Immunologic adapatations of high grade serous ovarian cancer patients to neoadjuvant carboplatin and paclitaxel therapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE201600 | GEO | 2022/09/28
REPOSITORIES: GEO
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Project description:The impact of platinum and taxol based neoadjuvant chemotherapy on tumour-associated macrophages (TAMs) was examined by analysis of TAMs extracted from high grade serous ovarian cancer (HGSOC) samples pre and post chemotherapy.
2021-04-20 | GSE158739 | GEO
Project description:Platinum chemoresistance results in disease recurrence in patients with high-grade serous ovarian cancer (HGSOC). Recent advances in the treatment of solid tumours using checkpoint inhibitor immunotherapy has not benefited platinum-resistant HGSOC. Epigenetic silencing of genes involved in triggering cell death and apoptosis in HGSOC is known to occur via hypermethylation during development of platinum resistance. DNA methyltransferase (DNMT) inhibitors block methylation from occurring and allow silenced genes to be expressed. In ovarian cancer, DNMT inhibitors alter the epigenome and transcriptome of the tumours, which primarily affected expression of immune reactivation pathways. We aimed to determine the epigenome and transcriptome response to sequential treatment of HGSOC cells with DNMTi followed by standard-of-care carboplatin.
2022-02-02 | GSE169617 | GEO
Project description:Platinum chemoresistance results in disease recurrence in patients with high-grade serous ovarian cancer (HGSOC). Recent advances in the treatment of solid tumours using checkpoint inhibitor immunotherapy has not benefited platinum-resistant HGSOC. Epigenetic silencing of genes involved in triggering cell death and apoptosis in HGSOC is known to occur via hypermethylation during development of platinum resistance. DNA methyltransferase (DNMT) inhibitors block methylation from occurring and allow silenced genes to be expressed. In ovarian cancer, DNMT inhibitors alter the epigenome and transcriptome of the tumours, which primarily affected expression of immune reactivation pathways. We aimed to determine the epigenome and transcriptome response to sequential treatment of HGSOC cells with DNMTi followed by standard-of-care carboplatin.
2022-02-02 | GSE168225 | GEO
Project description:While high-grade serous ovarian carcinoma (HGSOC) is the most common histological subtype of ovarian cancer, significant tumor heterogeneity exists. In addition, chemotherapy induces changes in gene expression and alters the mutational profile. To evaluate the notion that patients with HGSOC could be better classified for optimal treatment based on gene expression, we compared genetic variants (by DNA next-generation sequencing [NGS] using a 50 gene Ion Torrent panel) and gene expression (using the NanoString® PanCancer 770 gene Panel) in the tumor from 20 patients with HGSOC before and after neoadjuvant chemotherapy (NACT). NGS was performed on plasma cell free DNA (cfDNA) on a select group of patients (n=14) in order to assess the utility of using cfDNA to monitor these changes. A total of 86 genes had significant changes in RNA expression after NACT. Thirty-eight genetic variants (including SNPs) from 6 genes were identified in tumors pre-NACT, while 59 variants from 19 genes were detected in the cfDNA. The number of DNA variants were similar after NACT. Of the 59 variants in the plasma pre-NACT, only 6 persisted; whereas 33 of 38 specific variants in the tumor DNA remained unchanged. Pathway analysis showed the most significant alterations in the cell cycle and DNA damage pathways.
2018-02-01 | GSE109934 | GEO
Project description:Our data suggest that neoadjuvant chemotherapy enhances anti-cancer responses of T cells in peritoneal metastases of patients with high-grade serous ovarian cancer but does not decrease levels of immune checkpoint molecules, providing a rationale for sequential chemo-immunotherapy. tRNA was isolated from 35 omental tissue samples of HGSOC metastases either pre or post NACT treatment. RNASeq was performed on poly-A selected mRNA fragments, 100 b.p paired end, and strand specific, on average 40 million reads per sample.
2016-07-27 | E-GEOD-71340 | biostudies-arrayexpress
Project description:In the present project, in order to explore the molecular basis of platinum resistance and further determine potential biomarkers and therapeutic targets for high-grade serous ovarian cancer (HGSOC), we conducted a comparative proteomic analysis to identify the differentially expressed proteins between tumor tissues from platinum-sensitive and platinum-resistant HGSOC patient groups.
2021-09-30 | PXD028225 | iProX
Project description:Platinum-based chemotherapies are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). To understand mechanisms of platinum resistance and identify potential therapeutic targets in resistant HGSOC, we generated a comprehensive, reproducible data resource comprised of dynamic (+/-carboplatin) proteomic/posttranslational modification and RNASeq profiles from HGSOC intra-patient cell line pairs derived from 3 patients before and after acquiring platinum resistance. The molecular profiles revealed extensive responses to carboplatin and differential responses between sensitive and resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that both pharmacologic inhibition and CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO is a candidate therapeutic target to overcome platinum resistance.
2022-01-04 | GSE163152 | GEO
Project description:Optimal cytoreduction to no residual disease (R0) correlates with improved disease outcome in the management of high-grade serous ovarian cancer (HGSOC) patients. Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) offers an alternate approach to management of HGSOC patients to achieve complete resection. This study assessed proteomic alterations in matched, chemotherapy naïve and NACT-treated patients tumors obtained from HGSOC patients with suboptimal (R1) versus optimal (R0) debulking at IDS. We describe distinct proteome profiles in pre- and post-NACT HGSOC tumors correlating with residual disease status providing prognostic biomarkers for residual disease at IDS as well as candidate proteins associated with NACT resistance warranting further pre-clinical investigation.
2022-10-05 | PXD031929 | Pride
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:Introduction: Although High Grade Serous Ovarian Cancer (HGSOC) is considered a chemo-responsive disease, a proportion of patients do not respond to platinum-based chemotherapy at presentation or have progression-free survival of <6 months. Validated biomarkers of lack of response would enable alternative treatment stratification for these patients and identify novel mechanisms of resistance. Methods: Differential DNA methylation was investigated in independent tumour sets using Illumina 27K HumanMethylation arrays and validated by bisulphite pyrosequencing. Gene expression was by Affymetrix arrays and qRT-PCR. The role of Msh homeobox 1 (MSX1) in drug sensitivity was investigated by gene reintroduction into ovarian cancer cell lines. Results: CpG sites at contiguous genomic locations within the MSX1 gene have significantly lower levels of methylation in HGSOC which recur by 6 months compared to after 12 months and/or with RECIST response (p<0.05, q<0.05). A decrease in methylation at these intragenic CpG sites was significantly correlated with decreased MSX1 gene expression. Low expression of MSX1 was associated with poor progression-free survival independent of known clinical prognostic features (p=0.014). Three mutant or wild-type TP53 expressing ovarian cancer cell lines, resistant to cisplatin, have reduced MSX1 expression compared to matched parental, platinum sensitive, lines. Re-expression of MSX1 in resistant lines led to cisplatin sensitisation, increased apoptosis, increased p21 and BAX expression. However, in two TP53-null cell lines, MSX1 failed to change cisplatin sensitivity. Conclusion: Hypomethylation of MSX1 is a biomarker of resistant HGSOC disease at presentation and identifies a novel mechanism of platinum drug resistance. Bisulphite converted DNA from the 86 samples were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2
2015-11-26 | E-GEOD-75414 | biostudies-arrayexpress