cortisol, and vegetative depression, and may have implications for treatment of depression in ovarian cancer patients.
doi:10.1200/JCO.2007.14.1978
PMCID: PMC2653140  PMID: 18779606
3.  A Framework for personalized surgical approach to ovarian cancer 
Nature reviews. Clinical oncology  2015;12(4):239-245.
The standard therapeutic approach for advanced ovarian cancer is upfront cytoreductive surgery followed by a combination of platinum and taxane-based chemotherapy. The degree of residual disease following upfront cytoreductive surgery correlates with objective response to adjuvant chemotherapy, rate of pathological complete response at second-look assessment operations, progression-free survival and overall survival. Contemporary data and meta-analyses have documented a continuous relationship between volume of residual disease and patient outcomes with those patients undergoing complete gross resection having the best outcomes, thereby focusing attention of surgical effort to remove as much disease as possible with the metric of “optimal” cytoreduction being R0 disease. Since patients with R0 resection appear to have the best overall outcomes, efforts to spare unnecessary primary debulking surgery by pre- or intra-operative assessment have abounded without external validity to incorporate into general practice. Serum CA125, physical examination and CT imaging have lacked accuracy in determining if disease can be optimally debulked. Therefore, an algorithm that identifies patients likely to achieve complete gross resection at primary surgery would be expected to improve patient survival. Herein, we review contemporary definitions of “optimal” residual disease, and discuss opportunities to personalize surgical therapy and improve the quality of surgical care delivered to patients with advanced ovarian cancer.
doi:10.1038/nrclinonc.2015.26
PMCID: PMC4528308  PMID: 25707631
4.  Anti-vascular therapies in ovarian cancer: moving beyond anti-VEGF approaches 
Cancer metastasis reviews  2015;34(1):19-40.
Resistance to chemotherapy is among the most important issues in the management of ovarian cancer. Unlike cancer cells, which are heterogeneous as a result of remarkable genetic instability, stromal cells are considered relatively homogeneous. Thus, targeting the tumor microenvironment is an attractive approach for cancer therapy. Arguably, anti-vascular endothelial growth factor (anti-VEGF) therapies hold great promise, but their efficacy has been modest, likely owing to redundant and complementary angiogenic pathways. Components of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and other pathways may compensate for VEGF blockade and allow angiogenesis to occur despite anti-VEGF treatment. In addition, hypoxia induced by antiangiogenesis therapy modifies signaling pathways in tumor and stromal cells, which induces resistance to therapy. Because of tumor cell heterogeneity and angiogenic pathway redundancy, combining cytotoxic and targeted therapies or combining therapies targeting different pathways can potentially overcome resistance. Although targeted therapy is showing promise, much more work is needed to maximize its impact, including the discovery of new targets and identification of individuals most likely to benefit from such therapies.
doi:10.1007/s10555-014-9538-9
PMCID: PMC4369424  PMID: 25544368
Ovarian cancer; targeted therapy; angiogenesis; anti-vascular agent; resistance to anti-VEGF therapy
5.  New ways to successfully target tumor vasculature in ovarian cancer 
Purpose of review
The aim of this paper was to review the recent literature on potential therapeutic strategies for overcoming resistance to anti-VEGF drugs in ovarian cancer.
Recent findings
Although clinical benefits of anti-VEGF therapy were observed in ovarian cancer treatment trials, this use yielded only modest improvement in progression-free survival, and with the exception of cediranib no effect on overall survival. Adaptive resistance and escape from anti-angiogenesis therapy is likely a multifactorial process, including induction of hypoxia, vascular modulators and the immune response. New drugs targeting the tumor vasculature or other components of the surrounding microenvironment have shown promising results.
Summary
When to start and end antiangiogenesis therapy and the choice of optimal treatment combinations remain controversial. Further evaluation of personalized novel angiogenesis-based therapy is warranted. Defining the critical interaction of these agents and pathways and the appropriate predictive markers will become an increasingly important objective for effective treatment.
doi:10.1097/GCO.0000000000000136
PMCID: PMC4529067  PMID: 25502429
Angiogenesis; adaptive resistance; ovarian cancer
6.  Differential platelet levels affect response to taxane-based therapy in ovarian cancer 
Purpose
We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy.
Experimental Design
The medical records of patients with recurrent or progressive ovarian cancer were retrospectively queried for changes in platelet and CA-125 levels during primary therapy. In vitro co-culture experiments and in vivo orthotopic models of human ovarian cancer in mice were used to test the effect of modulating platelet levels on tumor growth and responsiveness to docetaxel.
Results
Thrombocytosis at the diagnosis of ovarian cancer correlated with decreased interval to progression (p = 0.05) and median overall survival (p = 0.007). Mean platelet levels corrected during primary therapy and rose at recurrence. Contrary to treatment-responsive patients, in a cohort of patients refractory to primary therapy, platelet levels did not normalize during therapy. In A2780, HeyA8, and SKOV3-ip1 ovarian cancer cell lines, platelet co-culture protected against apoptosis (p < 0.05). In orthotopic models of human ovarian cancer, platelet depletion resulted in 70% reduced mean tumor weight (p < 0.05). Compared to mice treated with docetaxel, mice treated with both docetaxel and platelet-depleting antibody had a 62% decrease in mean tumor weight (p = 0.04). Platelet transfusion increased mean aggregate tumor weight 2.4-fold (p < 0.05), blocked the effect of docetaxel on tumor growth (p = 0.55) and decreased tumor cell apoptosis. Pre-transfusion aspirinization of the platelets blocked the growth-promoting effects of transfusion.
Conclusions
Platelet-driven effects of chemotherapy response may explain clinical observations.
doi:10.1158/1078-0432.CCR-14-0870
PMCID: PMC4315757  PMID: 25473001
Platelets; docetaxel; ovarian cancer; aspirin
7.  Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer 
Purpose
Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized monoclonal antibody against FRα, in ovarian cancer models.
Experimental Design
We first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003–induced cell death.
Results
MORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In add, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cystadenocarcinoma.
Conclusions
MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation.
doi:10.1158/1078-0432.CCR-14-1578
PMCID: PMC4297546  PMID: 25416196
Folate receptor α; MORAB-003; ovarian cancer; autophagy; cell death
8.  Long noncoding RNA ceruloplasmin promotes cancer growth by altering glycolysis 
Cell reports  2015;13(11):2395-2402.
SUMMARY
Long noncoding RNAs (lncRNAs) significantly influence the development and regulation of genome expression in cells. Here, we demonstrate the role of lncRNA ceruloplasmin (NRCP) in cancer metabolism and elucidate functional effects leading to increased tumor progression. NRCP was highly upregulated in ovarian tumors and knockdown of NRCP resulted in significantly increased apoptosis, decreased cell proliferation, and decreased glycolysis compared with control cancer cells. In an orthotopic mouse model of ovarian cancer, siNRCP delivered via a liposomal carrier significantly reduced tumor growth compared with control treatment. We identified NRCP as an intermediate binding partner between STAT1 and RNA polymerase II, leading to increased expression of downstream target genes such as glucose-6-phosphate isomerase. Collectively, we report a unrecognized role of the lncRNA NRCP in modulating cancer metabolism. As demonstrated, DOPC nanoparticle-incorporated siRNA-mediated silencing of this lncRNA in vivo provides therapeutic avenue towards modulating lncRNAs in cancer.
doi:10.1016/j.celrep.2015.11.047
PMCID: PMC4691557  PMID: 26686630
9.  Molecular Pathways: Translational and Therapeutic Implications of the Notch Signaling Pathway in Cancer 
Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and crosstalk with other signaling pathways. The canonical Notch pathway with four Notch receptors (Notch1-4) and five ligands (DLL1, 3-4, Jagged 1-2) is an evolutionarily conserved cell signaling pathway that plays critical roles in cell-fate determination, differentiation, development, tissue patterning, cell proliferation, and death. In cancer, these roles have a critical impact on tumor behavior and response to therapy. Since the role of Notch remains tissue and context dependent, alterations within this pathway may lead to tumor suppressive or oncogenic phenotypes. Although no FDA approved therapies currently exist for the Notch pathway, multiple therapeutics (e.g., demcizumab, tarextumab, GSI MK0752, R04929097, and PF63084014) have been developed to target different aspects of this pathway for both hematologic and solid malignancies. Understanding the context-specific effects of the Notch pathway will be important for individualized therapies targeting this pathway.
doi:10.1158/1078-0432.CCR-14-0809
PMCID: PMC4333206  PMID: 25388163
10.  Molecular Pathways: Translational and Therapeutic Implications of the Notch Signaling Pathway in Cancer 
Over 100 years have passed since the first observation of the notched wing phenotype in Drosophila melanogaster, and significant progress has been made to characterize the role of the Notch receptor, its ligands, downstream targets, and crosstalk with other signaling pathways. The canonical Notch pathway with four Notch receptors (Notch1-4) and five ligands (DLL1, 3–4, Jagged 1–2) is an evolutionarily conserved cell signaling pathway that plays critical roles in cell-fate determination, differentiation, development, tissue patterning, cell proliferation, and death. In cancer, these roles have a critical impact on tumor behavior and response to therapy. Since the role of Notch remains tissue and context dependent, alterations within this pathway may lead to tumor suppressive or oncogenic phenotypes. Although no FDA approved therapies currently exist for the Notch pathway, multiple therapeutics (e.g., demcizumab, tarextumab, GSI MK0752, R04929097, and PF63084014) have been developed to target different aspects of this pathway for both hematologic and solid malignancies. Understanding the context-specific effects of the Notch pathway will be important for individualized therapies targeting this pathway.
doi:10.1158/1078-0432.CCR-14-0809
PMCID: PMC4333206  PMID: 25388163
11.  Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer 
Cancer Biology & Therapy  2014;15(8):1061-1067.
Purpose
Bisphosphonates have been shown to inhibit and deplete macrophages. The effects of bisphosphonates on other cell types in the tumor microenvironment have been insufficiently studied. Here, we sought to determine the effects of bisphosphonates on ovarian cancer angiogenesis and growth via their effect on the microenvironment, including macrophage, endothelial and tumor cell populations.
Experimental Design
Using in vitro and in vivo models, we examined the effects of clodronate on angiogenesis and macrophage density, and the overall effect of clodronate on tumor size and metastasis.
Results
Clodronate inhibited the secretion of pro-angiogenic cytokines by endothelial cells and macrophages, and decreased endothelial migration and capillary tube formation. In treated mice, clodronate significantly decreased tumor size, number of tumor nodules, number of tumor-associated macrophages and tumor capillary density.
Conclusions
Clodronate is a potent inhibitor of tumor angiogenesis. These results highlight clodronate as a potential therapeutic for cancer.
doi:10.4161/cbt.29184
PMCID: PMC4119073  PMID: 24841852
anti-angiogenesis; bisphosphonate; clodronate; ovarian cancer; tumor angiogenesis; tumor microenvironment; tumor-associated macrophages
12.  Hematogenous metastasis of ovarian cancer: Rethinking mode of spread 
Cancer cell  2014;26(1):77-91.
SUMMARY
Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis.
doi:10.1016/j.ccr.2014.05.002
PMCID: PMC4100212  PMID: 25026212
13.  Metronomic docetaxel in PRINT® nanoparticles and EZH2 silencing have synergistic antitumor effect in ovarian cancer 
Molecular cancer therapeutics  2014;13(7):1750-1757.
The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and anti-angiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT-docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models (p<0.05). Individual as well as combination therapies showed significant anti-angiogenic, anti-proliferative, and pro-apoptotic effects, and combination therapy had additive effects. Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA has significant antitumor activity in preclinical models of ovarian cancer.
doi:10.1158/1535-7163.MCT-13-0930
PMCID: PMC4090269  PMID: 24755199
ovarian cancer; metronomic chemotherapy; PRINT particles; EZH2; chitosan
14.  Focal adhesion kinase 
Cancer Biology & Therapy  2014;15(7):919-929.
This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAKY397 were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRT-PCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P < 0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P < 0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P < 0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors.
doi:10.4161/cbt.28882
PMCID: PMC4100993  PMID: 24755674
angiogenesis; metastasis; cancer/molecular biology; targeted therapy
15.  MOLECULAR BIOMARKERS OF RESIDUAL DISEASE AFTER SURGICAL DEBULKING OF HIGH-GRADE SEROUS OVARIAN CANCER 
Purpose
Residual disease (RD) following primary cytoreduction is associated with adverse overall survival in patients with epithelial ovarian cancer. Accurate identification of patients at high risk of RD has been elusive, lacking external validity and prompting many to undergo unnecessary surgical exploration. Our goal was to identify and validate molecular markers associated with high rates of residual disease.
Methods
We interrogated two publicly available datasets from chemonaïve primary high-grade serous ovarian tumors for genes overexpressed in patients with RD and significant at a 10% false discovery rate (FDR) in both datasets. We selected genes with wide dynamic range for validation in an independent cohort using qRT-PCR to assay gene expression, followed by blinded prediction of a patient subset at high risk for RD. Predictive success was evaluated using a one-sided Fisher’s exact test.
Results
Forty-seven probesets met the 10% FDR criterion in both datasets. These included FABP4 and ADH1B, which tracked tightly, showed dynamic ranges >16-fold, and had high expression levels associated with increased incidence of RD. In the validation cohort (n=189), FABP4 and ADH1B were again highly correlated. Using the top quartile of FABP4 PCR values as a pre-specified threshold, we found 30/35 cases of RD in the predicted high-risk group (positive predictive value 86%), and 54/104 among the remaining patients (P=0.0002; odds ratio 5.5).
Conclusion
High FABP4 and ADH1B expression are associated with significantly higher risk of residual disease in high-grade serous ovarian cancer. Patients with high tumoral levels of these genes may be candidates for neoadjuvant chemotherapy.
doi:10.1158/1078-0432.CCR-14-0445
PMCID: PMC4062703  PMID: 24756370
Ovarian cancer; residual disease; neoadjuvant chemotherapy; biomarker; FABP4
16.  Platelet effects on ovarian cancer 
Seminars in oncology  2014;41(3):378-384.
Growing understanding of the role of thrombocytosis, high platelet turnover, and the presence of activated platelets in the circulation in cancer progression and metastasis has brought megakaryocytes into focus. Platelet biology is essential to hemostasis, vascular integrity, angiogenesis, inflammation, innate immunity, wound healing, and cancer biology. However, before megakaryocyte/platelet-directed therapies can be considered for clinical use, understanding of the mechanism and biology of paraneoplastic thrombocytosis in malignancy is required. Here, we provide an overview of the clinical implications, biological significance, and mechanisms of paraneoplastic thrombocytosis in the context of ovarian cancer.
doi:10.1053/j.seminoncol.2014.04.004
PMCID: PMC4100073  PMID: 25023353
17.  Biological effects of platelet-derived growth factor receptor α blockade in uterine cancer 
Purpose
Platelet-derived growth factor receptor alpha (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biological significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer.
Experimental Design
Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biological effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer.
Results
PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and MAPK. Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2), but not in PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The anti-tumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis.
Conclusions
These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer.
doi:10.1158/1078-0432.CCR-13-2507
PMCID: PMC4024372  PMID: 24634380
PDGFRα; 3G3; uterine cancer
18.  Hypoxia Mediated Downregulation of miRNA Biogenesis Promotes Tumor Progression 
Nature communications  2014;5:5202.
Cancer-related deregulation of miRNA biogenesis has been suggested, but the underlying mechanisms remain elusive. Here, we report a previously unrecognized effect of hypoxia in the downregulation of Drosha and Dicer in cancer cells that leads to dysregulation of miRNA biogenesis and increased tumor progression. We show that hypoxia mediated downregulation of Drosha is dependent on ETS1/ELK1 transcription factors. Moreover, mature miRNA array and deep sequencing studies reveal altered miRNA maturation in cells under hypoxic conditions. At a functional level, this phenomenon results in increased cancer progression in vitro and in vivo, and data from patient samples are suggestive of miRNA biogenesis downregulation in hypoxic tumors. Rescue of Drosha by siRNAs targeting ETS1/ELK1 in vivo results in significant tumor regression. These findings provide a new link in the mechanistic understanding of global miRNA downregulation in the tumor microenvironment.
doi:10.1038/ncomms6202
PMCID: PMC4215647  PMID: 25351346
19.  Antagonism of Tumoral Prolactin Receptor Promotes Autophagy Related Cell Death 
Cell reports  2014;7(2):488-500.
Summary
Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism for cell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets because of their roles as growth factors in tumor growth and progression. We utilized a novel antagonist peptide of PRL, G129R, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced accumulation of redundant autolysosomes in three-dimensional cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a non-canonical beclin-1–independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR in clinical samples were associated with longer patient survival. Our findings provide a new understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications.
doi:10.1016/j.celrep.2014.03.009
PMCID: PMC4038960  PMID: 24703838
20.  Crosstalk between EphA2 and BRaf/CRaf is a Key Determinant of Response to Dasatinib 
Purpose
EphA2 is an attractive therapeutic target due to its diverse roles in cancer growth and progression. Dasatinib is a multi-kinase inhibitor that targets EphA2 and other kinases. However, reliable predictive markers and a better understanding of the mechanisms of response to this agent are needed.
Experimental design
The effects of dasatinib on human uterine cancer cell lines were examined using a series of in vitro experiments, including MTT, Western blot, and plasmid transfection. In vivo, an orthotopic mouse model of uterine cancer was utilized to identify the biological effects of dasatinib. Molecular markers for response prediction and the mechanisms relevant to response to dasatinib were identified by using RPPA, immunoprecipitation, and double immunofluorescence staining.
Results
We show that high levels of CAV-1, EphA2 phosphorylation at S897 and the status of PTEN are key determinants of dasatinib response in uterine carcinoma. A set of markers essential for dasatinib response was also identified and includes CRaf, pCRafS338, pMAPKT202/Y204 (MAPK pathway), pS6S240/244, p70S6kT389 (mTOR pathway) and pAKTS473. A novel mechanism for response was discovered whereby high expression level of CAV-1 at the plasma membrane disrupts the BRaf/CRaf heterodimer and thus inhibits the activation of MAPK pathway during dasatinib treatment.
Conclusions
Our in vitro and in vivo results provide a new understanding of EphA2 targeting by dasatinib and identify key predictors of therapeutic response. These findings have implications for ongoing dasatinib-based clinical trials.
doi:10.1158/1078-0432.CCR-13-2141
PMCID: PMC3975695  PMID: 24486585
Dasatinib; EphA2; Caveolin-1 (CAV-1); Uterine Cancer
21.  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
22.  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
23.  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
24.  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
25.  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

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