RNA-seq tumor immunome analysis of murine breast cancer model EMT6-hHER2 responsive to novel antibody drug conjugate T-PNU
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA494830 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
Project description:RPPA profiling of ES8 Ewing sarcoma xenografts after Endoglin-targeting antibody-drug conjugate treatments
| PRJNA472943 | ENA
Project description:Endoglin (EDG) is a cell surface protein with an important role in the establishment of neo-angiogenesis and vasculogenic mimicry. EDG is part of the transforming growth factor-β (TGF-β) family, acting as an important co-receptor. EDG is shed from the cell surface into the extracellular compartment by matrix metalloproteinase 14 (MMP14), in its soluble form (sEDG). Both transmembrane and soluble forms of EDG exert important signaling functions in the development of new blood vessels and tumour progression. To better understand the role of EDG in Ewing sarcoma (ES), a deadly neoplasm of late childhood and adolescence, we test the efficacy of OMTX703, an endoglin-targeting antibody-drug conjugate in ES8 xenograft. Having determined an optimal dose for OMTX703, an additional experiment was conducted to assess the mechanism(s) of OMTX703 action and its potential mechanism(s) of resistance following a 2-week exposure to OMTX703 at 0, 10, 30, and 60 mg/kg; 246 proteins were assessed by reverse-phase protein array (RPPA). Analysis of variance (ANOVA), Pearson’s correlation as distance metric and Ward’s linkage as the clustering method using a false discovery rate (FDR) of 0.01, identified 60 proteins that discriminated between treatment groups (Matrix#1-Normalized Values). To investigate the proteomic changes associated with the heightened clinical activity of the 60 mg/kg dose, a secondary analysis was performed, which grouped the 10 mg/kg OMTX703 samples and the 10 mg/kg OMTX003 ones with the placebo-treated samples (Matrix#2-Normalized Values). Using a FDR of 0.0001, an absolute log2 fold change of 1.5, Pearson’s correlation as distance metric and Ward’s linkage as the clustering method, 22 proteins were discriminately identified between the 3 treatment groups (Matrix#2-Normalized Values). Notably, a protein regulator of altered metabolism (RPS6) was exclusively upregulated following OMTX703 (60mg/kg), and a second metabolism biomarker (LDHA) was down-expressed in the 30 and 60 mg/kg-treated groups. Conversely, BRD4 was one of about a dozen proteins that were preferentially down-regulated in samples treated only by 60 mg/kg.
2018-12-31 | GSE114866 | GEO
Project description:Parallel genomic alterations of antigen and payload targets mediate polyclonal acquired clinical resistance to the antibody drug conjugate sacituzumab govitecan
| PRJNA754210 | ENA
Project description:Parallel genomic alterations of antigen and payload targets mediate polyclonal acquired clinical resistance to the antibody drug conjugate sacituzumab govitecan
| PRJNA754211 | ENA
Project description:Glucocorticoids are key component of the immuno-chemotherapy regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for the treatment of B-cell non-Hodgkin lymphoma (NHL). However, prolonged systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) engineered to reduce glucocorticoid-associated toxicity while possessing three distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced Fc-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven anti-tumor activity against multiple B-cell NHL cell lines in vitro as well as in cell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) in vivo. Remarkably, a single-dose of ABBV-319 induced sustained tumor regression and enhanced anti-tumor activity compared to repeat dosing of systemic prednisolone at the maximum tolerated dose (MTD) in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed anti-proliferative activity on a subset of B-cell lymphoma cell lines through the inhibition of PI3K signaling. Moreover, afucosylation of the CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), and this activity was maintained after conjugation with GRM payloads. Notably, ABBV-319 displayed superior efficacy compared to afucosylated CD19 mAb in human CD34+ PBMC-engrafted NSG-Tg(Hu-IL15) transgenic mice, demonstrating enhanced anti-tumor activity when different MOAs are combined. ABBV-319 also showed durable anti-tumor activity across multiple preclinical B-cell lymphoma models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing testing of ABBV-319 in Phase I clinical trial (NCT05512390)
2023-12-15 | GSE249542 | GEO
Project description:Glucocorticoids are key component of the immuno-chemotherapy regimens (e.g., R-CHOP, EPOCH-R, Hyper-CVAD) for the treatment of B-cell non-Hodgkin lymphoma (NHL). However, prolonged systemic glucocorticoid treatment is associated with several adverse events. ABBV-319 is a CD19-targeting antibody-drug conjugate (ADC) engineered to reduce glucocorticoid-associated toxicity while possessing three distinct mechanisms of action (MOA) to increase therapeutic efficacy: (1) antibody-mediated delivery of glucocorticoid receptor modulator (GRM) payload to activate apoptosis, (2) inhibition of CD19 signaling, and (3) enhanced Fc-mediated effector function via afucosylation of the antibody backbone. ABBV-319 elicited potent GRM-driven anti-tumor activity against multiple B-cell NHL cell lines in vitro as well as in cell line-derived xenografts (CDXs) and patient-derived xenografts (PDXs) in vivo. Remarkably, a single-dose of ABBV-319 induced sustained tumor regression and enhanced anti-tumor activity compared to repeat dosing of systemic prednisolone at the maximum tolerated dose (MTD) in mice. The unconjugated CD19 monoclonal antibody (mAb) also displayed anti-proliferative activity on a subset of B-cell lymphoma cell lines through the inhibition of PI3K signaling. Moreover, afucosylation of the CD19 mAb enhanced Fc-mediated antibody-dependent cellular cytotoxicity (ADCC), and this activity was maintained after conjugation with GRM payloads. Notably, ABBV-319 displayed superior efficacy compared to afucosylated CD19 mAb in human CD34+ PBMC-engrafted NSG-Tg(Hu-IL15) transgenic mice, demonstrating enhanced anti-tumor activity when different MOAs are combined. ABBV-319 also showed durable anti-tumor activity across multiple preclinical B-cell lymphoma models, including non-germinal center B-cell (GCB) DLBCL and relapsed lymphoma after R-CHOP treatment. Collectively, these data support the ongoing testing of ABBV-319 in Phase I clinical trial (NCT05512390)
2023-12-15 | GSE249023 | GEO
Project description:Deletion (Del) of 17p involving the TP53 tumor suppressor remains an adverse prognostic factor in multiple myeloma, and more effective targeted therapies are needed for these patients. Genomic studies revealed that del17p was associated with reduced copy number and mRNA expression of RNA polymerase II subunit alpha (POLR2A), which is located near TP53. We therefore studied HDP-101, an anti-B-cell maturation antigen (BCMA) antibody drug conjugate (ADC) with the POLR2A poison α-amanitin, which showed potent anti-proliferative and pro-apoptotic activity against cell lines and primary samples. POLR2A knockdown (KD) in both TP53 wild-type (WT) and knockout (KO) cells, with the latter being a model of del17p, enhanced sensitivity to HDP-101 compared to POLR2A WT cells. Gene expression profiling and proteomic studies showed evidence for activation of endoplasmic reticulum stress and the unfolded protein response, as well as a reduction of anti-apoptotic proteins such as Myeloid cell leukemia (MCL)-1. Bortezomib enhanced the activity of HDP-101, as did a gamma-secretase inhibitor, and this ADC overcame resistance both due to microenvironmental factors and in acquired drug resistance models. Finally, HDP-101 was well tolerated in vivo, reduced disease burden with single, 2-4 mg/kg doses, and no evidence of relapse was seen out to 100 days, even in xenografts that modeled del17p through dual TP53 KO/POLR2A KD, which grew more aggressively without treatment. Together, the data validate the efficacy of a new BCMA ADC that is ready for clinical translation, and suggest that it could be equipotent, or perhaps even more effective against myeloma with del17p. We used microarray to investigate the global changes caused by HDP-101 across p53 Wt and p53 KO multiple myeloma cell lines
2020-04-08 | GSE148242 | GEO
Project description:This is the first report evaluating the use of fluorescent imaging to determine the pharmacokinetics, lymphatic uptake, and bioavailability of a near-infrared dye-labeled antibody conjugate. Model is encoded by Matthew Roberts and submitted to BioModels by Krishna Tiwari
2020-03-05 | MODEL2003030003 | BioModels
Project description:Gene expression data from multiple myeloma cell lines treated with Novel Anti-B-cell Maturation Antigen α-Amanitin Antibody-drug Conjugate, HDP-101.
| PRJNA623567 | ENA