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Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154463 | GEO | 2021/08/26

REPOSITORIES: GEO

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BET proteolysis targeted chimera-based therapy of novel models of Richter Transformation-diffuse large B-cell lymphoma.

Project description: Not available

| S-EPMC8410602 | biostudies-literature

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [RNA-Seq]

Project description:RichterTransformation (RT) develops in CLL as an aggressive, therapy resistant diffuse large B cell lymphoma (RT-DLBCL), commonly clonally related (CLR) to the antecedent CLL. Lack of available pre-clinical models has hampered development of novel therapies for RT-DLBCL. Here,we report the profiles of genetic alterations, active enhancers, gene-expressions and anti-lymphoma drug-sensitivity patterns of first-ever established, patient-derived xenograft models of RT-DLBCLs, including CLR and clonally unrelated (CLUR) to antecedent CLL. The CLR and CLUR RT-DLBCL cells display active enhancers, higher single-cell RNA-Seq-determined mRNA, and protein-expressions of IRF4, TCF4 and BCL2. This correlated with higher sensitivity to BET inhibitor and BET-PROTAC-based combinations with ibrutinib or venetoclax, including improved in vivo tumor burden and survival in the PDX model of CLR-RT-DLBCL.

2021-08-26 | GSE154462 | GEO

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ChIP-Seq]

2021-08-26 | GSE154457 | GEO

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ATAC-Seq]

2021-08-26 | GSE154456 | GEO

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma

Project description:Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma

| PRJNA646378 | ENA

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ChIP-Seq]

Project description:Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ChIP-Seq]

| PRJNA646372 | ENA

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ATAC-Seq]

Project description:Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [ATAC-Seq]

| PRJNA646373 | ENA

Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [RNA-Seq]

Project description:Efficacy of BET protein proteolysis targeted chimera-based combinations against novel patient-derived models of Richter Transformation-Diffuse Large B-Cell Lymphoma [RNA-Seq]

| PRJNA646385 | ENA

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy.

Project description: Not available

| S-EPMC7218526 | biostudies-literature

BET protein proteolysis targeting chimera (PROTAC) exerts potent lethal activity against Mantle Cell Lymphoma cells

Project description:Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells. BET-PROTACs induce more apoptosis than BETi of MCL cells, including those resistant to ibrutinib. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi, with depletion of c-Myc, CDK4, cyclin D1, and the NFkB transcriptional targets Bcl-xL, XIAP and BTK, while inducing the level of HEXIM1, NOXA and CDKN1A/p21. Treatment with ARV-771, which possesses superior pharmacological properties compared to ARV-825, inhibited the in vivo growth and induced greater survival improvement than the BETi OTX015 of immune-depleted mice engrafted with MCL cells. Co-treatment of ARV-771 with ibrutinib or the BCL2-antagonist venetoclax or CDK4/6 inhibitor palbociclib synergistically induced apoptosis of MCL cells. These studies highlight promising and superior pre-clinical activity of BET-PROTAC than BETi, requiring further in vivo evaluation of BET-PROTAC as a therapy for ibrutinib-sensitive or resistant MCL.

2019-04-26 | GSE98268 | GEO

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