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Nab-paclitaxel induces DNA damage and inhibits M2 polarization of macrophages to achieve radiosensitization of cholangiocarcinoma cells.

ABSTRACT: Through transcriptome sequencing, it was determined that AMPK is a key pathway involved in the radiosensitization effect of nab-paclitaxel, and its sensitization effect may be attributed to ZMAT3 and NF- κB signaling pathway is closely related.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262746 | GEO | 2024/06/01

REPOSITORIES: GEO

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c-Myc drives nab-paclitaxel resistance in pancreatic cancer

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

A whole-genome CRISPR screen identifies the spindle accessory checkpoint as a locus of nab-paclitaxel resistance in pancreatic cancer cells.

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

c-Myc drives nab-paclitaxel resistance in pancreatic cancer

Project description:c-Myc drives nab-paclitaxel resistance in pancreatic cancer

| PRJNA544707 | ENA

Focal adhesion kinase inhibition synergizes with nab-paclitaxel to target pancreatic ductal adenocarcinoma

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

RNA-seq of tissue biopsies obtained from metastatic lesions of patients with treatment-naïve pancreatic carcinoma at pre- and post-treatment with gemcitabine/nab-paclitaxel/indoximod.

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

Distinct Transcriptional Landscapes Identified by Radiographic Response in Metastatic Triple-Negative Breast Cancer Treated with Carboplatin, Nab-Paclitaxel, and Pembrolizumab in a Single-Arm Phase II Trial

Project description:A single arm, Phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, and identify pathologic and transcriptomic correlates of response to therapy.

2023-10-19 | GSE241876 | GEO

Examination of the rating system of peripheral neuropathy by oxaliplatin, paclitaxel using the nerve conduction survey instrument and nab paclitaxel

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

Label-free proteomics quantification of pancreatic ductal adenocarcinoma patient-derived xenografts with treatment combining Gemcitabine and nab-Paclitaxel

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

Scheduling Nab-paclitaxel With Gemcitabine

Project description:Metastatic pancreatic cancer is difficult to treat. Until recently, most patients would be offered treatment with a chemotherapy drug called gemcitabine. However, a large international trial showed that combining gemcitabine with a drug called nab-paclitaxel (or abraxane) was more effective compared with gemcitabine alone. The purpose of this study is to compare two different ways of combining gemcitabine with abraxane. Conventionally, both drugs are given on the same day via a drip into a vein in the arm but research suggests that giving abraxane 24 hours in advance of gemcitabine could possibly be more beneficial. In this study, blood and tumour samples will be collected and analysed to try to confirm what has been seen in the laboratory studies. In addition, the investigators wish to find out whether certain tumour characteristics (called biomarkers) can be used to predict for response to chemotherapy.

| 2273237 | ecrin-mdr-crc

Phase 1 Study Combining Alisertib with Nab-Paclitaxel in Patients with Advanced Solid Malignancies (NCT01677559)

Project description:Phase 1 Study Combining Alisertib with Nab-Paclitaxel in Patients with Advanced Solid Malignancies (NCT01677559)

| PRJNA731485 | ENA