Apoptosis enhancing drugs overcome innate platinum resistance in CA125 negative tumor initiating populations of high grade serous ovarian cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE70072 | GEO | 2015/08/01
SECONDARY ACCESSION(S): PRJNA287643
REPOSITORIES: GEO
Similar Datasets
Project description:High grade serous ovarian cancers (HGSC) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSCs contain a CA125 negative population enriched for carboplatin resistant cancer initiating cells. Transcriptome analysis reveals up-regulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125 negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125 negative population. Birinapant sensitizes CA125 negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase-8 and restoration of apoptosis. This co-therapy significantly improved disease free survival in vivo compared to either therapy alone in tumor-bearing mice. These findings suggest that therapeutic strategies that target CA125 negative cells may be useful in the treatment of HGSC. mRNA profiles of CA125 positive and negative populations, generated by next generation sequencing of populations FACS isolated from 10 independent dissociated primary human high grade serous ovarian cancers, were compared.
2015-08-01 | E-GEOD-70072 | biostudies-arrayexpress
Project description:High grade serous ovarian cancers (HGSC) are deadly malignancies that relapse despite carboplatin chemotherapy. Many commercially ovarian cancer cell lines are not good models for HGSC. Here we demonstrate that 3 low passage cell lines derived from HGSC have similar transcriptomes to their parental bulk tumors. These cell lines recapitulated tumor characteristics of the primary cancer and had responded to therapy in the same manner as primary HGSC cells, demonstrating they are accurate models for HGSCs. mRNA profiles of low passage high grade serous tumor cell lines and their parental tumors, generated by next generation sequencing, were compared.
2015-08-01 | E-GEOD-70073 | biostudies-arrayexpress
Project description:High grade serous ovarian cancers (HGSC) are deadly malignancies that relapse despite carboplatin chemotherapy. Many commercially ovarian cancer cell lines are not good models for HGSC. Here we demonstrate that 3 low passage cell lines derived from HGSC have similar transcriptomes to their parental bulk tumors. These cell lines recapitulated tumor characteristics of the primary cancer and had responded to therapy in the same manner as primary HGSC cells, demonstrating they are accurate models for HGSCs.
2015-08-01 | GSE70073 | GEO
Project description:Migration of human glioma stem cells (hGSCs) within the brain parenchyma makes glioblastoma one of the most aggressive and lethal tumors. Studies of the cellular and molecular mechanisms underlying hGSC migration are hindered by the limitations of existing migration models. Here we developed a dorsal root ganglion axon-oligodendrocyte-hGSC co-culture to study in real time the migration and interaction of hGSCs with their microenvironment. hGSCs interact with myelinated and non-myelinated axons through the formation of pseudopodia. Isolation of pseudopodia-localized polysome-bound RNA reveals transcripts of Lck, Paxillin, Crk-II and Rac1 that undergo local translation. Inhibition of Lck blocks the activation of this pathway, the formation of pseudopodia and the migration of hGSCs. In vivo intraventricular administration of a Lck inhibitor using an orthotopic xenograft mouse model results in significant inhibition of tumor growth and significant down-regulation of stemness gene expression. Targeting this Lck pathway constitutes a novel treatment paradigm for human glioblastomas.
2018-06-01 | GSE95289 | GEO
Project description:The current paradigm in the development of high-grade serous carcinomas (HGSCs) proposes that the majority of HGSCs arise from precursor serous tubal intraepithelial carcinoma (STIC) lesions of the fallopian tube. The goal of this study is to identify genomic regions that exhibit high-specificity differential hypermethylation for potential use as biomarkers for detecting STIC and HGSC at stages when curative intervention likely remains feasible.
2020-07-29 | GSE155311 | GEO
Project description:Tumorigenesis for most high-grade serous ovarian cancers (HGSCs) likely initiates from fallopian tube (FT) epithelia. While epithelial subtypes have been characterized using single-cell RNA-sequencing (scRNA-Seq), heterogeneity of other cellular compartments and their involvement in tumor progression are poorly defined. Integrated analysis of human FT scRNA-Seq data and other relevant tissues, including HGSC tumors, revealed greater transcriptional diversity of immune and stromal cells. We identify an unprecedented abundance of monocytes in human FT myeloid cells across two independent donor cohorts. The ratio of macrophages to monocytes are relatively similar between benign FTs, ovaries, and adjacent normal tissues, but is significantly greater in tumor. FT-defined monocyte and macrophage signatures, cell-cell communication, and gene set enrichment analysis identified monocyte- and macrophage-specific ligand-receptor interactions and functional pathways in tumors and adjacent normal tissue. Further reanalysis of tumor scRNA-Seq from HGSC patients suggested different monocyte and macrophage subsets associated with neoadjuvant chemotherapy treatment. Taken together, our work provides evidence that an altered FT immune composition could inform early detection markers in HGSCs.
2024-03-07 | GSE233615 | GEO
Project description:Zhu2015 - combined gemcitabine and birinapant
in pancreatic cancer cells - mechanistic PD model
Mechanistic mathematical model to
illustrate the effectiveness of combination chemotherapy involving
gemcitabine and birinapant against pancreatic cancer.
This model is described in the article:
Mechanism-based mathematical
modeling of combined gemcitabine and birinapant in pancreatic
cancer cells.
Zhu X, Straubinger RM, Jusko
WJ.
J Pharmacokinet Pharmacodyn 2015 Oct;
42(5): 477-496
Abstract:
Combination chemotherapy is standard treatment for
pancreatic cancer. However, current drugs lack efficacy for
most patients, and selection and evaluation of new combination
regimens is empirical and time-consuming. The efficacy of
gemcitabine, a standard-of-care agent, combined with
birinapant, a pro-apoptotic antagonist of Inhibitor of
Apoptosis Proteins (IAPs), was investigated in pancreatic
cancer cells. PANC-1 cells were treated with vehicle,
gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and
combinations of the two drugs. Temporal changes in cell
numbers, cell cycle distribution, and apoptosis were measured.
A basic pharmacodynamic (PD) model based on cell numbers, and a
mechanism-based PD model integrating all measurements, were
developed. The basic PD model indicated that synergistic
effects occurred in both cell proliferation and death
processes. The mechanism-based model captured key features of
drug action: temporary cell cycle arrest in S phase induced by
gemcitabine alone, apoptosis induced by birinapant alone, and
prolonged cell cycle arrest and enhanced apoptosis induced by
the combination. A drug interaction term Ψ was employed in
the models to signify interactions of the combination when data
were limited. When more experimental information was utilized,
Ψ values approaching 1 indicated that specific mechanisms
of interactions were captured better. PD modeling identified
the potential benefit of combining gemcitabine and birinapant,
and characterized the key interaction pathways. An optimal
treatment schedule of pretreatment with gemcitabine for 24-48 h
was suggested based on model predictions and was verified
experimentally. This approach provides a generalizable modeling
platform for exploring combinations of cytostatic and cytotoxic
agents in cancer cell culture studies.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000669.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000669 | BioModels
Project description:Zhu2015 - Combined gemcitabine and birinapant
in pancreatic cancer cells - basic PD model
Mathematical model to illustrate the
effectiveness of combination chemotherapy involving gemcitabine and
birinapant against pancreatic cancer.
This model is described in the article:
Mechanism-based mathematical
modeling of combined gemcitabine and birinapant in pancreatic
cancer cells.
Zhu X, Straubinger RM, Jusko
WJ.
J Pharmacokinet Pharmacodyn 2015 Oct;
42(5): 477-496
Abstract:
Combination chemotherapy is standard treatment for
pancreatic cancer. However, current drugs lack efficacy for
most patients, and selection and evaluation of new combination
regimens is empirical and time-consuming. The efficacy of
gemcitabine, a standard-of-care agent, combined with
birinapant, a pro-apoptotic antagonist of Inhibitor of
Apoptosis Proteins (IAPs), was investigated in pancreatic
cancer cells. PANC-1 cells were treated with vehicle,
gemcitabine (6, 10, 20 nM), birinapant (50, 200, 500 nM), and
combinations of the two drugs. Temporal changes in cell
numbers, cell cycle distribution, and apoptosis were measured.
A basic pharmacodynamic (PD) model based on cell numbers, and a
mechanism-based PD model integrating all measurements, were
developed. The basic PD model indicated that synergistic
effects occurred in both cell proliferation and death
processes. The mechanism-based model captured key features of
drug action: temporary cell cycle arrest in S phase induced by
gemcitabine alone, apoptosis induced by birinapant alone, and
prolonged cell cycle arrest and enhanced apoptosis induced by
the combination. A drug interaction term Ψ was employed in
the models to signify interactions of the combination when data
were limited. When more experimental information was utilized,
Ψ values approaching 1 indicated that specific mechanisms
of interactions were captured better. PD modeling identified
the potential benefit of combining gemcitabine and birinapant,
and characterized the key interaction pathways. An optimal
treatment schedule of pretreatment with gemcitabine for 24-48 h
was suggested based on model predictions and was verified
experimentally. This approach provides a generalizable modeling
platform for exploring combinations of cytostatic and cytotoxic
agents in cancer cell culture studies.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000668.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000668 | BioModels
Project description:High grade serous ovarian carcinoma (HGSC) is the most common and lethal subtype of gynecologic malignancy in women. The current standard of treatment combines cytoreductive surgery and chemotherapy. Despite the efficacy of initial treatment, most patients develop cancer recurrence, and 70% of patients die within 5-years of initial diagnosis. CA125 is the current FDA-approved biomarker used in the clinic to monitor response to treatment and recurrence. Although increasing levels of CA125 precede clinical symptoms of recurrence, often second-look surgeries often reveal microscopic and macroscopic tumors present during remission. Here, we describe a novel strategy for the discovery of serum biomarkers aimed at earlier detection of cancer recurrence. We combined HGSC patient-derived xenograft models, chemoproteomic enrichment of N-glycosylated peptides and systematic development of targeted proteomics assays for rapid biomarker identification and orthogonal verification. The verification of candidates in two independent, longitudinal serum cohorts from HGSC patients (n=96 serum samples) identified four novel biomarker candidates for earlier detection of HGSC recurrence.
2018-08-27 | MSV000082853 | MassIVE
Project description:Despite decades of effort, pancreatic adenocarcinoma (PDAC) remains an intractable clinical challenge. An insufficient understanding of mechanisms underlying tumor cell responses to chemotherapy contributes significantly to the lack of effective treatment regimens. Here, paclitaxel, a first-line chemotherapeutic agent, was observed to interact synergistically with birinapant, a Second Mitochondrial-derived Activator of Caspases mimetic. Therefore, we investigated molecular-level drug interaction mechanisms using comprehensive, reproducible, and well-controlled ion-current-based MS1 quantification (IonStar). In a set of 40 biological samples, we compared temporal proteomic responses of PDAC cells treated with birinapant and paclitaxel, alone and combined. Using stringent criteria (e.g. strict false-discovery-rate FDR control, 2 peptides/protein), we quantified 4069 unique proteins confidently (99.8% without any missing data), and 541 proteins were significantly altered in the three treatment groups with a FDR of <1%. Interestingly, most of these proteins were altered only by combined birinapant/paclitaxel, and these predominantly represented three biological processes: mitochondrial function, cell growth and apoptosis, and cell cycle arrest. Proteins responsible for activation of oxidative phosphorylation, fatty acid β-oxidation, and inactivation of aerobic glycolysis were altered largely by combined birinapant/paclitaxel compared to single drugs, suggesting that the Warburg effect, which is employed by PDAC cells for survival and proliferation, was alleviated by the combination treatment. Metabolic profiling confirmed substantially greater suppression of the Warburg effect by the combined agents compared to either drug alone. Western blot analysis confirmed changes in apoptosis/survival signaling pathways, such as inhibition of PI3K/AKT, JAK/STAT, and MAPK/ERK signal transduction, as well as induction of G2/M arrest, and the drug combination induced much more apoptosis than did single agents. Overall, this in-depth, large-scale proteomics study provided novel insights into molecular mechanisms underlying synergy of combined birinapant/paclitaxel, and describes a proteomics/informatics pipeline that can be applied broadly to the development of cancer drug combination regimens.
2018-01-29 | PXD007890 | Pride