Genomic and Epigenomic Signatures of Platinum Re-sensitization in ovarian cancer
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ABSTRACT:
PROVIDER: PRJNA396728 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic changes, particularly DNA methylation aberrations have been implicated in acquired resistance to platinum in ovarian cancer. A multi-institutional randomized clinical trial compared a regimen of a DNA methyl transferase (DNMT) inhibitor guadecitabine and carboplatin to physician’s choice chemotherapy for patients with recurrent platinum resistant ovarian cancer. Tumor biopsies or malignant ascites were collected at day 1 of cycle 1 (pre-guadecitabine) and after two cycles of treatment (post-decitabine). The goal of the current study was to analyze guadecitabine-induced DNA methylation and gene expression changes and correlate pretreatment levels with clinical outcomes. Epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450) and RNA sequencing revealed extensive methylation and gene expression changes induced by guadecitabine in ovarian tumors. Ninety-four gene promoters were significantly hypomethylated after treatment with guadecitabine and 949 genes were differentially expressed in pre vs. post-treatment tumors. Pathways associated with immune reactivation and DNA repair were significantly altered by guadecitabine treatment. Expression levels of 1155 genes involved in 25 networks on day 1 of cycle 1 correlated with progression free survival. Increased expression of selected genes (e.g. DOK2, miR193a) silenced through promoter methylation restored platinum sensitivity in ovarian cancer cells. Together, these results support that guadecitabine altered DNA methylation and expression of genes and gene networks correlate with re-sensitization to carboplatin in ovarian cancer patients.
2018-06-05 | GSE102118 | GEO
Project description:Epigenetic changes, particularly DNA methylation aberrations have been implicated in acquired resistance to platinum in ovarian cancer. A multi-institutional randomized clinical trial compared a regimen of a DNA methyl transferase (DNMT) inhibitor guadecitabine and carboplatin to physician’s choice chemotherapy for patients with recurrent platinum resistant ovarian cancer. Tumor biopsies or malignant ascites were collected at day 1 of cycle 1 (pre-guadecitabine) and after two cycles of treatment (post-decitabine). The goal of the current study was to analyze guadecitabine-induced DNA methylation and gene expression changes and correlate pretreatment levels with clinical outcomes. Epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450) and RNA sequencing revealed extensive methylation and gene expression changes induced by guadecitabine in ovarian tumors. Ninety-four gene promoters were significantly hypomethylated after treatment with guadecitabine and 949 genes were differentially expressed in pre vs. post-treatment tumors. Pathways associated with immune reactivation and DNA repair were significantly altered by guadecitabine treatment. Expression levels of 1155 genes involved in 25 networks on day 1 of cycle 1 correlated with progression free survival. Increased expression of selected genes (e.g. DOK2, miR193a) silenced through promoter methylation restored platinum sensitivity in ovarian cancer cells. Together, these results support that guadecitabine altered DNA methylation and expression of genes and gene networks correlate with re-sensitization to carboplatin in ovarian cancer patients.
2018-06-05 | GSE102119 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-06-05 | GSE102120 | GEO
Project description:DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients.Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. Cancer Res; 78(3); 631-44. ©2017 AACR.
| S-EPMC5811373 | biostudies-literature
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:Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, particularly epithelial ovarian cancer. After initial response, patients often experience several response-relapse events, until tumors start to resist the treatment. Resistant patients have low response rate to other chemotherapy regimens, with life expectancy of 12-15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, and no novel drugs have been approved for resistant disease. By investigating the functional link between metabolic adaptations and resistance, we discovered that resistant cells modify their serine metabolism and acquire a specific NAD+ generating phenotype, which allows them to sustain PARP activity under treatment. Our findings reveal a novel metabolic vulnerability of resistant tumors that might have an immediate clinical implication, showing that ex vivo patient derived resistant models can be re-sensitized to platinum by combining it with PARP inhibition.
2022-05-16 | GSE176218 | 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:Using platinum-resistant OVCAR-3 cells treated with the selective mTORC1/2 inhibitor INK128/MLN128, we conducted genome-wide transcription and translation studies and analyzed the effect on cell proliferation, AKT-mTOR signaling and cell survival, to determine whether carboplatin resistance involves selective mRNA translational reprogramming, and whether it is sensitive to mTORC1/2 inhibitio.n
2018-07-31 | GSE116387 | GEO