Molecular analysis of platinum-resistant and -sensitive ovarian cacner based on RNA-Seq analysis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE214302 | GEO | 2024/05/30
REPOSITORIES: GEO
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Project description:Purpose: Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Most of these patients are treated with platinum-based chemotherapies, but there is no biomarker model to guide their responses to these therapeutic agents. We have developed and independently tested our novel multivariate molecular predictors for forecasting patients' responses to individual drugs on a cohort of 58 ovarian cancer patients. Experimental Design: We adapted and applied the previously-published COXEN algorithm to develop molecular predictors for therapeutic responses of patients' tumors based on expression signatures derived from the NCI-60 in vitro drug activities and genomic expression data. Genome-wide candidate biomarkers were first triaged by examining expression patterns of frozen and formalin-fixed paraffin embedded (FFPE) tissue samples. We then identify initial drug sensitivity biomarkers for carboplatin and paclitaxel, respectively. These biomarkers were further narrowed by examining concordant expression patterns between cell lines and a historical set of ovarian cancer patients. Multivariate predictors were obtained from the NCI-60 cell lines and refined using historical patient cohorts. To independent validate these molecular predictors, we performed genome-wide profiling on FFPE samples of 58 ovarian cancer patients obtained prior to adjuvant chemotherapy. Results: Carboplatin predictor significantly stratified platinum sensitive and resistant patients (p = 0.019) with sensitivity = 93%, specificity = 33%, PPV = 65%, and NPV = 78%. Paclitaxel predictor also significantly stratified patients' responses (p = 0.033) with sensitivity = 96%, specificity = 26%, PPV = 61%, and NPV = 86%. The combination predictor for platinum-taxane combination demonstrated a significant survival difference between the predicted responders and nonresponders with median survival of 12.9 months vs. 8.1 months (p = 0.045). Conclusions: COXEN predictors successfully stratified platinum resistance and taxane response in this retrospective cohort, especially based on their FFPE tumor samples. Accurate prediction of chemotherapeutic response, especially to platinum agents is highly clinically relevant and could alter primary management of ovarian cancer. Gene expression data from 58 stage III-IV ovarian cancer patients treated with Carboplatin and Taxol agents
2012-08-21 | E-GEOD-30161 | biostudies-arrayexpress
Project description:Resistance to platinum-based chemotherapy is a clinical challenge in the treatment of ovarian cancer (OC) and limits survival. Therefore, innovative drugs against platinum-resistance are 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 cleaved into active cytostatic metabolites. Here, we explore the activity of the duplex-prodrug 5-FdU-ECyd, covalently linking 2'-deoxy-5-fluorouridine (5-FdU) and 3'-C-ethynylcytidine (ECyd), on platinum-resistant OC cells. RNA-Sequencing was used for characterization of 5-FdU-ECyd treated platinum-sensitive A2780 and isogenic platinum-resistant A2780cis.
2018-02-22 | GSE98230 | GEO
Project description:This study aims at correlating changes in the transcriptional state in high grade serous epithelial ovarian cancer (HGS-EOC) to the response to therapy, in particular the insurgence of resistance to platinum-based treatment.
2020-02-11 | E-MTAB-7083 | biostudies-arrayexpress
Project description:This study aims at correlating changes in the microRNA state in high grade serous epithelial ovarian cancer (HGS-EOC) to the response to therapy, in particular the insurgence of resistance to platinum-based treatment.
2020-02-11 | E-MTAB-7084 | biostudies-arrayexpress
Project description:Background. One of the major limitations associated to the platinum use is the resistance that almost invariably will progress in lung and ovarian cancers. In the current study, we sought to identify epigenetically regulated miRNAs as novel biomarkers of platinum-resistance in those tumor types. Methods. We combined transcriptomic data from miRNA and mRNA under the influence of an epigenetic reactivation treatment, followed by qRT-PCR and epigenteic validations for an accurate candidate selection in 23 human cancer cell lines. Functional analysis were performed to study their biological and therapeutic implications, that were further tested in 257 primary samples obtained from lung and ovarian tumors. Results. We identified a group of 9 miRNAs belonging to the CM19 cluster and 7 potential miRNA-targets potentially involved in resistance development, in both tumor types. Deregulation of miR-7, -132, -335 and -148a may be a common event in the development of CDDP-resistance. miR-7 presented specific methylation in the resistant subtypes and its reexpression, decreased cell viability, suggesting a possible cell sensitization to cisplatin. Our translational approach indicated that miR-7 methylation is a frequent event that may play an important role in the early establishment of NSCLC tumorigenesis, and seems to play an additional platinum-predictive role in ovarian cancer. Conclusions. miR-7 is a novel potential epigenetic biomarker tool for the selection of ovarian cancer patients with higher risk to earlier relapse and worst response to platinum-based chemotherapy. Funding. FIS (ISCIII): PI12/00386, PI13/01450, PI15/00186, and FEDER/FSE (Una manera de hacer Europa).
2017-10-05 | GSE84200 | GEO
Project description:Platinum compounds display clinical activity against a wide variety of solid tumors. However, resistance to these agents is a major limitation in cancer therapy. Reduced platinum uptake and increased platinum export are examples of resistance mechanisms that limit the extent of DNA damage. Here, we report the discovery and characterization of the role of ATP11B, a P-type ATPase membrane protein, in cisplatin resistance. ATP11B gene silencing restored the sensitivity of ovarian cancer cell lines to cisplatin in vitro. Combined therapy of cisplatin and ATP11B-siRNA significantly decreased cancer growth in mice bearing ovarian tumors derived from cisplatin-sensitive and -resistant cells. In vitro mechanistic studies on cellular platinum content and cisplatin efflux-kinetics indicated that ATP11B enhances the export of cisplatin from cells. The co-localization of ATP11B with fluorescent cisplatin and with vesicular trafficking proteins such as syntaxin-6 (STX6) and vesicular associated membrane protein 4 (VAMP4) strongly suggests that ATP11B contributes to secretory vesicular transport of cisplatin from Golgi to plasma membrane. In conclusion, silencing ATP11B expression might be a therapeutic strategy to overcome cisplatin resistance. We performed the transfection of control-siRNA and ATP11B-siRNA to both cisplatin-sensitive A2780-PAR and cisplatin-resistant A2780-CP20 cells respectively.
2013-01-23 | E-GEOD-43694 | biostudies-arrayexpress
Project description:Background. One of the major limitations associated to the platinum use is the resistance that almost invariably will progress in lung and ovarian cancers. In the current study, we sought to identify epigenetically regulated miRNAs as novel biomarkers of platinum-resistance in those tumor types. Methods. We combined transcriptomic data from miRNA and mRNA under the influence of an epigenetic reactivation treatment, followed by qRT-PCR and epigenteic validations for an accurate candidate selection in 23 human cancer cell lines. Functional analysis were performed to study their biological and therapeutic implications, that were further tested in 257 primary samples obtained from lung and ovarian tumors. Results. We identified a group of 9 miRNAs belonging to the CM19 cluster and 7 potential miRNA-targets potentially involved in resistance development, in both tumor types. Deregulation of miR-7, -132, -335 and -148a may be a common event in the development of CDDP-resistance. miR-7 presented specific methylation in the resistant subtypes and its reexpression, decreased cell viability, suggesting a possible cell sensitization to cisplatin. Our translational approach indicated that miR-7 methylation is a frequent event that may play an important role in the early establishment of NSCLC tumorigenesis, and seems to play an additional platinum-predictive role in ovarian cancer. Conclusions. miR-7 is a novel potential epigenetic biomarker tool for the selection of ovarian cancer patients with higher risk to earlier relapse and worst response to platinum-based chemotherapy. Funding. FIS (ISCIII): PI12/00386, PI13/01450, PI15/00186, and FEDER/FSE (Una manera de hacer Europa).
2017-10-05 | GSE84146 | GEO
Project description:In the United States, high grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy and tumor response to platinum-based chemotherapy is a major determinant of clinical outcome. Although recent efforts have dramatically improved the median survival of advanced ovarian cancer, the initial treatment of the disease has remained the same. The initial therapy includes surgery and chemotherapy and the response rate is very high (85%). Unfortunately, 15% of patients do not respond to this therapy and have platinum-refractory disease. These patients have a very short survival and there is an urgent need to identify novel pharmaceutically targetable pathways to treat these patients. We generated extensive proteomic (global, phospho, ubiquitin, acetylation, pTyr) and RNASeq-based dynamic molecular profiles (+/-carboplatin at 8 and 24 hours) from HGSOC intra-patient cell line pairs (PEA1/PEA2, PEO1/PEO4, PEO14/PEO23) derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed a multi-faceted response to carboplatin (e.g., induction of a DNA damage response, ubiquitination of ribosomal proteins, and metabolic changes), as well as novel carboplatin-induced post-translational modifications. Higher oxidative phosphorylation (OXPHOS) and fatty acid beta-oxidation (FAO) pathway expression was observed in resistant compared with sensitive cells. These expression findings were validated via metabolite profiling of cell lines and proteomic profiling of platinum sensitive and refractory HGSOC patient derived xenograft (PDX) models. Both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents the rate limiting step of FAO, sensitizes HGSOC cells to platinum. The metabolic signature identified in the cell line and PDX models is correlated with survival in a previously reported proteomic analysis of HGSOC, and thus FAO is a candidate druggable pathway to overcome platinum resistance.
2021-12-22 | PXD020764 | Pride
Project description:Purpose: Despite advances in radical surgery and chemotherapy delivery, ovarian cancer is the most lethal gynecologic malignancy. Most of these patients are treated with platinum-based chemotherapies, but there is no biomarker model to guide their responses to these therapeutic agents. We have developed and independently tested our novel multivariate molecular predictors for forecasting patients' responses to individual drugs on a cohort of 58 ovarian cancer patients. Experimental Design: We adapted and applied the previously-published COXEN algorithm to develop molecular predictors for therapeutic responses of patients' tumors based on expression signatures derived from the NCI-60 in vitro drug activities and genomic expression data. Genome-wide candidate biomarkers were first triaged by examining expression patterns of frozen and formalin-fixed paraffin embedded (FFPE) tissue samples. We then identify initial drug sensitivity biomarkers for carboplatin and paclitaxel, respectively. These biomarkers were further narrowed by examining concordant expression patterns between cell lines and a historical set of ovarian cancer patients. Multivariate predictors were obtained from the NCI-60 cell lines and refined using historical patient cohorts. To independent validate these molecular predictors, we performed genome-wide profiling on FFPE samples of 58 ovarian cancer patients obtained prior to adjuvant chemotherapy. Results: Carboplatin predictor significantly stratified platinum sensitive and resistant patients (p = 0.019) with sensitivity = 93%, specificity = 33%, PPV = 65%, and NPV = 78%. Paclitaxel predictor also significantly stratified patients' responses (p = 0.033) with sensitivity = 96%, specificity = 26%, PPV = 61%, and NPV = 86%. The combination predictor for platinum-taxane combination demonstrated a significant survival difference between the predicted responders and nonresponders with median survival of 12.9 months vs. 8.1 months (p = 0.045). Conclusions: COXEN predictors successfully stratified platinum resistance and taxane response in this retrospective cohort, especially based on their FFPE tumor samples. Accurate prediction of chemotherapeutic response, especially to platinum agents is highly clinically relevant and could alter primary management of ovarian cancer.
2012-08-21 | GSE30161 | GEO
Project description:We demonstrate that 6mer seed toxicity plays a role in platinum resistance of ovarian cancer
2021-02-02 | GSE165147 | GEO