TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin

Erriquez, Jessica; Becco, Paolo; Olivero, Martina; Ponzone, Riccardo; Maggiorotto, Furio; Ferrero, Annamaria; Scalzo, Maria Stella; Canuto, Emilie Marion; Sapino, Anna; Cantogno, Ludovica Verdun di; Bruna, P.; Aglietta, Massimo; Renzo, Maria Flavia Di; Valabrega, Giorgio

doi:10.1016/j.ygyno.2015.06.025

Cited by 41 publications

(34 citation statements)

References 36 publications

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“…Our experimental findings suggested that the combined use of doxorubicin and FOXM1 inhibition might be an alternative strategy to enhance the therapeutic efficacy of PLD while, at the same time, reducing its dosage and limiting toxicity. In agreement, we also demonstrated a significant variation of the expression level of TOP2A gene whose protein product, topoisomerase II alpha, is the actual target poisoned by doxorubicin [47]. …”

Section: Discussionsupporting

confidence: 64%

“…In addition to CENPF down-regulation, IPA analysis suggested many targets involved in tumor-stromal interactions and tumor vascularity by a complex regulatory network that might contribute to the effects of FOXM1 depletion in this cellular model. Finally, loss of FOXM1 in EOC-CC1 cells induced the down-regulation of the TOP2A gene, a marker of prognosis and response to therapy in platinum resistant/refractory EOCs [47]. …”

Section: Discussionmentioning

confidence: 99%

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FOXM1 expression is significantly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients

Tassi

Todeschini

Siegel

et al. 2017

J Exp Clin Cancer Res

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BackgroundEpithelial ovarian cancer (EOC) is a spectrum of different diseases, which makes their treatment a challenge. Forkhead box M1 (FOXM1) is an oncogene aberrantly expressed in many solid cancers including serous EOC, but its role in non-serous EOCs remains undefined. We examined FOXM1 expression and its correlation to prognosis across the three major EOC subtypes, and its role in tumorigenesis and chemo-resistance in vitro.MethodsGene signatures were generated by microarray for 14 clear-cell and 26 endometrioid EOCs, and 15 normal endometrium snap-frozen biopsies. Validation of FOXM1 expression was performed by RT–qPCR and immunohistochemistry in the same samples and additionally in 50 high-grade serous EOCs and in their most adequate normal controls (10 luminal fallopian tube and 20 ovarian surface epithelial brushings). Correlations of FOXM1 expression to clinic-pathological parameters and patients’ prognosis were evaluated by Kaplan-Meier and Cox proportional-hazards analyses. OVCAR-3 and two novel deeply characterized EOC cell lines (EOC-CC1 and OSPC2, with clear-cell and serous subtype, respectively) were employed for in vitro studies. Effects of FOXM1 inhibition by transient siRNA transfection were evaluated on cell-proliferation, cell-cycle, colony formation, invasion, and response to conventional first- and second-line anticancer agents, and to the PARP-inhibitor olaparib. Gene signatures of FOXM1-silenced cell lines were generated by microarray and confirmed by RT-qPCR.ResultsA significant FOXM1 mRNA up-regulation was found in EOCs compared to normal controls. FOXM1 protein overexpression significantly correlated to serous histology (p = 0.001) and advanced FIGO stage (p = 0.004). Multivariate analyses confirmed FOXM1 protein overexpression as an independent indicator of worse disease specific survival in non-serous EOCs, and of shorter time to progression in platinum-resistant cases. FOXM1 downregulation in EOC cell lines inhibited cell growth and clonogenicity, and promoted the cytotoxic effects of platinum compounds, doxorubicin hydrochloride and olaparib. Upon FOXM1 knock-down in EOC-CC1 and OSPC2 cells, microarray and RT-qPCR analyses revealed the deregulation of several common and other unique subtype-specific FOXM1 putative targets involved in cell cycle, metastasis, DNA repair and drug response.ConclusionsFOXM1 is up-regulated in all three major EOCs subtypes, and is a prognostic biomarker and a potential combinatorial therapeutic target in platinum resistant disease, irrespective of tumor histology.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0536-y) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

FOXM1 expression is significantly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients

Tassi

Todeschini

Siegel

et al. 2017

J Exp Clin Cancer Res

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“…In studies evaluating ovarian carcinoma, TOP2A gene gain and protein expression were associated with a higher clinical benefit in patients who received treatment with doxorubicin. 29 We observed that tubulin b3 (TUBB3) overexpression was significantly more frequent in patients with BRAF-mutated VVM than in those with wild-type VVM. The TUBB3 gene is an indicator of taxane resistance, because it is involved in a molecular pathway that promotes cell survival, which renders cancer cells resistant to apoptosis.…”

Section: Other Molecular Markers Of Interestmentioning

confidence: 83%

Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma

Hou

Baptiste

Hombalegowda

et al. 2016

Cancer

110

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“…To optimize the use of PLD and avoid unnecessary toxicity effects, predicting responses is of crucial importance [17,18].…”

Section: Discussionmentioning

confidence: 99%

Pegylated liposomal doxorubicin in patients with epithelial ovarian cancer

Yuan

Zhang

Cao

et al. 2020

Preprint

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Abstract Objective To evaluate the efficacy and safety of PLD in treating of in patients with epithelial ovarian, tubal, and peritoneal cancer progression within 12 months after the first-line platinum-based therapy. Methods This was an open-label, single-arm and multicenter clinical trial. ORR was the interim primary objective and DCR, AEs and QOL were the secondary objectives. The impact of factors on the efficacy outcomes, the change trend of CA125 and the artificial platinum-free interval were exploratory endpoints. Results Totally, 115 patients were enrolled in this study and included in the ITT. Moreover, 101 patients were included in the safety analysis. The median follow-up time was 4 months (IQR 2–6). In ITT, the confirmed ORR was 37.4% (95%CI, 28.4%-46.4%), and the DCR was 65.2% (95%CI, 56.4%-74.1%). The previous response status to platinum-based chemotherapy and baseline CA125 levels were statistically correlated with the ORR. The ORR was significantly higher in the patients with a CA125 decrease after the first cycle than in the patients with a CA125 increase. The most common grade 3 or higher AE was hand-foot syndrome (3 [3.0%] of 101 patients). No statistically significant differences existed between the baseline and the postbaseline questionnaires. Conclusions For patients with platinum-resistant and platinum refractory relapse, the use of PLD may be a favorite choice because of the associated satisfactory efficacy, low frequency of AEs and high patient QOL. Moreover, a lower CA125 level at baseline and a reduction in CA125 after the first cycle are predictive factors for a better efficacy.

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TOP2A gene copy gain predicts response of epithelial ovarian cancers to pegylated liposomal doxorubicin

Cited by 41 publications

References 36 publications

FOXM1 expression is significantly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients

FOXM1 expression is significantly associated with chemotherapy resistance and adverse prognosis in non-serous epithelial ovarian cancer patients

Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma

Pegylated liposomal doxorubicin in patients with epithelial ovarian cancer

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