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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:Richter Transformation (RT) develops in CLL as an aggressive, therapy-resistant, diffuse large B cell lymphoma (RT-DLBCL), commonly clonally-related (CLR) to the concomitant CLL. Lack of available pre-clinical human models has hampered the development of novel therapies for RT-DLBCL. Here, we report the profiles of genetic alterations, chromatin accessibility and active enhancers, gene-expressions and anti-lymphoma drug-sensitivity of three newly established, patient-derived, xenograft (PDX) models of RT-DLBCLs, including CLR and clonally-unrelated (CLUR) to concomitant 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, as well as increased sensitivity to BET protein inhibitors. CRISPR knockout of IRF4 attenuated c-Myc levels and increased sensitivity to a BET protein inhibitor. Co-treatment with BET inhibitor or BET-PROTAC and ibrutinib or venetoclax exerted synergistic in vitro lethality in the RT-DLBCL cells. Finally, as compared to each agent alone, combination therapy with BET-PROTAC and venetoclax significantly reduced lymphoma burden and improved survival of immune-depleted mice engrafted with CLR-RT-DLBCL. These findings highlight a novel, potentially effective therapy for RT-DLBCL.

| 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

A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL.

Project description:Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912.

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

Project description:Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting ~ 50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.

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