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Epithelial ovarian cancers (EOCs) are a heterogeneous collection of malignancies, each with their own developmental origin, clinical behavior and molecular profile. With less than 5% of EOC cases, mucinous ovarian carcinoma is a rare form with a poor prognosis and a 5-year survival of 11% for advanced stages (III/IV). At the early stages, these malignant forms are clinically difficult to distinguish from borderline (15%) and benign (80%) forms with a better prognosis due to the large size and heterogeneity of mucinous tumors. Improving their diagnosis is therefore a challenge with regard to the risk of under-treating a malignant form or of unnecessarily undertaking radical surgical excision. The involvement of microRNAs (miRNAs) in tumor progression and their potential as biomarkers of diagnosis are becoming increasingly recognized. In this study, the comparison of miRNA microarray expression profiles between malignant and borderline tumor FFPE samples identified 10 down-regulated and 5 up-regulated malignant miRNAs, which were validated by individual RT-qPCR. To overcome normalization issues and to improve the accuracy of the results, a ratio analysis combining paired up-regulated and down-regulated miRNAs was performed. Although 21/50 miRNA expression ratios were significantly different between malignant and borderline tumor samples, any ratio could perfectly discriminate the two groups. However, a combination of 14 pairs of miRNA ratios (double ratio) showed high discriminatory potential, with 100% of accuracy in distinguishing malignant and borderline ovarian tumors, which suggests that miRNAs may hold significant clinical potential as a diagnostic tool. In summary, these ratio miRNA-based signatures may help to improve the precision of histological diagnosis, likely to provide a preoperative diagnosis in order to adapt surgical procedures. [ABSTRACT FROM AUTHOR]

Circulating miRNAs are promising biomarkers in oncology but have not yet been implemented in the clinic given the lack of concordance across studies. In order to increase the cross-studies reliability, we attempted to reduce and to control the circulating miRNA expression variability between patients. First, to maximize profiling signals and to reduce miRNA expression variability, three isolation kits were compared and the NucleoSpin ® kit provided higher miRNA concentrations than the other widely used kits. Second, to control inter-sample variability during the profiling step, the exogenous miRNAs normalization method commonly used for RT-qPCR validation step was adapted to microarray experiments. Importantly, exogenous miRNAs presented two-fold lower inter-sample variability than the widely used endogenous miR-16-5p reflecting that the latter is subject to both biological and technical variability. Although Caenorhabditis elegans miRNAs isolation yields were heterogeneous, they correlated to each other and to their geometrical mean across samples. The normalization based on the geometrical mean of three exogenous miRNAs increased the correlation up-to 0.97 between the microarrays and individual RT-qPCR steps of circulating miRNAs expression. Overall, this new strategy open new avenue to identify reliable circulating miRNA signatures for translation into clinical practice. [ABSTRACT FROM AUTHOR]

Lapatinib, a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), also inhibits breast cancer resistance protein (BCRP) involved in resistance to topotecan. The aim of this multicenter study was to assess the efficacy of the combination topotecan-lapatinib in epithelial ovarian cancer relapsing after a first line of chemotherapy.Patients having relapsed within 6 months (n = 20) or between 6 and 12 months (n = 19) received weekly topotecan (3.2 mg/m2 given intravenously on days 1, 8, and 15) and daily oral lapatinib (1250 mg). Translational studies were performed on tumor and serum.An objective (partial) response was observed for 5 patients (14%), all with late relapse. The rates of overall benefits, including responses and stabilizations, were 37% and 62% in patients having relapsed within or after 6 months, respectively. Corresponding median time to progression were 58 and 94 days. The most frequent toxicity was hematological, including grade 4 neutropenia (18%) and thrombocytopenia (3%). None of the tumors overexpressed HER2 or EGFR, and no mutation was found. Two Kras mutations were identified. Positive expressions of BCRP and cyclin A (median, 70% and 40%) were not correlated to the response to treatment.This study failed to demonstrate a clinical benefit of lapatinib-topotecan compared to previously described activity with topotecan alone in a context of low levels of EGFR and HER2 expressions, and no biomarkers could be identified. The absence of correlation between BCRP expression and clinical outcomes suggests that other mechanisms of resistance to topotecan could predominate. [ABSTRACT FROM AUTHOR]

PurposeWe assessed whether imaging αvβ3 integrin could distinguish mature teratoma from necrosis in human non-seminomatous germ cell tumour (NSGCT) post-chemotherapy residual masses.MethodsHuman embryonal carcinoma xenografts (six/rat) were untreated (controls) or treated to form mature teratomas with low-dose cisplatin and all-trans retinoic acid (ATRA) over a period of 8 weeks. In another group, necrosis was induced in xenografts with high-dose cisplatin plus etoposide (two cycles).18F-Fluorodeoxyglucose (18F-FDG) small animal positron emission tomography (SA PET) imaging was performed in three rats (one control and two treated for 4 and 8 weeks with cisplatin+ATRA). Imaging of αvβ3 expression was performed in six rats bearing mature teratomas and two rats with necrotic lesions on a microSPECT/CT device after injection of the tracer [99mTc]HYNIC-RGD [6-hydrazinonicotinic acid conjugated to cyclo(Arg-Gly-Asp-D-Phe-Lys)]. Correlative immunohistochemistry studies of human and mouse αvβ3 expression were performed.ResultsCisplatin+ATRA induced differentiation of the xenografts. After 8 weeks, some glandular structures and mesenchymal cells were visible; in contrast, control tumours showed undifferentiated tissues. SA PET imaging showed that mature teratoma had very low avidity for 18F-FDG [mean standardised uptake value (SUVmean) = 0.48 ± 0.05] compared to untreated embryonal carcinoma (SUVmean = 0.92 ± 0.13) (p = 0.005). αvβ3 imaging accurately distinguished mature teratoma (tumour to muscle ratio = 4.29 ± 1.57) from necrosis (tumour to muscle ratio = 1.3 ± 0.26) (p = 0.0002). Immunohistochemistry studies showed that αvβ3 integrin expression was strong in the glandular structures of mature teratoma lesions and negative in host stroma.ConclusionImaging αvβ3 integrin accurately distinguished mature teratoma from necrosis following cisplatin-based treatment in human NSGCT xenografts. [ABSTRACT FROM AUTHOR]

There are limited treatment options for ovarian cancer patients with early relapse after platinum chemotherapy. In preclinical studies, we previously demonstrated the promising activity of ABT-737, a Bcl-2/Bcl-x L anti-apoptotic protein inhibitor, in chemo-resistant ovarian cancer cells and tumors, suggesting its potential activity in platinum-resistant patients. We conducted a prospective multicenter single-arm phase II study to assess the efficacy of Navitoclax (orally available ABT-737 analogue) monotherapy in 46 heavily pretreated (2–12 lines, median = 4) patients with high-grade serous platinum-resistant ovarian tumors. Navitoclax was administered at the daily dose of 150 mg during a lead-in period (7–14 days) and then increased to 250 mg daily in the absence of dose-limiting thrombocytopenia (

Abstract Fibronectin (Fn) is an extracellular matrix (ECM) multifunctional glycoprotein essential for regulating cells behaviors. Within ECM, Fn is found as polymerized fibrils. Apart from fibrils, Fn could also form other kind of supramolecular assemblies such as aggregates. To gain insight into the impact of Fn aggregates on cell behavior, we generated several Fn oligomeric assemblies. These assemblies displayed various amyloid-like properties but were not cytotoxic. In presence of the more amyloid-like structured assemblies of Fn, the cell-ECM networks were altered and the cell shapes shifted toward extended mesenchymal morphologies. Additionnaly, the Fn amyloid-like aggregates promoted a single-cell and sparsed migration of SKOV3 cancer cells, which was associated with a relocalization of αv integrins from plasma membrane to perinuclear vesicles. These data pointed out that the features of supramolecular Fn assemblies could represent a higher level of fine-tuning cell phenotype, and especially migration of cancer cells. Graphical abstract fx1 Highlights • Fibronectin can polymerize into amyloid-like aggregates. • Fibronectin amyloid-like aggregates promote a sparsed cell migration. • The supramolecular state of fibronectin could fine-tune cell phenotype. [ABSTRACT FROM AUTHOR]

Abstract: We previously showed that Bcl-xL and Mcl-1 cooperatively protect platinum-resistant ovarian cancer cells from apoptosis. Here we assessed the anticancer potential of combining ABT-737-induced inhibition of Bcl-xL with Mcl-1 inhibition via PI3K/Akt/mTOR pathway disruption using NVP-BEZ235. NVP-BEZ235 inhibited cell proliferation without inducing apoptosis. It strongly repressed Mcl-1 expression and induced Puma expression in both cell lines tested while differentially modulating Bim between the two. Interestingly, NVP-BEZ235 efficiently sensitized ovarian carcinoma cells to ABT-737, provided that Bim expression was induced. Moreover, inhibiting the ERK1/2 pathway restored Bim expression and sensitized low Bim-expressing cancer cells to the BEZ235/ABT-737 treatment. [Copyright &y& Elsevier]