Sequential modulation of the Wnt/β-catenin signaling pathway enhances tumor-intrinsic MHC I expression and tumor clearance.

Background: Progress in immunotherapy use for gynecologic malignancies is hampered by poor tumor antigenicity and weak T cell infiltration of the tumor microenvironment (TME). Wnt/β-catenin pathway modulation demonstrated patient benefit in clinical trials as well as enhanced immune cell recruitment in preclinical studies. The purpose of this study was to characterize the pathways by which Wnt/β-catenin modulation facilitates a more immunotherapy-favorable TME.

Utilization of a 3-D tissue engineered model to investigate the effects of perfusion on gynecologic cancer biology.

Among gynecologic malignancies, ovarian cancer (OC) has the poorest survival rate, and its clinical management remains challenging due to the high rate of recurrence and chemoresistance. Improving survival for these patients is critical, although this requires the ability to translate preclinical studies to actual patient care: bench to bedside and back. Our objective was to develop a preclinical model that accurately represents tumor biology and its microenvironment.

Class I histone deacetylase inhibition promotes CD8 T cell activation in ovarian cancer.

Objective: Patients with epithelial ovarian cancer (EOC) typically present with late-stage disease, posing a significant challenge to treatment. Although taxane and platinum-based chemotherapy plus surgical debulking are initially effective, EOC is marked by frequent recurrence with resistant disease. Immunotherapy represents an appealing treatment paradigm given the ability of immune cells to engage metastatic sites and impede recurrence; however, response rates to checkpoint blockade in ovarian cancer have been disappointing.

Neutralization of TGFβ Improves Tumor Immunity and Reduces Tumor Progression in Ovarian Carcinoma.

The immunosuppressive effects of TGFβ promotes tumor progression and diminishes response to therapy. In this study, we used ID8-p53 tumors as a murine model of high-grade serous ovarian cancer. An mAb targeting all three TGFβ ligands was used to neutralize TGFβ.

Inhibition of the Wnt/β-catenin pathway enhances antitumor immunity in ovarian cancer.

Background: The Wnt/β-catenin pathway is linked to tumorigenesis in a variety of tumors and promotes T cell exclusion and resistance to checkpoint inhibitors. We sought to determine whether a small molecule inhibitor of this pathway, WNT974, would impair tumor growth, affect gene expression patterns, and improve the immune response in human and murine ovarian cancer models.

Methods: Human ovarian cancer cells were treated with WNT974 .

Inhibiting WNT Ligand Production for Improved Immune Recognition in the Ovarian Tumor Microenvironment.

In ovarian cancer, upregulation of the Wnt/β-catenin pathway leads to chemoresistance and correlates with T cell exclusion from the tumor microenvironment (TME). Our objectives were to validate these findings in an independent cohort of ovarian cancer subjects and determine whether inhibiting the Wnt pathway in a syngeneic ovarian cancer murine model could create a more T-cell-inflamed TME, which would lead to decreased tumor growth and improved survival. We preformed RNA sequencing in a cohort of human high grade serous ovarian carcinoma subjects.

Wnt signaling modulator DKK1 as an immunotherapeutic target in ovarian cancer.

Objectives: Wnt pathway mutations are a hallmark of endometrioid and clear cell subtypes of epithelial ovarian carcinoma (EOC). However, no drugs targeting the Wnt pathway in EOC are FDA-approved. Dickkopf-related protein 1 (DKK1), a modulator of the Wnt pathway, has emerged as a promising therapeutic target.

Large, Non-Cavity Distorting Intramural Leiomyomas Decrease Leukemia Inhibitory Factor in the Secretory Phase Endometrium.

Despite mounting evidence that large intramural leiomyomas decrease fecundity during in vitro fertilization cycles, few studies have demonstrated a mechanism for this impact. We hypothesize that large intramural leiomyomas (IM) decrease the expression of endometrial implantation factors during the window of implantation. We prospectively recruited sub-fertile patients with IM 3 cm or greater in size planning myomectomy and performed endometrial biopsies the day of planned myomectomy (n = 9).

The antitumor effects of entinostat in ovarian cancer require adaptive immunity.

Background: Ovarian cancer is poorly immunogenic; however, increased major histocompatibility complex class II (MHCII) expression correlates with improved immune response and prolonged survival in patients with ovarian cancer. The authors previously demonstrated that the histone deacetylase inhibitor entinostat increases MHCII expression on ovarian cancer cells. In the current study, they evaluated whether entinostat treatment and resultant MHCII expression would enhance beneficial immune responses and impair tumor growth in mice with ovarian cancer.

FTY720 enhances the anti-tumor activity of carboplatin and tamoxifen in a patient-derived xenograft model of ovarian cancer.

Ovarian cancer is the fifth leading cause of cancer-related deaths among women in the United States. Although most patients respond to frontline therapy, virtually all patients relapse with chemoresistant disease. This study addresses the hypothesis that carboplatin or tamoxifen + FTY720, a sphingosine analogue, will minimize or circumvent drug-resistance in ovarian cancer cells and tumor models.

Correction: Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer.

[This corrects the article DOI: 10.18632/oncotarget.13466.

Molecular Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma.

While high-grade serous ovarian carcinoma (HGSOC) is the most common histologic subtype of ovarian cancer, significant tumor heterogeneity exists. In addition, chemotherapy induces changes in gene expression and alters the mutational profile. To evaluate the notion that patients with HGSOC could be better classified for optimal treatment based on gene expression, we compared genetic variants [by DNA next-generation sequencing (NGS) using a 50 gene Ion Torrent panel] and gene expression (using the NanoString PanCancer 770 gene Panel) in the tumor from 20 patients with HGSOC before and after neoadjuvant chemotherapy (NACT).

Targeting RNA-Polymerase I in Both Chemosensitive and Chemoresistant Populations in Epithelial Ovarian Cancer.

A hallmark of neoplasia is increased ribosome biogenesis, and targeting this process with RNA polymerase I (Pol I) inhibitors has shown some efficacy. We examined the contribution and potential targeting of ribosomal machinery in chemotherapy-resistant and -sensitive models of ovarian cancer. Pol I machinery expression was examined, and subsequently targeted with the Pol I inhibitor CX-5461, in ovarian cancer cell lines, an immortalized surface epithelial line, and patient-derived xenograft (PDX) models with and without chemotherapy.

Epigenetic modifiers upregulate MHC II and impede ovarian cancer tumor growth.

Expression of MHC class II pathway proteins in ovarian cancer correlates with prolonged survival. Murine and human ovarian cancer cells were treated with epigenetic modulators - histone deacetylase inhibitors and a DNA methyltransferase inhibitor. mRNA and protein expression of the MHC II pathway were evaluated by qPCR and flow cytometry.

B7-H3-targeted Pb radioimmunotherapy of ovarian cancer in preclinical models.

Introduction: Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of human ovarian cancer.

Niclosamide and its analogs are potent inhibitors of Wnt/β-catenin, mTOR and STAT3 signaling in ovarian cancer.

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of cancer stem cells (CSCs) include Wnt/β-catenin, mTOR, and STAT3.

Proteasome inhibition reverses hedgehog inhibitor and taxane resistance in ovarian cancer.

The goal of this study was to determine whether combined targeted therapies, specifically those against the Notch, hedgehog and ubiquitin-proteasome pathways, could overcome ovarian cancer chemoresistance. Chemoresistant ovarian cancer cells were exposed to gamma-secretase inhibitors (GSI-I, Compound E) or the proteasome inhibitor bortezomib, alone and in combination with the hedgehog antagonist, LDE225. Bortezomib, alone and in combination with LDE225, was evaluated for effects on paclitaxel efficacy.

Using heterogeneity of the patient-derived xenograft model to identify the chemoresistant population in ovarian cancer.

A cornerstone of preclinical cancer research has been the use of clonal cell lines. However, this resource has underperformed in its ability to effectively identify novel therapeutics and evaluate the heterogeneity in a patient's tumor. The patient-derived xenograft (PDX) model retains the heterogeneity of patient tumors, allowing a means to not only examine efficacy of a therapy, but also basic tenets of cancer biology in response to treatment.

An ex vivo assay of XRT-induced Rad51 foci formation predicts response to PARP-inhibition in ovarian cancer.

Objective: BRCA-positive ovarian cancer patients derive benefit PARP inhibitors. Approximately 50% of ovarian cancer tumors have homologous recombination (HR) deficiencies and are therefore "BRCA-like," possibly rendering them sensitive to PARP inhibition. However, no predictive assay exists to identify these patients.

Endoglin (CD105) contributes to platinum resistance and is a target for tumor-specific therapy in epithelial ovarian cancer.

Purpose: Endoglin (CD105) is a membranous protein overexpressed in tumor-associated endothelial cells, chemoresistant populations of ovarian cancer cells, and potentially stem cells. Our objective was to evaluate the effects and mechanisms of targeting endoglin in ovarian cancer.

Experimental Design: Global and membranous endoglin expression was evaluated in multiple ovarian cancer lines.

Smoothened antagonists reverse taxane resistance in ovarian cancer.

The hedgehog pathway has been implicated in the formation and maintenance of a variety of malignancies, including ovarian cancer; however, it is unknown whether hedgehog signaling is involved in ovarian cancer chemoresistance. The goal of this study was to determine the effects of antagonizing the hedgehog receptor, Smoothened (Smo), on chemotherapy response in ovarian cancer. Expression of hedgehog pathway members was assessed in three pairs of parental and chemotherapy-resistant ovarian cancer cell lines (A2780ip2/A2780cp20, SKOV3ip1/SKOV3TRip2, HeyA8/HeyA8MDR) using quantitative PCR and Western blot analysis.

Stem cell pathways contribute to clinical chemoresistance in ovarian cancer.

Purpose: Within heterogeneous tumors, subpopulations often labeled cancer stem cells (CSC) have been identified that have enhanced tumorigenicity and chemoresistance in ex vivo models. However, whether these populations are more capable of surviving chemotherapy in de novo tumors is unknown.

Experimental Design: We examined 45 matched primary/recurrent tumor pairs of high-grade ovarian adenocarcinomas for expression of CSC markers ALDH1A1, CD44, and CD133 using immunohistochemistry.

Therapeutic potential and anti-amyloidosis mechanisms of tert-butylhydroquinone for Alzheimer's disease.

Alzheimer's disease (AD) is a major cause of dementia in the elderly with no effective treatment. Accumulation of amyloid-β peptide (Aβ) in the brain, one of the pathological features of AD, is considered to be a central disease-causing and disease-promoting event in AD. In this study, we showed that feeding male AβPP/PS1 transgenic mice, a well established mouse model of AD, with a diet containing phenolic antioxidant tert-butylhydroquinone (TBHQ) dramatically reduced brain Aβ load with no significant effect on the amounts of alpha- and beta-C-terminal fragments or full-length AβPP.

Targeting the notch ligand JAGGED1 in both tumor cells and stroma in ovarian cancer.

Purpose: Jagged1, a Notch ligand, is expressed on both tumor epithelial and endothelial cells and therefore may be amenable to dual targeting of the tumor stroma and malignant cell compartments of the tumor microenvironment.

Experimental Design: We describe in vitro effects of targeting of Jagged1 on ovarian cancer cells and in vivo effects of independent targeting of stromal and malignant cell Jagged1 using species-specific human or murine siRNA constructs incorporated into chitosan nanoparticles and delivered intravenously in an orthotopic mouse model.

Results: Jagged1 expression was prominent in SKOV3ip1 and IGROV-AF1, and significantly overexpressed in SKOV3TRip2, a taxane-resistant SKOV3 subclone.