scholarly journals Considerations for Chemotherapy Treatment in Platinum Resistant High-Grade Serous Ovarian Cancer

2019 ◽  
pp. 14-18
Author(s):  
Caitlin Marie Reintjes
Keyword(s):  
Ovarian Cancer ◽  
Gynecological Cancer ◽  
Cancer Prognosis ◽  
Alternative Methods ◽  
Platinum Resistance ◽  
Primary Concern ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Individual Scale ◽  
Platinum Chemotherapy

Ovarian cancer is considered to be the most fatal type of any gynecological cancer. Prognosis for the disease is poor, with a median survival of only thirty-two months following diagnosis and a five-year survival rate of only 39%. Many of the most lethal ovarian cancer cases are classified as part of the high-grade serous ovarian cancer (HGSOC) subtype, which is the most aggressive form of the disease. The primary concern with regards to treatment is that nearly 30% of patients will develop a resistance to forms of platinum chemotherapy, which is the main method of treatment. This suggests that a one-size fits all approach cannot be taken to treat ovarian cancer, and that further research must be done to understand how to treat the patients who present with platinum resistance. This literature review examines the mutations within two susceptible loci, specifically, the p53 and BRCA1/2 genes, in order to understand how platinum resistance develops and why it is present in some patients. The objectives of this review are  to characterize the underlying genetic mechanisms affecting platinum resistance, specify the biomarkers associated with those mechanisms, and describe alternative methods for approaching the treatment of ovarian cancer on an individual scale.

scholarly journals Promoter Methylation of the MGRN1 Gene Predicts Prognosis and Response to Chemotherapy of High-Grade Serous Ovarian Cancer Patients

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiao-fei Li ◽  
Hai-yan Sun ◽  
Tian Hua ◽  
Hai-bo Zhang ◽  
Yun-jie Tian ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Promoter Region ◽  
Upstream Region ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Kaplan Meier ◽  
Response To Chemotherapy ◽  
Low Expression

Aberrant DNA methylation is considered to play a critical role in the chemoresistance of epithelial ovarian cancer (EOC). In this study, we explored the relationship between hypermethylation of the Mahogunin Ring Finger 1 (MGRN1) gene promoter and primary chemoresistance and clinical outcomes in high-grade serous ovarian cancer (HGSOC) patients. The MALDI-TOF mass spectrometry assays revealed a strong association between hypermethylation of the MGRN1 upstream region and platinum resistance in HGSOC patients. Spearman’s correlation analysis revealed a significantly negative connection between the methylation level of MGRN1 and its expression in HGSOC. In vitro analysis demonstrated that knockdown of MGRN1 reduced the sensitivity of cells to cisplatin and that expression of EGR1 was significantly decreased in SKOV3 cells with low levels of MGRN1 expression. Similarly, EGR1 mRNA expression was lower in platinum-resistant HGSOC patients and was positively correlated with MGRN1 mRNA expression. Kaplan-Meier analyses showed that high methylation of the MGRN1 promoter region and low expression of MGRN1 were associated with worse survival of HGSOC patients. In multivariable models, low MGRN1 expression was an independent factor predicting poor outcome. Furthermore, low expression of EGR1 was also been confirmed to be significantly related to the poor prognosis of HGSOC patients by Kaplan-Meier. The hypermethylation of the MGRN1 promoter region and low expression of MGRN1 were associated with platinum resistance and poor outcomes in HGSOC patients, probably by altering EGR1 expression.

scholarly journals Development of a Genomic Signatures-Based Predictor of Initial Platinum-Resistance in Advanced High-Grade Serous Ovarian Cancer Patients

2021 ◽  
Vol 10 ◽  
Author(s):  
Yuan Li ◽  
Xiaolan Zhang ◽  
Yan Gao ◽  
Chunliang Shang ◽  
Bo Yu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Predictive Accuracy ◽  
Predictive Performance ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Single Nucleotide Variants ◽  
Tissue Samples ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy

BackgroundHigh grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. Although platinum-based chemotherapy has been the cornerstone for HGSOC treatment, nearly 25% of patients would have less than 6 months of interval since the last platinum chemotherapy, referred to as platinum-resistance. Currently, no precise tools to predict platinum resistance have been developed yet.MethodsNinety-nine HGSOC patients, who have finished cytoreductive surgery and platinum-based chemotherapy in Peking University Third Hospital from 2018 to 2019, were enrolled. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were performed on the collected tumor tissue samples to establish a platinum-resistance predictor in a discovery cohort of 57 patients, and further validated in another 42 HGSOC patients.ResultsA high prevalence of alterations in DNA damage repair (DDR) pathway, including BRCA1/2, was identified both in the platinum-sensitive and resistant HGSOC patients. Compared with the resistant subgroup, there was a trend of higher prevalence of homologous recombination deficiency (HRD) in the platinum-sensitive subgroup (78.95% vs. 47.37%, p=0.0646). Based on the HRD score, microhomology insertions and deletions (MHID), copy number changes load, duplication load of 1–100 kb, single nucleotide variants load, and eight other mutational signatures, a combined predictor of platinum-resistance, named as DRDscore, was established. DRDscore outperformed in predicting the platinum-sensitivity than the previously reported biomarkers with a predictive accuracy of 0.860 at a threshold of 0.7584. The predictive performance of DRDscore was validated in an independent cohort of 42 HGSOC patients with a sensitivity of 90.9%.ConclusionsA multi-genomic signature-based analysis enabled the prediction of initial platinum resistance in advanced HGSOC patients, which may serve as a novel assessment of platinum resistance, provide therapeutic guidance, and merit further validation.

Evolution of platinum resistance in high-grade serous ovarian cancer

2011 ◽  
Vol 12 (12) ◽  
pp. 1169-1174 ◽  
Author(s):  
Susanna L Cooke ◽  
James D Brenton
Keyword(s):  
Ovarian Cancer ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals Correction to: Kallistatin inhibits tumour progression and platinum resistance in high-grade serous ovarian cancer

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Huan Wu ◽  
Rongrong Li ◽  
Zhiwei Zhang ◽  
Huiyang Jiang ◽  
Hanlin Ma ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumour Progression ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer

scholarly journals FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

2019 ◽  
Author(s):  
Carlos J. Díaz Osterman ◽  
Duygu Ozmadenci ◽  
Elizabeth G. Kleinschmidt ◽  
Kristin N. Taylor ◽  
Allison M. Barrie ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Gene Copy ◽  
Platinum Resistance ◽  
List Type ◽  
High Grade ◽  
Cancer Resistance ◽  
Platinum Chemotherapy

AbstractGene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-β-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encodingKRAS,MYCandFAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosisin vitroandin vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/β-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.Graphical SummaryKey PointsHigh grade serous ovarian carcinoma tumors containPTK2(FAK) 8q24.3 gains associated with prognostic differences.KMF, a new murine ovarian cancer model withK-Ras,Myc, andFAK gene gains and intrinsic platinum resistance.FAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.FAK facilitates a β-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.FAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance.

scholarly journals Metabolism of Estrogens: Turnover Differs between Platinum-Sensitive and -Resistant High-Grade Serous Ovarian Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 279
Author(s):  
Stefan Poschner ◽  
Judith Wackerlig ◽  
Dan Cacsire Castillo-Tong ◽  
Andrea Wolf ◽  
Isabel von der Decken ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Resolution Mass Spectrometry ◽  
Estrogen Metabolism ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Platinum Sensitive ◽  
Platinum Based Chemotherapy ◽  
The Impact

High-grade serous ovarian cancer (HGSOC) is currently treated with cytoreductive surgery and platinum-based chemotherapy. The majority of patients show a primary response; however, many rapidly develop drug resistance. Antiestrogens have been studied as low toxic treatment options for HGSOC, with higher response rates in platinum-sensitive cases. Mechanisms for this difference in response remain unknown. Therefore, the present study investigated the impact of platinum resistance on steroid metabolism in six established HGSOC cell lines sensitive and resistant against carboplatin using a high-resolution mass spectrometry assay to simultaneously quantify the ten main steroids of the estrogenic metabolic pathway. An up to 60-fold higher formation of steroid hormones and their sulfated or glucuronidated metabolites was observed in carboplatin-sensitive cells, which was reversible by treatment with interleukin-6 (IL-6). Conversely, treatment of carboplatin-resistant cells expressing high levels of endogenous IL-6 with the monoclonal anti-IL-6R antibody tocilizumab changed their status to “platinum-sensitive”, exhibiting a decreased IC50 value for carboplatin, decreased growth, and significantly higher estrogen metabolism. Analysis of these metabolic differences could help to detect platinum resistance in HGSOC patients earlier, thereby allowing more efficient interventions.

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