Gene expression of peripheral blood cells reveals pathways downstream of glucocortoroid receptor antagonism and nab-paclitaxel treatment
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE268708 | GEO | 2024/08/28
REPOSITORIES: GEO
Similar Datasets
Project description:Whereas paclitaxel treatment is associated with leukopenia, the mechanisms that underlie this effect are not well-characterized. In addition, despite the importance of glucocorticoid signaling in cancer treatment, the genomic effects of glucocorticoid receptor antagonism by mifepristone treatment in primary human cells have never been described.As part of a randomized phase 1 clinical trial, we used microarrays to profile gene expression in peripheral blood cells sampled from each of four patients at baseline, after placebo/nanoparticle albumin-bound paclitaxel (nab-paclitaxel) treatment (cycle 1), and after mifepristone/nab-paclitaxel treatment (cycle 2).We found that 63 genes were differentially expressed following treatment with nab-paclitaxel, including multiple genes in the tubulin pathway. We also found 606 genes that were differentially expressed in response to mifepristone; genes downregulated by mifepristone overlapped significantly with those previously identified as being upregulated by dexamethasone.These results provide insights into the mechanisms of paclitaxel and glucocorticoid receptor inhibition in peripheral blood cells.
| S-EPMC4122588 | biostudies-literature
Project description:Gene expression of peripheral blood cells reveals pathways downstream of glucocortoroid receptor antagonism and nab-paclitaxel treatment
| PRJNA1118303 | ENA
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel has been added to the arsenal of first line therapies, and the combination of gemcitabine and nab-paclitaxel has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying nab-paclitaxel (n-PTX) resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naive PDAC patients. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the nab-paclitaxel-resistant cells. Depletion of c-Myc restored nab-paclitaxel sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small molecule activator of protein phosphatase 2a (SMAP). Implications: The strategies we have devised, including the patient-derived primary cells and the unique drug resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis
2019-05-31 | GSE131762 | GEO
Project description:Cell cycle inhibitors, including paclitaxel, are among the most widely used and effective cancer therapies. However, several challenges limit the success of paclitaxel including drug resistance and toxic side effects. Paclitaxel is thought to act primarily by stabilizing microtubules and locking cells in a mitotic state. However, the resulting cytotoxicity and tumor shrinkage rates observed cannot be fully explained by this mechanism alone. Here we apply quantitative chemical cross-linking with mass spectrometry analysis to paclitaxel treated cells. Our results provide large scale measurements of relative protein levels and, perhaps more importantly, changes to protein conformations and interactions that occur upon paclitaxel treatment. Drug concentration dependent changes are revealed in known drug targets including tubulins, as well as many other proteins and protein complexes involved in apoptotic signaling and cellular homeostasis. As such this study provides insight into systems-level changes to protein structures and interactions which occur with paclitaxel treatment.
2019-11-21 | PXD015751 | Pride
Project description:Primary outcome(s): 1) The distinction of the neuropathic disorder type by oxaliplatin, paclitaxel by the examination of nerve conduction and nab paclitaxel and the comparison.
2) The predictability of the examination using the examination of nerve conduction DPN check for the neuropathy with the chemotherapy of nerve conduction or the vibratory sensation examination using the tuning fork system and validity.
| 2613063 | ecrin-mdr-crc
Project description:Pancreatic adenocarcinoma is one of the most aggressive and lethal forms of cancer. Chemotherapy is the primary treatment for pancreatic cancer, but resistance to the drugs used remains a major challenge. A genome-wide CRISPR interference and knockout screen in the PANC-1 cell line with the drug nab-paclitaxel has identified a group of spindle assembly checkpoint (SAC) genes that enhance survival in nab-paclitaxel. Knockdown of these SAC genes (BUB1B, BUB3, and TTK) attenuates paclitaxel-induced cell death. Cells treated with the small molecule inhibitors BAY 1217389 or MPI 0479605, targeting the threonine tyrosine kinase (TTK), also enhance survival in paclitaxel. Overexpression of these SAC genes does not affect sensitivity to paclitaxel. These discoveries have helped to elucidate the mechanisms behind paclitaxel cytotoxicity. The outcomes of this investigation may pave the way for a deeper comprehension of the diverse responses of pancreatic cancer to therapies including paclitaxel. Additionally, they could facilitate the formulation of novel treatment approaches for pancreatic cancer.
2024-03-21 | GSE262149 | GEO
Project description:To investigate the impact of first-line treatment with gemcitabine/nab-paclitaxel/indoximod on the transcriptional profile of metastatic lesions in patients with pancreatic carcinoma, we collected tissue biopsies at pre- and post- (8wks) treatment and performed RNAseq.
2023-06-22 | GSE223463 | GEO
Project description:Aberrant tyrosine kinase activity can influence tumor growth and is regulated by phosphorylation. Pancreatic ductal adenocarcinoma (PDAC) is a very lethal disease, with minimal therapeutic options. We investigated phosphorylated kinases as target in PDAC. Mass spectrometry-based phosphoproteomic analysis was performed of PDAC cell lines to evaluate active kinases. Pathway analysis and inferred kinase activity was performed to identify novel targets. We investigated targeting of focal adhesion kinase in vitro with drug perturbations in combination with chemotherapeutics used against PDAC. Phosphoproteome analysis upon treatment was performed to evaluate signaling..PDAC cell lines portrayed high activity of multiple receptor tyrosine kinases. Non-receptor kinase, focal adhesion kinase (FAK), was identified in all cell lines by our phosphoproteomic screen and pathway analysis. Targeting of this kinase with defactinib validated reduced phosphorylation profiles. Additionally, FAK inhibition had anti-proliferative and anti-migratory effects. Combination with (nab-)paclitaxel had a synergistic effect on cell proliferation in vitro and reduced tumor growth in vivo. In conclusion, our study shows a high phosphorylation of several oncogenic receptor tyrosine kinases in PDAC cells and validated FAK inhibition as potential synergistic target with Nab-paclitaxel
2021-09-10 | PXD024548 | Pride
Project description:Tumor-stroma interactions are critical in pancreatic ductal adenocarcinoma (PDAC) progression and therapeutics. Patient-derived xenograft (PDX) models faithfully recapitulate tumor-stroma interactions in PDAC, but conventional antibody-based immunoassay is largely inadequate to resolve or quantify tumor and stromal proteins. A species-deconvolved proteomics approach embedded in the ultra-high-resolution (UHR)-IonStar workflow can unambiguously quantify the proteins from tumor (human-derived) and stroma (mouse-derived) in PDX samples, enabling unbiased investigation of their proteomes with excellent quantitative reproducibility. With this strategy, 3 PDAC PDXs were analyzed. They were showed differential responses to treatment with Gemcitabine combined with nab-Paclitaxel (GEM+PTX), which is a first-line treatment regimen for PDAC. For each PDAC PDX, samples were collected after 24 hour and 192 hour with/without treatment, and each condition contained four biological replicates.
2023-07-05 | PXD042267 | Pride
Project description:Acquired drug resistance represents a major challenge in chemo-therapy treatment for various types of cancers. We have found that the retinoid X receptorâselective agonist bexarotene (LGD1069, Targretin) was efficacious in treating chemo-resistant cancer cells. The goal of this microarray study was to understand the mechanism of bexaroteneâs role in overcoming acquired drug resistance using human breast cancer cells MDA-MB-231 as a model system and paclitaxel as model compound. After MDA-MB-231 cells were repeatedly treated with paclitaxel for 8 cycles with each cycle including a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium, MDA cells resistant to paclitaxel were developed and their growth was no longer inhibited by paclitaxel treatment. Those MDA cells with acquired drug resistance, when treated with paclitaxel and bexarotene in combination, could regain their sensitivity and their growth were again inhibited. Therefore, RNA samples from parental MDA-MB-231 cells, paclitaxel-resistant MDA cells treated with vehicle, paclitaxel alone or in combination with bexarotene, were used for perform global gene expression profiling with Affymetrix HG-U133A gene chips. Keywords: Drug Treatment MDA-MB-231 cells were exposed to regimens on a 10-day cycle: a 3-day treatment with 30 nM paclitaxel and followed by a 7-day exposure to control medium. Paclitaxel resistant MDA-MB-231 cells (MDA-PR) were established within 8 cycles of such treatment (80 days). These MDA-PR cells were then treated with vehicle control, paclitaxel along, or the combination of 30 nM paclitaxel ( 3 days on and 7 days off) and 1 µM Targretin (10 days on) in a new 10-day cycle for 3 months. Thus, there are four treatment groups, parent MDA cells, MDA-PR, MDA-PR treated with paclitaxel, MDA-PR treated with paclitaxel and bexarotene, and each group had four biological replicates.
2011-07-18 | E-GEOD-12791 | biostudies-arrayexpress