Similar Datasets
Project description:Aberrant activation of PI3K pathway is frequently observed in triple negative breast cancer (TNBC). However single agent PI3K inhibitors have shown limited anti-tumor activity. To investigate biomarkers of response and resistance mechanisms, we tested 17 TNBC patient-derived xenograft (PDX) models representing diverse genomic backgrounds and varying degrees of PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor BKM120. Baseline and post-treatment PDX tumors harvested following 3 days of BKM120 or vehicle administration were subjected to reverse phase protein array (RPPA) to identify protein markers associated with tumor growth response. While BKM120 consistently reduced PI3K pathway activity, as demonstrated by reduced levels of phosphorylated AKT, percentage tumor growth inhibition (%TGI) ranged from 35% in the least sensitive to 84% in the most sensitive PDX model at the completion of approximately 3-4 weeks of treatment. Several biomarkers showed significant association with resistance, including elevated baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment-induced increase in the levels of phosphorylated forms of Aurora kinases. Sensitivity to BKM120 was associated with higher baseline levels of proapoptotic markers (Bak and Caspase 3) and a greater number of markers differentially changed following BKM120 therapy. Interestingly, markers indicating PI3K pathway signaling activation or PTEN loss at baseline were not significantly correlated to %TGI. These results provide important insights into biomarker development for PI3K inhibitors in TNBC.
2021-01-27 | GSE149720 | GEO
Project description:Aberrant activation of PI3K pathway is frequently observed in triple negative breast cancer (TNBC). However single agent PI3K inhibitors have shown modest anti-tumor activity. To investigate biomarkers of response, we tested 17 TNBC PDX models with diverse genetic and proteomic background, with varying PI3K pathway signaling activities for their tumor growth response to the pan-PI3K inhibitor BKM120 as well as baseline and treatment induced proteomic changes as assessed by reverse phase protein array (RPPA). We demonstrated that PI3K inhibition induces varying degrees of tumor growth inhibition (TGI), with 5 models demonstrating over 80% TGI. BKM120 consistently reduced PI3K pathway activity as demonstrated by reduced pAKT following therapy. Several biomarkers showed significant association with resistance, including baseline levels of growth factor receptors (EGFR, pHER3 Y1197), PI3Kp85 regulatory subunit, anti-apoptotic protein BclXL, EMT (Vimentin, MMP9, IntegrinaV), NFKB pathway (IkappaB, RANKL), and intracellular signaling molecules including Caveolin, CBP, and KLF4, as well as treatment induced increase in the levels of phosphorylated forms of Aurora kinases. Sensitivity was associated with higher baseline levels of proapoptotic markers (Bak and Caspase 3) and higher number of markers being changed following BKM120 therapy. Interestingly, markers indicating PI3K pathway signaling activation at baseline were not significantly correlated to %TGI. These results provide important insights in biomarker development for PI3K inhibitors in TNBC.
2020-12-31 | GSE148949 | GEO
Project description:The objective of this study was to analyze the mitochondrial mutations induced by chronic cigarette smoke extract treatment in human oral immortal OKF6 cells. The objective of this study was to analyze the mitochondrial mutations induced by chronic cigarette smoke extract treatment in human oral immortal OKF6 cells.
2011-02-10 | GSE24414 | GEO
Project description:We developed a novel antibody-drug conjugate (ADC), C6-EBET. To analyze mechanism of action of C6-EBET, we obtained bulk and single cell RNA-seq data of two patient-derived xenograft (PDX) models derived from pancreatic ductal adenocarcinoma (PDAC) patients. The two PDX models were treated with gemcitabine, C6-EBET or a non-targeting control ADC (HEL3-EBET), and then gene expression changes were analyzed with bulk RNA-seq. In addition, we characterized stromal cells of the two PDX models with scRNA-seq.
| EGAS00001007070 | EGA
Project description:End-stage breast cancers are clonally heterogeneous and harbor many poorly-understood treatment resistance mechanisms. We therefore established multiple Patient-Derived-Xenograft (PDX) models to study genomic events driving advanced disease. Comparative whole-genome sequencing of paired primary tumors and their PDX models demonstrated that PDX retain the vast majority of the structural variations and copy number aberrations seen within the originating tumor, and with high fidelity. Variant allele fractions (VAF) were preserved, even for rare mutations. Clonal representation is therefore a transplantable phenotype, indicating that genomic heterogeneity can be regulated in a tumor-autonomous mechanism, indifferent to host immune status. Mutations and gene rearrangements were documented in the ESR1 gene in three of five sequenced luminal PDX/progenitor tumor pairs (amplification, point mutation and translocation), and were associated with clinical endocrine response phenotypes, differential PDX estradiol responsiveness and all induced estradiol-independent growth in standard cell lines. PDX models are therefore a significant new tool for fundamental studies on the molecular basis for resistance to endocrine treatment in advanced breast cancer. reference x sample
2013-12-22 | E-GEOD-46604 | biostudies-arrayexpress
Project description:The objective of this study was to analyze the mitochondrial mutations induced by chronic cigarette smoke extract treatment in human oral immortal OKF6 cells. The objective of this study was to analyze the mitochondrial mutations induced by chronic cigarette smoke extract treatment in human oral immortal OKF6 cells. 2 samples were included, a control passaged human oral immortal OKF6 cells and cigarette smoke extract-treated OKF6 cells. The chronic treatment for cigarette smoke extract is 7 months. Genomic DNAs were extracted from both cells and then used for Affymetix MitoChip Version 2.0 analysis.
2011-02-10 | E-GEOD-24414 | biostudies-arrayexpress
Project description:The goal is the characterization of the off-target activity of BKM120 observed in A2058 human melanoma cell line at IC90 concentration (3.606 µM) but not at lower concentrations. Controls are BEZ235, GDC0941, showing no off-target activity. A secondary objective is the characterizations of drug effects on transcript expression with respect to a control treatment (DMSO) of those PI3K inhibitors. 3 compounds, 3 concentrations per compound treatment, DMSO control treatement, 4 biological replicates
2012-06-30 | E-GEOD-33643 | biostudies-arrayexpress
Project description:Microarrays were used to examine gene expression changes in patient derived tracheal basal cell lines after treatment with Lenti-SOX2. Comparisons were made between baseline, Lenti-SOX2 and Lenti-SOX2 with a PI3K inhibitor (BKM120).
2015-07-01 | GSE59866 | GEO
Project description:Objective of this study was to find changes in gene expression of mouse multiple myeloma cells upon treatment with IGF-1
2010-02-28 | GSE17140 | GEO
Project description:In this study, we aimed to investigate the gene expression changes associated with the development of paclitaxel resistance in patient-derived xenograft (PDX) models. We established paclitaxel-resistant PDX models in mice by administering 10 mg/kg of paclitaxel via intraperitoneal injection once a week. The treatment continued until the sixth generation of the PDX models was successfully established. RNA sequencing was performed on samples from the first generation (control and treated groups) and the sixth generation (control and treated groups) to identify differentially expressed genes and pathways involved in drug resistance. Our findings provide insights into the molecular mechanisms underlying paclitaxel resistance and may inform the development of more effective therapeutic strategies.
2024-08-10 | GSE272834 | GEO