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A Novel Compound ARN-3236 Inhibits Salt-Inducible Kinase 2 and Sensitizes Ovarian Cancer Cell Lines and Xenografts to Paclitaxel.
Purpose: Salt-inducible kinase 2 (SIK2) is a centrosome kinase required for mitotic spindle formation and a potential target for ovarian cancer therapy. Here, we examine the effects of a novel small-molecule SIK2 inhibitor, ARN-3236, on sensitivity to paclitaxel in ovarian cancer.Experimental Design: SIK2 expression was determined in ovarian cancer tissue samples and cell lines. ARN-3236 was tested for its efficiency to inhibit growth and enhance paclitaxel sensitivity in cultures and xenografts of ovarian cancer cell lines. SIK2 siRNA and ARN-3236 were compared for their ability to produce nuclear-centrosome dissociation, inhibit centrosome splitting, block mitotic progression, induce tetraploidy, trigger apoptotic cell death, and reduce AKT/survivin signaling.Results: SIK2 is overexpressed in approximately 30% of high-grade serous ovarian cancers. ARN-3236 inhibited the growth of 10 ovarian cancer cell lines at an IC50 of 0.8 to 2.6 μmol/L, where the IC50 of ARN-3236 was inversely correlated with endogenous SIK2 expression (Pearson r = -0.642, P = 0.03). ARN-3236 enhanced sensitivity to paclitaxel in 8 of 10 cell lines, as well as in SKOv3ip (P = 0.028) and OVCAR8 xenografts. In at least three cell lines, a synergistic interaction was observed. ARN-3236 uncoupled the centrosome from the nucleus in interphase, blocked centrosome separation in mitosis, caused prometaphase arrest, and induced apoptotic cell death and tetraploidy. ARN-3236 also inhibited AKT phosphorylation and attenuated survivin expression.Conclusions: ARN-3236 is the first orally available inhibitor of SIK2 to be evaluated against ovarian cancer in preclinical models and shows promise in inhibiting ovarian cancer growth and enhancing paclitaxel chemosensitivity. Clin Cancer Res; 23(8); 1945-54. ©2016 AACR.
A Novel Optical Bioimaging Method for Direct Assessment of Ovarian Cancer Chemotherapy Response at Laparoscopy.
In patients with advanced ovarian cancer (AOC), additional imaging of disseminated disease at laparoscopy could complement conventional imaging for estimation of chemotherapy response. We developed an image segmentation method and evaluated its use in making accurate and objective measurements of peritoneal metastases in comparison to Response Evaluation Criteria In Solid Tumors (RECIST) criteria. A software tool using a custom ImageJ macro-based approach was employed to estimate lesion size by converting image pixels into unit length. The software tool was tested as a proof-of-principle in an AOC patient with two isolated peritoneal deposits. Image analysis of representative laparoscopic snapshots before and after three cycles of neoadjuvant chemotherapy (NACT) revealed an average tumor nodule response ratio (TNRR) of 40% (partial response), which was in concordance with RECIST evaluation by computed tomography (CT). We demonstrated the feasibility of using this novel anatomical analysis for direct assessment of chemotherapy response in an AOC patient as an adjunct to RECIST criteria.
Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer.
High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.
Serous tubal intraepithelial carcinomas associated with high-grade serous ovarian carcinomas: a systematic review.
BACKGROUND: Serous tubal intraepithelial carcinomas (STICs) have been documented in high-grade serous ovarian carcinomas (HGSOCs). However, the rate of association between STICs and HGSOCs and, therefore, the fraction of HGSOCs that are likely to have originated from the fallopian tube (FT), has remained unclear. OBJECTIVE: To appraise the literature describing the association between STICs and established HGSOCs. SEARCH STRATEGY: Ovid MEDLINE and EMBASE were searched. SELECTION CRITERIA: Studies were included if they evaluated the frequency of STICs in HGSOCs, and were published in an English peer-reviewed journal. DATA COLLECTION AND ANALYSIS: Appropriate studies were evaluated for their compliance with the 'Strengthening and Reporting of Observational Studies in Epidemiology (STROBE)' criteria. MAIN RESULTS: Ten articles met the study selection criteria. The reported coexistence between STICs and HGSOCs ranged from 11% to 61% (mean: 31%, 95% CI: 17-46%). STICs were rarely found in other gynaecological cancers. Small sample size, lack of objective criteria to identify STICs and the retrospective nature of the studies contributed to the variability in reporting the rate of the association. CONCLUSIONS: STICs were identified commonly in the FTs of women with HGSOC. Finding the true rate of association between STICs and HGSOCs will require further investigations. While there is evidence that a fraction of HGSOCs arise from the FTs, an accurate estimate of that fraction remains to be determined. The lack of an accurate estimate of the association makes it difficult to evaluate the potential magnitude of reduction of HGSOCs following prophylactic salpingectomy. TWEETABLE ABSTRACT: A systematic review of the incidence of STICs in HGSOCs identifies significant methodological inconsistencies.
Tubal ligation and incidence of 26 site-specific cancers in the Million Women Study.
BACKGROUND: Tubal ligation is known to be associated with a reduction in ovarian cancer risk. Associations with breast, endometrial and cervical cancers have been suggested. We investigated associations for 26 site-specific cancers in a large UK cohort. METHODS: Study participants completed a questionnaire on reproductive and lifestyle factors in 1996-2001, and were followed for cancer and death via national registries. Using Cox regression models, we estimated adjusted relative risks (RRs) for 26 site-specific cancers among women with vs without tubal ligation. RESULTS: In 1 278 783 women without previous cancer, 167 430 incident cancers accrued during 13.8 years' follow-up. Significantly reduced risks were found in women with tubal ligation for cancers of the ovary (RR=0.80, 95% CI: 0.76-0.85; P<0.001; n=8035), peritoneum (RR=0.81, 0.66-0.98; P=0.03; n=730), and fallopian tube (RR=0.60, 0.37-0.96; P=0.04; n=168). No significant associations were found for endometrial, breast, or cervical cancers. CONCLUSIONS: The reduced risks of ovarian, peritoneal and fallopian tube cancers are consistent with hypotheses of a common origin for many tumours at these sites, and with the suggestion that tubal ligation blocks cells, carcinogens or other agents from reaching the ovary, fallopian tubes and peritoneal cavity.
Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs.
Cytotoxic drug resistance is a major cause of cancer treatment failure. We report an RNA interference screen to identify genes influencing sensitivity of different cancer cell types to chemotherapeutic agents. A set of genes whose targeting leads to resistance to paclitaxel is identified, many of which are involved in the spindle assembly checkpoint. Silencing these genes attenuates paclitaxel-induced mitotic arrest and induces polyploidy in the absence of drug. We also identify a ceramide transport protein, COL4A3BP or CERT, whose downregulation sensitizes cancer cells to multiple cytotoxic agents, potentiating endoplasmic reticulum stress. COL4A3BP expression is increased in drug-resistant cell lines and in residual tumor following paclitaxel treatment of ovarian cancer, suggesting that it could be a target for chemotherapy-resistant cancers.
Expression microarray reproducibility is improved by optimising purification steps in RNA amplification and labelling.
BACKGROUND: Expression microarrays have evolved into a powerful tool with great potential for clinical application and therefore reliability of data is essential. RNA amplification is used when the amount of starting material is scarce, as is frequently the case with clinical samples. Purification steps are critical in RNA amplification and labelling protocols, and there is a lack of sufficient data to validate and optimise the process. RESULTS: Here the purification steps involved in the protocol for indirect labelling of amplified RNA are evaluated and the experimentally determined best method for each step with respect to yield, purity, size distribution of the transcripts, and dye coupling is used to generate targets tested in replicate hybridisations. DNase treatment of diluted total RNA samples followed by phenol extraction is the optimal way to remove genomic DNA contamination. Purification of double-stranded cDNA is best achieved by phenol extraction followed by isopropanol precipitation at room temperature. Extraction with guanidinium-phenol and Lithium Chloride precipitation are the optimal methods for purification of amplified RNA and labelled aRNA respectively. CONCLUSION: This protocol provides targets that generate highly reproducible microarray data with good representation of transcripts across the size spectrum and a coefficient of repeatability significantly better than that reported previously.
An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment.
Metastasis is a complex multistep process that involves critical interactions between cancer cells and a variety of stromal components in the tumor microenvironment, which profoundly influence the different aspects of the metastatic cascade and organ tropism of disseminating cancer cells. Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Evidence has demonstrated that ovarian cancer possesses specific metastatic tropism for the adipose-rich omentum, which has a pivotal role in the creation of the metastatic tumor microenvironment in the intraperitoneal cavity. Considering the distinct biology of ovarian cancer metastasis, the elucidation of the cellular and molecular mechanisms underlying the reciprocal interplay between ovarian cancer cells and surrounding stromal cell types in the adipose-rich metastatic microenvironment will provide further insights into the development of novel therapeutic approaches for patients with advanced ovarian cancer. Herein, we review the biological mechanisms that regulate the highly orchestrated crosstalk between ovarian cancer cells and various cancer-associated stromal cells in the metastatic tumor microenvironment with regard to the omentum by illustrating how different stromal cells concertedly contribute to the development of ovarian cancer metastasis and metastatic tropism for the omentum.