Discovery of metabolomic biomarkers for discriminating platinum-sensitive and platinum-resistant ovarian cancer by using GC-MS

This study aims to determine ovarian cancer (OC) patients with platinum resistance for alternative treatment protocols by using metabolomic methodologies. Urine and serum samples of platinum-resistant and platinum-sensitive OC were analyzed using GC-MS. After data processing of GC-MS raw data, multivariate analyses were performed to interpret complex data for biologically meaningful information and to identify the biomarkers that cause differences between two groups. The biomarkers were verified after univariate, multivariate, and ROC analysis. Finally, metabolomic pathways related to group separations were specified. The results of biomarker analysis showed that 3,4-dihydroxyphenylacetic acid, 4-hydroxybutyric acid, L-threonine, D- mannose, and sorbitol metabolites were potential biomarkers in urine samples. In serum samples, L-arginine, linoleic acid, L-glutamine, and hypoxanthine were identified as important biomarkers. R2Y, Q2, AUC, sensitivity and specificity values of platinum-resistant and sensitive OC patients’ urine and serum samples were 0.85, 0.545, 0.844, 91.30%, 81.08 and 0.570, 0.206, 0.743, 77.78%, 74.28%, respectively. In metabolic pathway analysis of urine samples, tyrosine metabolism and fructose and mannose metabolism were found to be statistically significant (p < 0.05) for the discrimination of the two groups. While 3,4-dihydroxyphenylacetic acid, L-tyrosine, and fumaric acid metabolites were effective in tyrosine metabolism. D-sorbitol and D-mannose metabolites were significantly important in fructose and mannose metabolism. However, seven metabolomic pathways were significant (p < 0.05) in serum samples. In terms of p-value, L-glutamine in the nitrogen metabolic pathway from the first three pathways; L-glutamine and pyroglutamic acid metabolites in D-glutamine and D-glutamate metabolism. In the arginine and proline metabolic pathway, L-arginine, L-proline, and L-ornithine metabolites differed significantly between the two groups.

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Extracellular vesicle-associated miRNAs in ovarian cancer – design of an integrated NGS-based workflow for the identification of blood-based biomarkers for platinum-resistance

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2018-1048 ◽

2019 ◽

Vol 57 (7) ◽

pp. 1053-1062 ◽

Cited By ~ 14

Author(s):

Jan Dominik Kuhlmann ◽

Issam Chebouti ◽

Rainer Kimmig ◽

Paul Buderath ◽

Michael Reuter ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Independent Set ◽

Extracellular Vesicle ◽

Platinum Resistance ◽

Diagnostic Purpose ◽

Illumina Platform ◽

Platinum Sensitive ◽

Platinum Resistant ◽

Next Generation Sequencing Ngs

AbstractBackgroundExtracellular vesicle (EV)-associated microRNAs (miRNAs) have been suggested as promising biomarkers for blood-based cancer diagnosis. However, one of the major limitations for the use of EVs with diagnostic purpose is the lack of standardized EV-profiling techniques. In this regard, the objective of our study was to design an integrated next-generation sequencing (NGS)-based workflow for analyzing the signature of EV-associated miRNA in the plasma of platinum-resistant ovarian cancer patients.MethodsFor EV-extraction, different enrichment methods were compared (ExoQuick vs. exoRNeasy). NGS was performed with the Illumina platform.ResultsWe established an integrated NGS-based workflow, including EV-enrichment with the ExoQuick system, which resulted in an optimal RNA-yield and consistent small RNA libraries. We applied this workflow in a pilot cohort of clinically documented platinum-sensitive (n=15) vs. platinum-resistant (n=15) ovarian cancer patients, resulting in a panel of mature EV-associated miRNAs (including ovarian cancer associated miR-181a, miR-1908, miR-21, miR-486 and miR-223), which were differentially abundant in the plasma of platinum-resistant patients.ConclusionsThis is the first study, analyzing the profile of EV-associated miRNAs in platinum-resistant ovarian cancer patients. We provide rationale to further validate these miRNA candidates in an independent set of patients, in order to characterize their biomarker potential as predictors for platinum-resistance.

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Early clearance of serum HE4 and CA125 in predicting platinum sensitivity and prognosis in epithelial ovarian cancer

10.21203/rs.3.rs-44934/v2 ◽

2020 ◽

Author(s):

Yan Rong ◽

Li Li

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Clinical Data ◽

First Line ◽

Clinical Value ◽

Platinum Sensitivity ◽

Platinum Sensitive ◽

Platinum Resistant ◽

Line Chemotherapy ◽

Sensitive Group

Abstract Objectives: To assess the clinical value of early clearance of HE4 and CA125 for platinum sensitivity and prognosis in patients with ovarian cancer.Method: HE4 and CA125 value including clinical data of 89 patients with ovarian cancer were collected. The clearance of HE4 and CA125 were assessed base on the platinum sensitivity, two-year PFS, PFS and OS.Results: 16 patients were classified as platinum resistant and 73 as platinum sensitive according to the response to platinum-base chemotherapy. When HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle chemotherapy, it gave the highest AUC of 0.788, with 100% of sensitivity and 57.5% of specificity respectively between platinum resistant and platinum sensitive group. In addition, 59 patients were classified as two-year PFS group and 30 as not achieved two-year PFS group according to obtaining two-year PFS or not. It gave the highest AUC of 0.730, with 83.3% of sensitivity and 62.7% of specificity respectively when HE4 clearance after 3rd cycle chemotherapy or CA125 clearance after 1st cycle. The prolonged PFS and OS were significantly associated by the clearance of HE4 after 3rd cycle chemotherapy (p<0.0001, p<0.0001) as well as CA125 after 1st cycle chemotherapy (p<0.0001, p<0.0001).Conclusions: Our data suggested that the early clearance of HE4 and CA125 could predict platinum response and prognosis in patients with ovarian cancer. Monitoring the HE4 and CA125 during first-line chemotherapy might be helpful in predicting platinum sensitivity and risk to progress and relapse.

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Measurement of urinary constituents with the Astra-8 Multichannel Analyzer.

Clinical Chemistry ◽

10.1093/clinchem/26.13.1883 ◽

1980 ◽

Vol 26 (13) ◽

pp. 1883-1886 ◽

Cited By ~ 7

Author(s):

T A Blumenfeld ◽

B Griffith

Keyword(s):

Clinical Chemistry ◽

Urine Samples ◽

Serum Samples ◽

Urea Nitrogen ◽

Multiple Test ◽

Multichannel Analyzer ◽

Urine And Serum

Abstract The Beckman Astra-8 is a computerized, discrete-microsample, multiple-test clinical chemistry analyzer. We have examined its capability to measure urine Na+, K+, Cl-, urea nitrogen, glucose, and creatinine and found that (a) the Astra measurements are linear, accurate, and precise in concentration ranges of urine analytes; (b) urine analyte concentrations measured with the Astra correlate well with those by comparison micromethods (p < 0.001); and (c) the Astra has no significant carryover from adjacent urine samples or from adjacent urine and serum samples.

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Salvage Chemotherapy in Recurrent Ovarian Cancer: a Combination of Gemcitabine and Treosulfan is Equally Active in Platinum-Resistant and Platinum-Sensitive Disease

Annals of Oncology ◽

10.1093/annonc/mdu338.36 ◽

2014 ◽

Vol 25 ◽

pp. iv316

Author(s):

C.M. Kurbacher ◽

S. Herz ◽

G. Wessling ◽

O. Horn ◽

S. Sperling ◽

...

Keyword(s):

Ovarian Cancer ◽

Recurrent Ovarian Cancer ◽

Salvage Chemotherapy ◽

Platinum Sensitive ◽

Platinum Resistant

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Clinical benefit of bevacizumab in Mexican ovarian cancer patients according to the intention of treatment by the oncologist.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17097 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17097-e17097

Author(s):

Dolores Gallardo-Rincon ◽

Antonio Bahena-Gonzalez ◽

Edgar Montes-Servín ◽

Elizabeth Montes-Servín ◽

David Michel-Tello ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Benefit ◽

Gynecological Cancer ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Debulking Surgery ◽

Platinum Sensitive ◽

Platinum Resistant ◽

Venous Thromboembolic Events

e17097 Background: Ovarian cancer (OC) is the first cause of gynecological cancer, and the fifth cause of women cancer-death in US. In Mexico, more than 4,500 new cases of ovarian cancer are diagnosed yearly and it represents the second cause of gynecological cancer mortality. Bevacizumab (BVZ) is an antiangiogenic antibody that has been approved for first-line and recurrence therapy in OC patients. The aim of the study was to evaluate the clinical benefit of BVZ in different lines of treatment in Mexican OC patients. Methods: A total of 94 OC patients treated with BVZ were recruited at the Ovarian Cancer Program of the Instituto Nacional de Cancerología, from February 2012 to September 2018. Clinicopathological characteristics and toxicity was correlated with line of treatment. PFS curves were estimated by the Kaplan–Meier method, while comparisons among groups were analyzed with log-rank or Breslow tests. Results: Most of the patients were stage IIIC (69.1%) with HGSP histology (73.4%). 24 patients (25.5%) received BVZ as first-line treatment before debulking surgery (50% for suboptimal and 45.8% for optimal cytoreduction). 48 patients (51.1%) received BVZ for second-line (72.9% after a platinum-resistant and 27.1% after a platinum-sensitive recurrence) and 22 patients (23.4%) for three or more lines of treatment. Venous thromboembolic events (VTE) were more frequent in multi-treated patients ( P= 0.030). The median PFS was 23.7, 11.7 and 5.8 months for first, second and third or more lines, respectively. Patients with optimal debulking surgery had a better PFS compared with suboptimal and BVZ in first-line patients (24.8 vs 20.9; P= 0.050). Patients with BVZ in second-line who are a platinum-sensitive recurrence had better PFS compared to those with a platinum-resistant disease (15.1 vs 7.6; P= 0.040). Conclusions: OC patients had clinical benefit from treatment with BVZ when used as first-line and first recurrence treatments. The use of BVZ for third or later line treatment has a questionable benefit and is associated with a higher rate of VTE. Also, we highlight that 77% of the patients had the greatest-benefit while 33% had limited-benefit.

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Bevacizumab in the Management of Epithelial Ovarian Cancer

Oncology & Hematology Review (US) ◽

10.17925/ohr.2013.09.2.129 ◽

2013 ◽

Vol 09 (02) ◽

pp. 129

Author(s):

Maurie Markman ◽

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Cancer Progression ◽

Single Agent ◽

Strong Support ◽

Progression Free Survival ◽

Optimal Dose ◽

Phase Iii ◽

Platinum Sensitive ◽

Platinum Resistant

Preclinical investigations have provided strong support for the hypothesis that angiogenesis is a potent driver of epithelial ovarian cancer progression. Phase II data have revealed the activity of single-agent bevacizumab in previously treated and clinically defined platinum-resistant ovarian cancer. Several reported phase III randomized trials, involving primary and both ‘platinum-sensitive’ recurrent and platinum-resistant disease, have demonstrated the addition of bevacizumab to a cytotoxic chemotherapy regimen improves progression-free survival compared with chemotherapy alone. While there continues to be considerable debate regarding the optimal dose, timing, and duration of bevacizumab administration in ovarian cancer, the existing data provide strong support for an important role for this agent in the overall management paradigm for this malignancy.

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Efficacy of Platinum Plus Gemcitabine (G) in Platinum-Resistant (R) Compared to Platinum-Sensitive (S) Ovarian Cancer: the Royal Marsden Experience

Annals of Oncology ◽

10.1016/s0923-7534(20)33575-4 ◽

2012 ◽

Vol 23 ◽

pp. ix320

Author(s):

A. George ◽

N. Tunariu ◽

N. Wilkinson ◽

S. Gupta ◽

M.E. Gore ◽

...

Keyword(s):

Ovarian Cancer ◽

Platinum Sensitive ◽

Platinum Resistant

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The activity of the conjugated antimetabolite 5-FdU-ECyd against platinum-resistant ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e17077 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e17077-e17077

Author(s):

Pauline Wimberger ◽

Barbara Klink ◽

Konrad Gruetzmann ◽

Julian Puppe ◽

Daniel Klotz ◽

...

Keyword(s):

Ovarian Cancer ◽

Parp Cleavage ◽

Strong Increase ◽

Platinum Resistance ◽

Secondary Resistance ◽

Therapeutic Concept ◽

Platinum Sensitive ◽

Platinum Resistant ◽

Platinum Based Chemotherapy

e17077 Background: Primary or secondary resistance to platinum-based chemotherapy is an important clinical challenge in the treatment of ovarian cancer (OC) and limits survival. Therefore, the development of innovative drugs against platinum resistance is urgently needed. Our therapeutic concept is based on the conjugation of two chemotherapeutic compounds to a monotherapeutic pro-drug, which is taken up by cancer cells and is subsequently cleaved into several active cytostatic metabolites. Our in vitro study evaluates the effects of the conjugated antimetabolite 5-FdU-ECyd, consisting of 2-deoxy-5-fluorouridine (5-FdU) and ethynylcytidine (ECyd), on platinum-resistant OC cells. Methods: In vitro assays and RNA-Seq (Illumina) were applied for characterization of 5-FdU-ECyd treated platinum-sensitive A2780 and isogenic platinum-resistant A2780cis as well as independent platinum-resistant Skov-3-IP OC cells. Results: Nano molar 5-FdU-ECyd concentrations induced a rapid dose-dependent decline of cell viability in platinum-sensitive and platinum-resistant OC cells. The cytotoxicity of 5-FdU-ECyd was accompanied by the formation of DNA double strand breaks and by the induction of apoptosis, indicated by a strong increase of pro-apoptotic molecular markers (caspase-3/7 activation, PARP-cleavage). Moreover, 5-FdU-ECyd efficiently decreased cell migration of platinum-resistant OC cells and inhibited other tumor-associated cellular functions, such as clonogenic or spheroidal growth. Transcriptome analysis indicated that, independently of platinum-resistance status, 5-FdU-ECyd influences distinct cellular pathways, involved in cell cycle regulation, apoptosis, DNA-damage response and RNA/pyrimidine metabolism. Combination treatment of 5-FdU-ECyd and platin did not show a synergistic cellular response, suggesting the potential use of 5-FdU-ECyd as a monotherapeutic agent. Conclusions: Our data provide a rationale to characterize the effect of 5-FdU-ECyd in a pre-clinical in vivo setting. We hypothesize that this conjugate is a promising therapeutic option for OC patients with resistance to conventional platinum-based chemotherapy.

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