TMT-based Quantitative Proteomics Identifies Protein Markers of Resistance to Neoadjuvant Chemotherapy in Ovarian Cancer
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ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Zhuo Yang
PROVIDER: PXD044243 | iProX | Tue Aug 01 00:00:00 BST 2023
REPOSITORIES: iProX
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Project description:The development of drug resistance is still a major impediment for the successful treatment of cancer, such as advanced stage ovarian cancer, which has a 5-year survival rate of only 30%. The molecular processes that contribute to resistance have been extensively studied, however, not much is known about the role of microRNAs. We compared microRNA expression profiles of three isogenic cisplatin sensitive and resistant cell line pairs. The only microRNA that was consistently downregulated (FDR = 0.000) in all resistant cell lines was miR-634. We investigated the effects of miR-634 modulation in ovarian cancer cell lines and patient derived tumor cells. Overexpression of miR-634 gave rise to a modest G1 phase block and enhanced apoptosis. Furthermore, miR-634 resensitized resistant ovarian cancer cell lines and patient derived tumor cells to cisplatin chemotherapy. Similarly, miR-634 enhanced the response of tumor cells to carboplatin and doxorubicin, but not to paclitaxel. We showed that miR-634 regulates cyclin D1 (CCND1), which is required for the G1-S phase transition, explaining the effects on the cell cycle. In addition, miR-634 repressed expression of GRB2, ERK2, RSK1 and RSK2, components of the Ras-MAPK pathway. Altogether, our findings suggest that miR-634 modulates several cancer relevant targets and therefore miR-634 is an attractive therapeutic candidate to resensitize chemotherapy resistant ovarian tumors. The miRNA expression profile was determined of three cisplatin sensitive/resistant cell line pairs (ovarian cancer cell line pair A2780/A2780 DDP; colon cancer cell line pair HCT8/HCT8 DDP; bladder cancer cell line pairT24/T24 DDP10).
2014-02-04 | E-GEOD-54665 | biostudies-arrayexpress
Project description:Epithelial ovarian cancer is the leading cause of death from gynecological malignancies. Currently platinum-based chemotherapy, coupled with a taxane based drug is the primary treatment for ovarian cancer. Approximately 25% of patients either present with or rapidly develop resistance to platinum based chemotherapy and all recurrent tumors ultimately become resistant. Epigenetic modifications have been associated with tumor formation and progression and may contribute to therapy response. We performed a methylation screen on a set of tumors and have found a number of genes and family members differentially methylated between resistant patients and sensitive patients. Here we show that loss of expression of CHD3, a member of the Mi-2/NuRD complex, causes increased resistance to platinum chemotherapy drugs. Additionally, ovarian cell lines transcriptionally silenced for CHD3 are more invasive, have migratory ability, and display a transformed epithelial to mesenchymal (EMT) phenotype. Taken together, we provide the first evidence of a role for CHD3 as an important epigenetic regulator of chemoresistance in ovarian cancer and hypothesize EMT as one of the underlying mechanisms. Furthermore, CHD3 expression might represent a therapy response predictor and could be a future therapeutic target for ovarian cancer. We have developed a method to profile genome wide methylation. 71 ovarian tumor samples and 9 normal tissue samples from individuals were analyzed for CpG methylation. Some of these regions were validated for their methylation as a proof of principle for the method. Kamalakaran S., et. al. Mol Oncol. 2011;5:77-92 (PMID: 21169070).
2012-05-14 | E-GEOD-33011 | biostudies-arrayexpress
Project description:An alternative or follow-up adjunct to conventional maximum tolerated dose (MTD) chemotherapy now in advanced phase III clinical trial assessment is metronomic chemotherapy?the close regular administration of low doses of drug with no prolonged breaks. A number of preclinical studies have shown metronomic chemotherapy can cause long term survival of mice with advanced cancer, including metastatic disease, in the absence of overt toxicity, especially when combined with targeted antiangiogenic drugs. However, similar to MTD chemotherapy acquired resistance eventually develops, the basis of which is unknown. Using a preclinical model of advanced human ovarian (SKOV-3-13) cancer in SCID mice, we show that acquired resistance can develop after terminating prolonged (over 3 months) successful therapy utilizing daily oral metronomic topotecan plus pazopanib, an oral antiangiogenic tyrosine kinase inhibitor (TKI). Two resistant sublines were isolated from a single mouse, one from a solid tumor (called KH092-7SD, referred to as 7SD) and another from ascites tumor cells (called KH092-7AS, referred to as 7AS). Using these sublines we show acquired resistance to the combination treatment is due to tumor cell alterations that confer relative refractoriness to topotecan. The resistant phenotype is heritable, associated with reduced cellular uptake of topotecan and could not be reversed by switching to MTD topotecan or to another topoisomerase-1 inhibitor, CPT-11, given either in a metronomic or MTD manner nor switching to another antiangiogenic drug, e.g. the anti-VEGFR-2 antibody, DC101, or another TKI, sunitinib. Thus, in this case cross resistance seems to exist between MTD and metronomic topotecan, the basis of which is unknown. However, gene expression profiling revealed several potential genes that are stably upregulated in the resistant lines, that previously have been implicated in resistance to various chemotherapy drugs, and which, therefore, may contribute to the drug resistant phenotype. Two-condition experiment, ovarian cell line (SKOV-3-13) sensitive to daily oral metronomic topotecan plus pazopaniband treatemnt compared to two in- vivo selected resistant sublines from a solid tumor (called KH092-7SD) and another from ascites tumor cells (called KH092-7AS). Biological replicates: 4 independently grown and harvested cell line passages. Two technical replicate per condition (including dye swap).
2014-02-04 | E-GEOD-54621 | biostudies-arrayexpress
Project description:Pemetrexed is a drug largely used in lung cancer, mesothelioma and proposed in some cases of ovarian cancers, a particularly severe cancer type. In this latest tumor type, therapy relies on debulking surgery and platinum-based chemotherapy. Despite the initial high response rates to platinum drugs, most patients relapse and die from the disease. Considering the high levels of thymidylate synthase, dhydrofolate reductase and other folate related proteins in platinum drug resistant patients, pemetrexed was proposed as a second line drugs due to its known mechanism of action that engage the mentioned proteins. However a successful outcome could only be expected on the basis of patients’ stratifications. In the present study, a discovery proteomics approach was applied to tissue samples collected beforepemetrexed treatment from platinum resistant patients who relapsed after the first-line carboplatin-based chemotherapy but responded differently to the pemetrexed treatment.
2018-06-06 | PXD007056 | Pride
Project description:The development of drug resistance is still a major impediment for the successful treatment of cancer, such as advanced stage ovarian cancer, which has a 5-year survival rate of only 30%. The molecular processes that contribute to resistance have been extensively studied, however, not much is known about the role of microRNAs. We compared microRNA expression profiles of three isogenic cisplatin sensitive and resistant cell line pairs. The only microRNA that was consistently downregulated (FDR = 0.000) in all resistant cell lines was miR-634. We investigated the effects of miR-634 modulation in ovarian cancer cell lines and patient derived tumor cells. Overexpression of miR-634 gave rise to a modest G1 phase block and enhanced apoptosis. Furthermore, miR-634 resensitized resistant ovarian cancer cell lines and patient derived tumor cells to cisplatin chemotherapy. Similarly, miR-634 enhanced the response of tumor cells to carboplatin and doxorubicin, but not to paclitaxel. We showed that miR-634 regulates cyclin D1 (CCND1), which is required for the G1-S phase transition, explaining the effects on the cell cycle. In addition, miR-634 repressed expression of GRB2, ERK2, RSK1 and RSK2, components of the Ras-MAPK pathway. Altogether, our findings suggest that miR-634 modulates several cancer relevant targets and therefore miR-634 is an attractive therapeutic candidate to resensitize chemotherapy resistant ovarian tumors.
2014-02-04 | GSE54665 | GEO
Project description:Epithelial ovarian cancer is the leading cause of death from gynecological malignancies. Currently platinum-based chemotherapy, coupled with a taxane based drug is the primary treatment for ovarian cancer. Approximately 25% of patients either present with or rapidly develop resistance to platinum based chemotherapy and all recurrent tumors ultimately become resistant. Epigenetic modifications have been associated with tumor formation and progression and may contribute to therapy response. We performed a methylation screen on a set of tumors and have found a number of genes and family members differentially methylated between resistant patients and sensitive patients. Here we show that loss of expression of CHD3, a member of the Mi-2/NuRD complex, causes increased resistance to platinum chemotherapy drugs. Additionally, ovarian cell lines transcriptionally silenced for CHD3 are more invasive, have migratory ability, and display a transformed epithelial to mesenchymal (EMT) phenotype. Taken together, we provide the first evidence of a role for CHD3 as an important epigenetic regulator of chemoresistance in ovarian cancer and hypothesize EMT as one of the underlying mechanisms. Furthermore, CHD3 expression might represent a therapy response predictor and could be a future therapeutic target for ovarian cancer.
2012-05-15 | GSE33011 | GEO
Project description:Background: Current protocols for the treatment of ovarian cancer include combination chemotherapy with a platinating agent and a taxane. However, many patients experience relapse of their cancer and the development of drug resistance is not uncommon, making successful second line therapy difficult to achieve. The objective of this study was to develop a cell line resistant to both carboplatin and docetaxel (dual drug resistant ovarian cell line A2780CBNDXL), along with single agent resistant lines (docetaxel resistant A2780DXL and carboplatin resistant A2780CBN), to investigate the mechanisms which underlie the development of dual drug resistance. Methods: The A2780 epithelial ovarian cancer cell line was used to select for isogenic carboplatin, docetaxel and dual drug resistant cell lines. A selection method of gradually increasing drug doses was implemented to avoid clonal selection. Resistance was confirmed using a clonogenic assay. Changes in gene expression associated with the development of drug resistance were determined by microarray analysis compared to parental co-culture control A2780CC. Changes in selected genes were validated by QPCR and immunoblotting. Results: Three isogenic cell lines were developed and resistance to each drug or the combination of drugs was confirmed. Development of resistance was accompanied by a reduced growth rate. The microarray and QPCR analyses showed that unique changes in gene expression occurred in the dual drug resistant cell line and that genes known to be involved in resistance could be identified in all cell lines. Conclusions: Novel changes in gene expression can occur in the development of dual drug resistance, indicating that dual drug resistance is not a simple combination of the changes occurring in single agent resistance Carboplatin, docetaxel (GSE26129) and carboplatin/docetaxel dual resistant cell lines of ovarian A2780 were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with two replicate of both forward and reverse labellings for each cell line. Four arrays were used for this experiments. And it was four replicate of both forward and reverse labellings for A2780 cells. Eight arrays were used for this experiments
2013-07-22 | E-GEOD-39337 | biostudies-arrayexpress
Project description:Abstract Introduction Response rates to chemotherapy remain highly variable in breast cancer patients. We set out to identify genes associated with chemotherapy resistance. We analyzed what is currently the largest single-institute set of gene expression profiles derived from breast cancers prior to a single neoadjuvant chemotherapy regimen (dose-dense doxorubicine and cyclophophamide). Methods We collected, gene expression-profiled and analyzed 178 HER2-negative breast tumor biopsies (M-bM-^@M-^XNKI datasetM-bM-^@M-^Y). We employed a recently developed approach for detecting imbalanced differential signal (DIDS) in order to identify markers of resistance to treatment. In contrast to traditional methods, DIDS is able to identify markers that show aberrant expression in only a small subgroup of the non-responder samples. Results We found a number of markers of resistance to anthracycline-based chemotherapy. We validated our findings by the analysis of three external datasets, which contained 456 HER2-negative samples in total. Since these external sets included patients who received differing treatment regimens we could only validate markers of general chemotherapy resistance. There was a highly significant overlap in the markers identified in the NKI dataset and the other three datasets. Five resistance markers, SERPINA6, BEX1, AGTR1, SLC26A3, and LAPTM4B, were identified in three of the four datasets (p-value overlap <1e-6). These five genes identified resistant tumors that could not have been identified by merely taking ER-status or proliferation into account. Conclusion The identification of these genes might lead to a better understanding of the mechanisms involved in (clinically) observed chemotherapy resistance and could possibly assist in the recognition of breast cancers in which chemotherapy does not contribute to response or survival. We collected, gene expression profiled and analyzed 178 HER2-negative breast tumor biopsies, obtained from patients scheduled to undergo neoadjuvant therapy.
2012-12-01 | E-GEOD-34138 | biostudies-arrayexpress
Project description:Using single-cell RNA sequencing, we assessed the systemic impact of chemotherapy on tumor, stromal, and immune cells in the high-grade serous ovarian carcinoma. The results reveal remodeling of the T cell profiles towards a more naïve state and the upregulation of the epithelial-mesenchymal transition signatures in surviving tumor cells. These alterations suggest cellular and molecular targets for the therapeutic development in chemotherapy-resistant ovarian cancer.
2024-03-13 | GSE241221 | GEO
Project description:Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We developed in vitro ovarian cancer cell line models of acquired paclitaxel resistance using 2 immortalized human ovarian cancer cell lines, OVCAR3 and TOV-21G. We also developed in vitro primary ovarian cancer organoid models using tumor tissue from 7 patients with gynecologic malignancies. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing to identify potential mechanisms of paclitaxel resistance in primary ovarian cancer.
2021-07-02 | GSE172016 | GEO