Olaparib for the treatment of epithelial ovarian cancer

McLachlan, Jennifer; Banerjee, Susana

doi:10.1517/14656566.2016.1165205

Cited by 12 publications

(16 citation statements)

References 31 publications

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“…However, BRCA1/2 status is not the only useful biomarker to predict PARP-inhibitor effectiveness [60]. In the present study, we tested olaparib, the first PARP inhibitor approved for EOC [8], as a single agent, and found reduced cell viability at increasing drug concentrations, in both cellular models. The OSPC2 cell line was more sensitive than EOC-CC1 to olaparib, but they both showed a lower sensitivity if compared to published data derived from commercially available EOC cell lines [61].…”

Section: Discussionmentioning

confidence: 91%

“…Significant expression changes were also confirmed by RT-qPCR for some genes involved in homologous (HR) and non-homologous end joining (NHEJ) DNA damage-repair mechanisms in ovarian cancer, such as XRCC1 [55] in EOC-CC1, and XRCC4, RAD51 and BRCA2 [56] in OSPC2. Their molecular alteration might be also associated to the increased cellular response of FOXM1-depleted cells to second-line treatment drugs, such as doxorubicin [7] and olaparib [8, 9], clinically employed for relapsed EOC patients. Previously, the involvement of FOXM1 in resistance to doxorubicin has been reported in various carcinoma cell lines [57].…”

Section: Discussionmentioning

confidence: 99%

“…Other promising therapeutic approaches aim at inhibiting cell-specific signal transduction pathways and DNA repair mechanisms. Olaparib is the first poly-ADP-ribose polymerase (PARP) inhibitor approved by the United States Food and Drug Administration for use in advanced EOC patients harboring germline or somatic BRCA1 and BRCA2 mutations, who have received three or more prior lines of chemotherapy [8]. Moreover, its efficacy also has been evaluated in a subset of recurrent platinum-sensitive non-serous EOC that display defects in the homologous-recombination (HR) pathway of DNA repair [9].…”

Section: Introductionmentioning

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: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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“…Recent advances in our knowledge of the molecular traits underlying ovarian cancer not only contribute to the identification of familial cancer predisposition but also address potential predictive biomarkers and therapeutic alternatives such as anti-angiogenic agents (Bevacizumab) and poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) [4]. The PARP-1 protein is critical for the repair of single-strand DNA breaks.…”

Section: Introductionmentioning

confidence: 99%

Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing

Zhao

Yang

et al. 2017

J Gynecol Oncol

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ObjectiveTo define genetic profiling of homologous recombination (HR) deficiency in Chinese ovarian cancer patients.Methodswe have applied next-generation sequencing to detect deleterious mutations through all exons in 31 core HR genes. Paired whole blood and frozen tumor samples from 50 Chinese women diagnosed with epithelial ovarian carcinomas were tested to identify both germline and somatic variants.ResultsDeleterious germline HR-mutations were identified in 36% of the ovarian cancer patients. Another 5 patients had only somatic mutations. BRCA2 was most frequently mutated. Three out of the 5 somatic mutations were in RAD genes and a wider distribution of other HR genes was involved in non-serous carcinomas. BRCA1/2-mutation carriers had favorable platinum sensitivity (relative risk, 1.57, p<0.05), resulting in a 100% remission probability and survival rate. In contrast, mutations in other HR genes predicted poor prognosis. However, multivariate analysis demonstrated that platinum sensitivity and optimal cytoreduction were the independent impact factors influencing survival (hazards ratio, 0.053) and relapse (hazards ratio, 0.247), respectively.Conclusionour results suggest that a more comprehensive profiling of HR defect than merely BRCA1/2 could help elucidate tumor heterogeneity and lead to better stratification of ovarian cancer patients for individualized clinical management.

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“…1 Because of its high incidence and mortality rates, ovarian cancer is a lethal and underrecognized detriment to women's health all over the world. Despite the improvement in therapy, patients with advanced ovarian cancer have a low 5-year survival rate of only 10%-20%.…”

Section: Introductionmentioning

confidence: 99%

Efficient delivery of Notch1 siRNA to SKOV3 cells by cationic cholesterol derivative-based liposome

Zhao¹,

Zhang²,

Feng³

et al. 2016

IJN

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A novel cationic cholesterol derivative-based small interfering RNA (siRNA) interference strategy was suggested to inhibit Notch1 activation in SKOV3 cells for the gene therapy of ovarian cancer. The cationic cholesterol derivative, N -(cholesterylhemisuccinoyl-amino-3-propyl)- N , N -dimethylamine (DMAPA-chems) liposome, was incubated with siRNA at different nitrogen-to-phosphate ratios to form stabilized, near-spherical siRNA/DMAPA-chems nanoparticles with sizes of 100–200 nm and zeta potentials of 40–50 mV. The siRNA/DMAPA-chems nanoparticles protected siRNA from nuclease degradation in 25% fetal bovine serum. The nanoparticles exhibited high cell uptake and Notch1 gene knockdown efficiency in SKOV3 cells at an nitrogen-to-phosphate ratio of 100 and an siRNA concentration of 50 nM. They also inhibited the growth and promoted the apoptosis of SKOV3 cells. These results may provide the potential for using cationic cholesterol derivatives as efficient nonviral siRNA carriers for the suppression of Notch1 activation in ovarian cancer cells.

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Olaparib for the treatment of epithelial ovarian cancer

Cited by 12 publications

References 31 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

Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing

Efficient delivery of Notch1 siRNA to SKOV3 cells by cationic cholesterol derivative-based liposome

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