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ABSTRACT:
PROVIDER: PRJEB53800 | ENA |
REPOSITORIES: ENA
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Project description:Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2’-deoxycytidine (5-Aza-2’) enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1. Here, we combine SUMOylation inhibitor TAK981 and DNA-hypomethylating agent 5-Aza-2’ to improve treatment of MYC driven hematopoietic malignancies, since MYC overexpressing tumors are sensitive to SUMOylation inhibition. We studied the classical MYC driven malignancy Burkitt lymphoma, as well as diffuse large B-cell lymphoma (DLBCL) with and without MYC translocation. SUMO inhibition prolonged the entrapment of DNMT1 to DNA, resulting in DNA damage. An increase in DNA damage was observed in cells co-treated with TAK981 and 5-Aza-2’. Both drugs synergized to reduce cell proliferation in vitro in a B cell lymphoma cell panel, including Burkitt lymphoma and DLBCL. In vivo experiments combining TAK981 (25 mg/kg) and 5-Aza-2’ (2.5 mg/kg) showed a significant reduction in outgrowth of Burkitt lymphoma in an orthotopic xenograft model. In contrast, single dosing of TAK981 was ineffective and single dosing of 5-Aza-2’ only led to a modest outgrowth reduction. TAK981 and 5-Aza-2’ synergize to reduce B cell Lymphoma outgrowth in vitro and in vivo. SUMOylation is a key-player in the repair of DNA damage, hence upon TAK981 treatment the repair of DNA damage induced by 5-Aza-2’ treatment is impaired. Our results demonstrate the potential of tailored combination of drugs, based on insight in molecular mechanisms, to improve the efficacy of cancer therapies.
2023-03-17 | PXD038620 | Pride
Project description:Combination therapies targeting malignancies aim to increase treatment efficacy and reduce toxicity. Hypomethylating drug 5-Aza-2’-deoxycytidine (5-Aza-2’) enhances transcription of tumor suppressor genes and induces replication errors via entrapment of DNMT1. Post-translational modification by SUMO plays major roles in the DNA damage response and is required for degradation of entrapped DNMT1. Here, we combine SUMOylation inhibitor TAK981 and DNA-hypomethylating agent 5-Aza-2’ to improve treatment of MYC driven hematopoietic malignancies, since MYC overexpressing tumors are sensitive to SUMOylation inhibition. We studied the classical MYC driven malignancy Burkitt lymphoma, as well as diffuse large B-cell lymphoma (DLBCL) with and without MYC translocation. SUMO inhibition prolonged the entrapment of DNMT1 to DNA, resulting in DNA damage. An increase in DNA damage was observed in cells co-treated with TAK981 and 5-Aza-2’. Both drugs synergized to reduce cell proliferation in vitro in a B cell lymphoma cell panel, including Burkitt lymphoma and DLBCL. In vivo experiments combining TAK981 (25 mg/kg) and 5-Aza-2’ (2.5 mg/kg) showed a significant reduction in outgrowth of Burkitt lymphoma in an orthotopic xenograft model. In contrast, single dosing of TAK981 was ineffective and single dosing of 5-Aza-2’ only led to a modest outgrowth reduction. TAK981 and 5-Aza-2’ synergize to reduce B cell Lymphoma outgrowth in vitro and in vivo. SUMOylation is a key-player in the repair of DNA damage, hence upon TAK981 treatment the repair of DNA damage induced by 5-Aza-2’ treatment is impaired. Our results demonstrate the potential of tailored combination of drugs, based on insight in molecular mechanisms, to improve the efficacy of cancer therapies.
2023-03-17 | PXD038617 | Pride
Project description:Study of a mouse model of angioimmunoblastic T-cell lymphoma
| PRJEB54074 | ENA
Project description:SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we identified the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to PARP inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.
2021-07-16 | GSE180052 | GEO
Project description:SUMO inhibition restores the MHC-I APM
| PRJEB49824 | ENA
Project description:Acute myeloid leukemia (AML) is a hematopoietic cancer characterized by the proliferation and accumulation of aberrant immature myeloid progenitor blasts in bone marrow and peripheral blood. Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, has received FDA approval for AML treatment in combination with hypomethylating agents (HMA). However, treatment failure and therapy resistance present an urgent need for new therapies to overcome VEN resistance and enhance VEN efficacy. We propose inhibition of SUMOylation as a novel therapy with the potential to address this need. SUMOylation regulates protein function by covalently attaching Small Ubiquitin-like MOdifier (SUMO) proteins to target proteins via an enzymatic cascade. Our study aims to evaluate the effects of SUMOylation inhibition on anti-AML activity of VEN and dissert the underlying mechanism.
2024-05-27 | GSE267885 | GEO
Project description:Macrophages in the B-cell lymphoma microenvironment represent a functional node in progression and therapeutic response. We assessed metabolic regulation of macrophages in the context of therapeutic antibody mediated phagocytosis. Pentose phosphate pathway (PPP) inhibition by specific inhibitors and genetic targeting induced increased phagocytic lymphoma cell clearance. Moreover, macrophages provided decreased support for survival of lymphoma cells. PPP inhibition induced metabolic activation, cytoskeletal re-modelling and pro-inflammatory polarization of macrophages. A connection between PPP and immune regulation was identified as mechanism of macrophage repolarization. PPP inhibition causes suppression of glycogen synthesis and subsequent modulation of the immune modulatory STAT1-IRG1-itaconate axis. PPP inhibition rewired macrophage activation in vivo. Addition of the PPP inhibitor S3 to antibody therapy achieved significant increased overall survival in an aggressive B cell lymphoma mouse model. We hypothesize the PPP as key regulator and targetable modulator of macrophage activity in lymphoma to improve efficacy of immunotherapies.
2024-11-25 | PXD042428 | Pride
Project description:The purpose of this phase 2 study is to evaluate the efficacy and safety of NIR178 in combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to optimize immune activation through inhibition of A2aR.
| 2248580 | ecrin-mdr-crc
Project description:Myc is an oncogenic transcription factor frequently dysregulated in human cancer. To identify pathways supporting the Myc oncogenic program, we employed a genome-wide RNAi screen for Myc-synthetic-lethal (MySL) genes and uncovered a role for the SUMO-activating-enzyme (SAE1/2). Loss of SAE1/2 enzymatic activity drives synthetic lethality with Myc. Mechanistically, SAE2 inhibition switches a transcriptional subprogram of Myc from activated to repressed. A subset of these SUMOylation-dependent Myc-switchers (SMS genes) governs mitotic spindle function and is required to support the Myc oncogenic program. comparison of 4 treatments: normal HMEC, High Myc in HMEC, SUMO depleted in HMEC, High Myc+Sumo Depleted in HMEC
2011-12-08 | E-GEOD-34055 | biostudies-arrayexpress