Dual-hit strategy for therapeutic targeting of pancreatic cancer in patient-derived xenograft tumors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA668382 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Paracrine activation of pro-fibrotic sonic hedgehog (sHH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of sHH-mediated tumor-stroma crosstalk with smoothened inhibitors transiently increases tumor permeability and macromolecule delivery. Using diffusion-weighted magnetic resonance (DW-MR) imaging, we demonstrate in multiple patient-derived xenografts (PDX) that responders to short-term sHH inhibitor exposure show increased permeability with proportionate increases in tumor diffusivity. However, a subset of PDXs fails to respond. Responders show co-induction of epithelial-mesenchymal transition (EMT), elevated FGF drive, and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1). A pan-FGFR inhibitor (NVP-BGJ398) reverses EMT and nuclear FGFR1 accumulation without compromising the tumor priming effect. This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical requirement for patient stratification
2023-12-12 | GSE159334 | GEO
Project description:The p53 protein is the most frequently inactivated tumor suppressor in human cancer. While p53 mutations are found in 50% of all cancers, the p53 pathway can also be suppressed by its interaction with endogenous inhibitors HDMX and HDM2, which are frequently overexpressed in patients with acute myeloid leukemia and other cancers. Thus, pharmacological disruption of both these interactions is an attractive strategy to restore p53-dependent tumor suppressor activity in AML with wild type P53. Strategies targeting HDM2 have recently generated promising results; however, cancer cells are still left vulnerable to p53 inhibition by HDMX, particularly in cancers such as leukemia that overexpress HDMX. In this study, we demonstrate that dual HDMX/HDM2 inhibition using a stapled alpha-helical peptide (ALRN-6924), which has recently entered clinical testing, leads to striking anti-leukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single cell and single molecule level, and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in a patient who received ALRN-6924 treatment. Dual HDMX/HDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patients’ cells, including in leukemic stem cell-enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 leads to significantly improved survival in an AML xenograft model in vivo. At the molecular level, dual HDMX/HDM2 inhibition leads to global transcriptional activation of p53-dependent pathways in leukemia cells. Our study provides insight into the effects of dual HDMX/HDM2 inhibition and proof-of-concept for ALRN-6924 as a novel therapeutic approach in AML and other cancers with high HDMX levels.
2018-05-24 | GSE99255 | GEO
Project description:Proteomic and phosphoproteomic characterization of 20 orthotopic patient-derived xenograft models of medulloblastoma
2022-09-01 | PXD035070 | Pride
Project description:Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated. Gene expression profiling experiments were conducted for 25 patient-derived xenograft glioblastoma samples using Affymetrix Human Gene 1.0 ST arrays according to manufacturer's protocol.
2014-06-12 | E-GEOD-58400 | biostudies-arrayexpress
Project description:Texas Pediatric Patient Derived Xenograft
| PRJNA939343 | ENA
Project description:Mass spectrometry profiling of orthotopically transplanted breast cancer patient-derived xenograft (PDX) tumors prior to chemotherapy treatment.
2022-12-06 | PXD035857 | Pride
Project description:To characterize the phenotype of human HIT T-cells endowed with a novel synthetic co-stimulatory molecule isolated from a mouse xenograft model compared to a control.
2024-01-10 | GSE223211 | GEO
Project description:It was our goal to discern the epigenomic signatures of the ventral hippocampus, in male and female mice in a double hit model of acute stress: one hit of acute restraint stress followed by forced swim stress one week later.
2022-06-20 | GSE200670 | GEO
Project description:Pleuropulmonary blastoma (PPB) is a rare pediatric lung neoplasm that recapitulates developmental pathways of early embryonic lungs. As lung development proceeds with highly regulated mesenchymal-epithelial interactions, a DICER1 mutation in PPB generates a faulty lung differentiation program with resultant biphasic tumors composed of a primitive epithelial and mesenchymal stroma with early progenitor blastomatous cells. Deciphering of PPB progression has been hampered by the difficulty of culturing PPB cells, and specifically progenitor blastomatous cells. Here we show that in contrast with in-vitro culture, establishment of PPB patient-derived xenograft (PDX) in NOD-SCID mice selects for highly proliferating progenitor blastoma overexpressing critical regulators of lung development and multiple imprinted genes. These stem-like tumors were sequentially interrogated by gene profiling to show a FGF module that is activated alongside Neural cell adhesion molecule 1 (NCAM1). Targeting the progenitor blastoma and these transitions with an anti-NCAM1 immunoconjugate (Lorvotuzumab-mertansine) inhibited tumor growth and progression providing new paradigms for PPB therapeutics. Altogether, we successfully establish a novel in-vivo model of PPB and uncover anti-NCAM1 as a potential therapeutic strategy for this aggressive malignancy.
2017-12-31 | GSE97236 | GEO
Project description:Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patient's surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated.
2014-06-12 | GSE58400 | GEO