Healthcare access dimensions and uterine cancer survival: a national cancer database study

ObjectiveDisparities exist throughout diagnosis, treatment, and survival for Black patients with uterine cancer. There is limited data on how several healthcare access (HCA) dimensions contribute to these disparities in patients with advanced stage uterine cancer.MethodsUsing the National Cancer Database (NCDB), we identified patients aged 40-89 years with Stage III-IV uterine cancer between 2004-2015 who received chemotherapy and/or radiotherapy. Race/ethnicity were classified as non-Hispanic (NH)-Black, Hispanic, and NH-White. Variables defined in the NCDB were used to assess HCA affordability, availability, and accessibility. Kaplan-Meier estimates, log-rank test, and multivariable Cox proportional hazards models were used to analyze overall survival.ResultsOf 43,134 patients, 78.8% of the cohort identified as NH-White, 15.3% NH-Black, and 5.9% Hispanic. NH-Black patients were the most likely to have type II (75.6% vs. 53.9% and 55.4%) and stage IV (40.8% vs. 30.7% and 32.3%) disease compared to NH-White and Hispanic patients. NH-Black patients were more likely than NH-White and Hispanic patients to have government funded insurance (58.6% vs. 50.3% and 50.4%), live in low-income areas (46.4% vs. 14.2% and 29.9%), and receive only chemotherapy (53.5% vs. 43.1% and 46.2%). Having private insurance and receiving treatment at an academic facility were positive predictors of survival. NH-Black patients had worse survival than NH-White patients after adjusting for clinical characteristics and healthcare access dimensions (HR 1.29; 95% CI 1.24, 1.34).ConclusionWhile HCA affordability and availability predicted survival in patients with advanced stage uterine cancer, additional factors contribute to racial disparities. Compared to NH-White patients, NH-Black patients had more aggressive disease, received only chemotherapy rather than combined therapy, and had worse survival regardless of cancer subtype. Additional dimensions of healthcare access must be explored to remedy uterine cancer disparities

YAP1 expression predicts sensitivity to dual AKT/P70S6K inhibition in ovarian and uterine malignancies

Purpose: The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies due to its high rate of dysregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K. Experimental Design: Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. Moreover, in vitro experiments (MTT, Western blot analysis, plasmid transfection, and reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. Results: MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer and reduced proliferation (Ki67) and angiogenesis (CD31) indices and increased cell death (cleaved caspase-3) markers. Synergy between MSC2363318A and paclitaxel was observed in vitro in protected (IC50 ≥ 5 µM) cell lines. RPPA identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R=0.675, p=0.0015). After establishment of a bevacizumab resistant endothelial cell line, RF-24, we demonstrate that resensitization to bevacizumab occurs with the addition of MSC2363318A. Conclusions: MSC2363318A has therapeutic efficacy in multiple pre-clinical models of ovarian and uterine cancer. These findings support clinical development of dual AKT/P70S6K inhibition

Obesity Is Associated With Worse Overall Survival in Women With Low-Grade Papillary Serous Epithelial Ovarian Cancer

To evaluate prognostic risk factors for survival in women with low grade serous epithelial ovarian cancer (LGSC)

Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer

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

Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression

Abstract Purpose: VEGF-targeted therapies have modest efficacy in cancerpatients, butacquiredresistance iscommon. Themechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized roleofmacrophagesinsuchresistance.Macrophageswereactively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophagedeficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combinationapproachesforovarianandothercancers. ClinCancerRes; 23(22); 7034–46. �2017 AACR

2′-OMe-phosphorodithioate-modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

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 tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour 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

Erythropoietin Stimulates Tumor Growth via EphB4

While recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo’s effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin

Using genetically encoded fluorescent biosensors to interrogate ovarian cancer metabolism

Abstract Background Epithelial ovarian cancer (OC) is the most lethal gynecological malignancy and patients present with significant metastatic burden, particularly to the adipose-rich microenvironment of the omentum. Recent evidence has highlighted the importance of metabolic adaptations in enabling this metastasis, leading to significant interest in evolving the arsenal of tools used to study OC metabolism. In this study, we demonstrate the capability of genetically encoded fluorescent biosensors to study OC, with a focus on 3D organoid models that better recapitulate in vivo tumor microenvironments. Materials and methods Plasmids encoding the metabolic biosensors HyPer, iNap, Peredox, and Perceval were transfected into 15 ovarian cancer cell lines to assay oxidative stress, NADPH/NADP+, NADH/NAD+, and ATP/ADP, respectively. Fluorescence readings were used to assay dynamic metabolic responses to omental conditioned media (OCM) and 100 μM carboplatin treatment. SKOV3 cells expressing HyPer were imaged as 2D monolayers, 3D organoids, and as in vivo metastases via an intravital omental window. We further established organoids from ascites collected from Stage III/IV OC patients with carboplatin-resistant or carboplatin-sensitive tumors (n = 8 total). These patient-derived organoids (PDOs) were engineered to express HyPer, and metabolic readings of oxidative stress were performed during treatment with 100 μM carboplatin. Results Exposure to OCM or carboplatin induced heterogenous metabolic changes in 15 OC cell lines, as measured using metabolic sensors. Oxidative stress of in vivo omental metastases, measured via intravital imaging of metastasizing SKOV3-HyPer cells, was more closely recapitulated by SKOV3-HyPer organoids than by 2D monolayers. Finally, carboplatin treatment of HyPer-expressing PDOs induced higher oxidative stress in organoids derived from carboplatin-resistant patients than from those derived from carboplatin-sensitive patients. Conclusions Our study showed that biosensors provide a useful method of studying dynamic metabolic changes in preclinical models of OC, including 3D organoids and intravital imaging. As 3D models of OC continue to evolve, the repertoire of biosensors will likely serve as valuable tools to probe the metabolic changes of clinical importance in OC

Development and Characterization of a Luciferase Labeled, Syngeneic Murine Model of Ovarian Cancer

Despite advances in surgery and targeted therapies, the prognosis for women with high-grade serous ovarian cancer remains poor. Moreover, unlike other cancers, immunotherapy has minimally impacted outcomes in patients with ovarian cancer. Progress in this regard has been hindered by the lack of relevant syngeneic ovarian cancer models to study tumor immunity and evaluate immunotherapies. To address this problem, we developed a luciferase labeled murine model of high-grade serous ovarian cancer, STOSE.M1 luc. We defined its growth characteristics, immune cell repertoire, and response to anti PD-L1 immunotherapy. As with human ovarian cancer, we demonstrated that this model is poorly sensitive to immune checkpoint modulators. By developing the STOSE.M1 luc model, it will be possible to probe the mechanisms underlying resistance to immunotherapies and evaluate new therapeutic approaches to treat ovarian cancer