RNASeq of PDX and CDX tumours treated with ADC
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ABSTRACT:
PROVIDER: EGAS00001004562 | EGA |
REPOSITORIES: EGA
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Project description:Acquired drug resistance is the major therapeutic obstacle to maintenance treatment of advanced-stage non-small cell lung cancer. Lung adenocarcinoma (ADC) harboring driver mutations also showed poor response to immune checkpoint inhibitors (ICIs). Underlying mechanisms of how drug insensitivity evolves remain unclear. Here we explored the intratumoral heterogeneity of tyrosine kinase inhibitor (TKI)-resistant anaplastic lymphoma kinase (ALK)-rearranged lung ADC organoids using single-cell RNA-sequencing (scRNA-seq) transcriptomic analysis. IL-17 signaling pathway was found highly induced in a subpopulation of pre-existing ALK-TKI-resistant cells. These drug-tolerant persister (DTP) cells, also found to have high surface intracellular adhesion molecule 1 (ICAM-1) expression level, were more resistant towards ALK-TKI and expressed a higher level of cancer-stem cell transcriptional factors. Moreover, tumor cells with high ICAM-1 expression were found spatially correlated with RORɣt+ Th17 infiltration in ALK-rearranged NSCLC resected tumor tissues. In conclusion, our data revealed marked intratumoral heterogeneity in ALK-rearranged tumor, and pre-existing DTP cells may contribute to the development of drug insensitivity in ALK-rearranged lung ADC.
2023-08-09 | GSE223779 | GEO
Project description:The genomic studies was designed to identify genes differentially expressed in tumor versus normal breast tissue. We aimed at identifying novel Antibody Drug Conjugate (ADC) targets that could be used to treat Triple Negative Breast Cancer (TNBC). Comparative genomic studies between normal breast and TNBC tissues, together with proteomic and bioinformatic analyses resulted in the elaboration of a catalog of potential ADC targets.
2021-10-12 | GSE185645 | 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:It is gradually becoming a new aspect in research to search and explore embryo development for malignant information hidden in tumor cells. In this study, the gene expression profiles for human lungs at four developmental stages and lung adenocarcinoma (ADC) were depicted, respectively. The molecular dynamics was compared for development and lung ADC, and it was proposed that primary lung ADC may hijack part of the molecular mechanisms of lung development to down-regulate homeostasis-associated genes and up-regulate stemness-associated genes; and it was revealed that the genes with monotonely decreasing expression trend during lung development process are enriched with lung ADC prognostic information.
2014-08-25 | GSE43767 | GEO
Project description:Three subtypes of small cell/neuroendocrine bladder cancers (SCBCs) were identified: ASCL1, NEUROD1, and POU2F3. These subtypes are with neuroendocrine (NE) level, immune signature, and antibody-drug conjugate (ADC) target implications.
2024-06-13 | GSE269750 | GEO
Project description:No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
2021-11-11 | GSE188446 | GEO
Project description:Background: A gel-free proteomic approach was utilized to perform in-depth tissue protein profiling of lung adenocarcinoma (ADC) and normal lung tissues from early and advanced stages of the disease. The long-term goal of this study is to generate a large-scale, label-free proteomic data set from histologically well-classified lung ADC that can be used to increase further our understanding of disease progression and aid in identifying novel biomarkers. Methods and Results: Cases of early-stage (I-II) and advanced-stage (III-IV) lung ADCs were selected and paired with normal lung tissues from 22 patients. The histologically and clinically stratified human primary lung adenocarcinomas were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). From the analysis of ADC and normal specimens, 5,933 protein groups were identified. To examine the protein expression profile of ADC, a peak area-based quantitation method was used. In early- and advanced-stage ADC, 33 and 39 proteins were differentially-expressed respectively between normal and tumor tissue (adjusted p-value < 0.01, fold change ≥ 4). For early- and advanced stage ADC tumors compared to normal patient-matched tissue, 11 and 22 proteins and 23 and 16 proteins were identified as down- and up-regulated, respectively. In silico functional analysis of the up-regulated proteins in both tumor groups revealed that most of the enriched pathways are involved in mRNA metabolism. Furthermore, the most over-represented pathways in the proteins that were unique to ADC are related to mRNA metabolic processes. Conclusions: Further analysis of these data may provide an insight into the molecular pathways involved in disease etiology and may lead to the identification of biomarker candidates and potential targets for therapy. Our study provides potential diagnostic biomarkers for lung ADC and novel stage-specific drug targets for rational intervention.
2021-09-09 | PXD019259 | Pride
Project description:It is gradually becoming a new aspect in research to search and explore embryo development for malignant information hidden in tumor cells. In this study, the gene expression profiles for human lungs at four developmental stages and lung adenocarcinoma (ADC) were depicted, respectively. The molecular dynamics was compared for development and lung ADC, and it was proposed that primary lung ADC may hijack part of the molecular mechanisms of lung development to down-regulate homeostasis-associated genes and up-regulate stemness-associated genes; and it was revealed that the genes with monotonely decreasing expression trend during lung development process are enriched with lung ADC prognostic information. The study material for developing lung consisted of 29 cases of therapeutic or spontaneous abortion. The samples included whole embryos aged 3 to 5 weeks post ovulation (n = 10, named WholeE), lungs at 6 to 8 postovulatory weeks (PWs) (n = 10, named EarlyL) and lungs at 16 to 24 PWs (n = 9, named MiddleL). WholeE and EarlyL samples were carefully obtained from medical waste with the guidance of a Nikon stereo microscope SMZ1500 (Japan). MiddleL were collected when autopsies were performed. Embryo/Fetuses with known or suspected genetic disorders were excluded. Uninvolved peripheral lung tissue from adults (named MatureL) was obtained from fifteen patients operated on for benign lung diseases. 69 Lung ADC samples used for expression profiling analysis were obtained from patients. All these samples were examined with Agilent Whole Human Genome 4×44k microarray.
2014-08-25 | E-GEOD-43767 | biostudies-arrayexpress
Project description:Here we describe novel murine models of pulmonary adenocarcinoma (ADC) and sarcomatoid carcinoma (PSC) driven by the loss of two tumor suppressors: deletion of Trp53 and Pten. Combined deletion of Pten and Trp53 in the lungs of adult conditional mice leads to the development of both ADC and PSC irrespective of the lung targeted cell type or naphthalene induced airway epithelial regeneration. Although this model shows long latency periods and incomplete penetrance for tumor development, it is the first PSC mouse model reported so far, and sheds light on the relationships between ADC and PSC and their cells of origin. Moreover, human ADC show strong transcriptomic similarities to mouse PSC, providing a link between these tumor types and human ADC. Ablation of Trp53 and Pten in pulmonary cells was achieved by intratracheal administration of purified Ad5-CMVcre or Ad5-K5cre (Du Page et al, 2009) to Trp53F/F; PtenF/F 8–10 week old mice. Mice were sacrificed at different time points after the Ad5-cre infection and tumors processed for whole transcriptome analysis. As control animals, Trp53F/F; PtenF/F littermates were used.
2022-08-17 | GSE199905 | GEO
Project description:An orthotopic murine breast cancer model was created by transfecting the human HER2 gene into the breast cancer cell line EMT6 resulting in EMT6-hHER2. Previous in vivo tumor treatments with trastuzumab, trastuzumab-emtansine (T-DM1) and a novel antibody drug conjugate (ADC) T-PNU (provided by NBE therapeutics and carrying the highly potent anthracycline analogue PNU-159682) revealed that EMT6-hHER2 tumors are unresponsive to standard therapy treatments of trastuzumab and T-DM1, but respond well to the novel ADC T-PNU. Identifying immunogenic cell death properties of T-PNU, we postulated a therapeutic relevance for T-PNU mediated immune modulation of the tumor microenvironment. In order to identify the transcriptional pathways underlying the T-PNU anti-tumor response, we performed RNA-sequencing analysis of CD45+ tumor-derived cells from differently treated cohorts (untreated, trastuzumab, T-DM1, T-PNU; n=6).
2018-10-06 | GSE120888 | GEO