Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA235876 | ENA |
REPOSITORIES: ENA
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Project description:Rituximab alone or in combination with chemotherapeutics is the first-line therapy for variety of lymphoproliferative disorders including low- and high grade non-Hodgkin’s lymphomas (NHL). Although the complete response rate is quite impressive, vast majority of patient presents recurrent disease. The association between CD20 expression and clinical outcome in patients strongly suggests that reduced CD20 expression leads to inferior response to RCHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In order to understand how loss of CD20 leads to development of RCHOP resistance, we developed rituximab resistant DOHH2 model in vivo by chronic exposure to rituximab. Characterization of several resistant in vivo xenografts revealed one model that maintained resistance to an acute dose of rituximab and demonstrated loss of CD20. Further characterization of the model demonstrated a loss of CD20 is associated with over expression of BCL2 and BIM. In vivo efficacy studies showed resistant line is insensitive to acute dose of RCHOP and treatment with an inhibitor of BCL2 (ABT199) in combination with chemotherapy resulted in better efficacy than RCHOP alone. We have identified an in vivo model of DLBCL where loss of CD20 and over expression of anti-apoptotic protein BCL2 leads to RCHOP resistance. These data suggest the addition of BCL2 inhibitor to chemotherapy might be effective in treating CD20 negative lymphomas. mRNA profiles of parental and rituximab resistant DOHH2 xenograft were generated by deep sequencing using Illumina HiSeq
2014-09-01 | E-GEOD-54201 | biostudies-arrayexpress
Project description:Rituximab alone or in combination with chemotherapeutics is the first-line therapy for variety of lymphoproliferative disorders including low- and high grade non-Hodgkin’s lymphomas (NHL). Although the complete response rate is quite impressive, vast majority of patient presents recurrent disease. The association between CD20 expression and clinical outcome in patients strongly suggests that reduced CD20 expression leads to inferior response to RCHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In order to understand how loss of CD20 leads to development of RCHOP resistance, we developed rituximab resistant DOHH2 model in vivo by chronic exposure to rituximab. Characterization of several resistant in vivo xenografts revealed one model that maintained resistance to an acute dose of rituximab and demonstrated loss of CD20. Further characterization of the model demonstrated a loss of CD20 is associated with over expression of BCL2 and BIM. In vivo efficacy studies showed resistant line is insensitive to acute dose of RCHOP and treatment with an inhibitor of BCL2 (ABT199) in combination with chemotherapy resulted in better efficacy than RCHOP alone. We have identified an in vivo model of DLBCL where loss of CD20 and over expression of anti-apoptotic protein BCL2 leads to RCHOP resistance. These data suggest the addition of BCL2 inhibitor to chemotherapy might be effective in treating CD20 negative lymphomas.
2014-09-01 | GSE54201 | GEO
Project description:SUMOylation is a reversible post-translational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of Type I interferons (IFN1). In this report, we have explored the activity of the selective small molecule SUMOylation inhibitor TAK-981 in promoting antitumor innate immune responses. We demonstrate that treatment with TAK-981 results in IFN1-dependent macrophage and NK cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pre-treatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20-positive target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated synergistic antitumor activity of TAK-981 and rituximab in CD20-positive lymphoma xenograft models. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with lymphomas and solid tumors.
2024-04-24 | GSE185841 | GEO
Project description:Three triple negative breast cancer cell lines (MDAMB231, SUM159, and HCC1806) were treated with small molecule inhibitors (JQ1, BET bromodomain inhibitor; GSK2801, BAZ2A/B bromodomain inhibitor) alone and in combination for 72 hours
2019-07-09 | GSE116907 | GEO
Project description:Activation of the MYC oncogene is common in B-cell lymphomas, and frequently associated with compensatory events that dampen Myc-induced apoptosis, such as over-expression of anti-apoptotic Bcl2-family proteins. For example, concurrent translocations of MYC and BCL2 in a subset of Diffuse large B-cell lymphoma (DLBCL) lead to the high-grade “double-hit” lymphoma subtype (DHL), characterized by dismal prognosis in the face of current front-line regimens, thus calling for the pursuit of tailored therapeutic strategies. Here, we show that Myc and Bcl2 modulate the sensitivity of B-cells to IACS-010759, a selective inhibitor of mitochondrial respiratory complex I. Myc activation in non-transformed lymphoid precursors suppressed endogenous Bcl2 and sensitized the cells to IACS-010759-induced apoptosis. Treatment with the Bcl2 inhibitor venetoclax also sensitized to IACS-010759, while overexpression of Bcl-2 was protective. IACS-010759 engaged an ATF4-driven Integrated Stress Response (ISR) with dual anti- and pro-apoptotic effects, the latter mediated by the CHOP transcription factor, which contributed to selective killing of Myc-overexpressing cells. In line with the above data, IACS-010759 and venetoclax synergized in killing human DHL cells, and showed strong combinatorial effects in a pre-clinical setting. In a Bcl2-negative Burkitt’s lymphoma cell line, instead, IACS-010759 synergized with the Mcl-1 inhibitor S63845. Altogether, our data point to the combination of IACS-010759 with distinct Bcl2-family inhibitors for therapeutic reactivation of the intrinsic apoptotic pathway in Myc-associated B-cell lymphomas
2022-03-01 | GSE149073 | GEO
Project description:Three triple negative breast cancer cell lines (MDAMB231, SUM159, and HCC1806) were treated with small molecule inhibitors (JQ1, BET bromodomain inhibitor; GSK2801, BAZ2A/B bromodomain inhibitor) or BAZ siRNA alone and in combination with JQ1 for 48 hours
2019-07-09 | GSE116879 | GEO
Project description:Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to the absence of well-defined molecular targets and high invasive and proliferative capacities of these cells. Current treatments against TNBC have shown minimal activity due to the high recurrence rate in the patients. Therefore, a pressing need for novel and efficacious therapies against TNBC. Here, we found a novel small molecule inhibitor (NSC33353) with potent anti-tumor activity against TNBC cells. Anti-proliferative effects of NSC small molecule inhibitor were determined using 2D and 3D culture cell proliferation assays. Using proteomics, NGS and enrichment analysis, we globally investigated top regulatory pathways affected by this compound in TNBC cells. Subsequently, we validated the proteomics and NGS analysis data using seahorse and enzymatic assays. Finally, we showed the inhibitor anti-tumor effects and confirmed its potential mechanism in vivo. In this report, we showed that a novel NSC33353 small molecule inhibitor reduced the proliferation of TNBC cells. Proteomic analysis confirmed a significant metabolic reprograming including suppression of glycolysis and oxidative phosphorylation after treatment. Furthermore, we found that treatment with NSC33353 small molecule inhibitor impaired glycolysis and oxidative phosphorylation via modulating the activity of metabolic regulator enzymes. Altogether, our data indicate that NSC33353 small molecule inhibitor may exhibit anti-tumor activity in TNBC cells and provide a rationale for further investigation of the potential of NSC small molecule inhibitor as an attractive therapeutic drug for TNBC. Doxorubicin is one of the most effective agents in the treatment of TNBC and resistance to this drug is a major problem. We show that the combination of NSC33353 and doxorubicin synergistically suppressed the growth of TNBC cells suggesting the combination enhances the sensitivity to doxorubicin. Further in-depth investigations are required to evaluate the exact targets and mechanism of this potent small molecule inhibitor, and its anti-neoplasm effects on TNBC in vivo.
2022-12-30 | GSE207036 | GEO
Project description:Overexpression of antiapoptotic BCL2 family proteins occurs in various hematologic malignanices and contributes to leukemogenesis by inhibiting the apoptotic machinery of the cells. BH3 mimetics provide an option for medication, with venetoclax as the first drug applied for chronic lymphocytic leukemia and for acute myeloid leukemia. To find additional hematologic entities with ectopic expression of BCL2 family members, we performed expression screening applying the LL-100 panel. Primary effusion lymphoma (PEL) and anaplastic large cell lymphoma (ALCL), 2/22 entities covered by this panel, stood out by high expression of MCL1 and low expression of BCL2. The MCL1 inhibitor AZD-5991 induced apoptosis in both malignancies suggesting that this BH3 mimetic might be efficient as drug for these diseases. The ALCL cell lines also expressed BCLXL and BCL2A1, both contributing to survival of the cells. The combination of specific BH3 mimetics yielded synergistic effects, pointing to a novel strategy for the treatment of ALCL. The PI3K/AKT inhibitor BEZ-235 could also efficiently be applied in combination with AZD-5991, providing an alternative to avoid thrombocytothemia, which is associated with the use of BCLXL inhibitors.
2021-12-31 | E-MTAB-10903 | biostudies-arrayexpress
Project description:Immuno-chemotherapy regimens elicit high response rates in B-cell non-Hodgkin lymphoma but heterogeneity in response duration is observed, with some patients achieving cure and others showing refractory disease or relapse. Using a transcriptome-powered targeted proteomics screen, we discovered a gene regulatory circuit involving the nuclear factor CYCLON which characterizes aggressive disease and resistance to the anti-CD20 monoclonal antibody, Rituximab, in high-risk B-cell lymphoma. CYCLON knockdown was found to inhibit the aggressivity of MYC-overexpressing tumors in mice and to modulate gene expression programs of biological relevance to lymphoma. Furthermore, CYCLON knockdown increased the sensitivity of human lymphoma B cells to Rituximab in vitro and in vivo. Strikingly, this effect could be mimicked by in vitro treatment of lymphoma B cells with a small molecule inhibitor for BET bromodomain proteins (JQ1). In summary, this work has identified CYCLON as a new MYC cooperating factor that drives aggressive tumor growth and Rituximab resistance in lymphoma. This resistance mechanism is amenable to next-generation epigenetic therapy by BET bromodomain inhibition, thereby providing a new combination therapy rationale for high-risk lymphoma. We have identified CYCLON has a nuclear factor involved in tumor progression and treatment resistance in aggressive lymphoma. In order to get further insights into the molecular mechanisms related to the expression of this factor, we used Raji cells to compared gene expression profiles of control and CYCLON knock-down cell lines. Stable cell lines have been established using lentiviral transduction of Raji Burkitt lymphoma B cells with either a control (non-targeting) shRNA sequence or CYCLON shRNA constructs under puromycin selection. Non-transduced cells were also analyzed as a control. 4 replicates were analyzed for each conditions.
2013-06-01 | E-GEOD-46873 | biostudies-arrayexpress
Project description:Lymphomas are classified according to the World Health Organization (WHO) classification which defines subtypes on the basis of clinical, morphological, immunophenotypic, molecular and cytogenetic criteria. Using this model, 8 of 9 of the validation samples were classified successfully. This pilot study demonstrates that such a microarray tool may be a promising diagnostic approach for small B-cell non-Hodgkin’s lymphoma. Keywords: Small B-Cell non-Hodgkin’s Lymphoma, Low Density DNA Microarray, Diagnosis Fresh-frozen tumor biopsies performed before treatment and clinical data were obtained retrospectively from 68 patients in five different institutions after lab investigations involving cytology, immunohistochemistry, cytogenetics (conventional cytogenetics and fluorescent in situ hybridization [FISH]), and/or molecular analysis. The samples were then classified unanimously by a panel of five pathologists as one of the 4 subtypes: 17 B-CLL, 14 MZL, 23 FL and 14 MCL. The immunohistochemical criteria used for identifying the 4 subtypes of SBCL were: CD20+/-, CD5+, CD23+ for B-CLL; CD20+, CD5+, CD23-, Cyclin D1+ for MCL; CD20+, CD10+, Bcl2+ for FL; CD20+, CD5-, CD10- for S-MZL. 28 samples were rejected for technical issues with RNA. The remaining 40 samples include the 4 different subtypes with this following distribution: Follicular Lymphoma/FL (n=15), Mantle Cell Lymphoma/MCL (n=7), B-Chronic Lymphocytic Leukemia/B-CLL (n=6) and Splenic Marginal Zone Lymphoma/S-MZL (n=12). The expression profile of 107 genes was evaluated in these 40 samples defined as a training set. Replicates were performed for samples of sufficient quantity, and a total of 79 gene expression profiles, comprised of 12 samples in triplicate, 15 samples in duplicate and 13 samples evaluated singly, were then analyzed. A second group of 13 patients was defined as test set and used to validate the gene signatures highlighted from the training set analysis. These patients were selected by a pathologist independent from the first analysis and include 4 FL, 3 B-CLL, 5 MCL and 1 S-MZL. Four samples were rejected for technical issues with RNA. The remaining 9 samples include the 4 different subtypes: 2 FL, 3 B-CLL, 3 MCL and 1 S-MZL. A total of 13 gene expression profiles were analyzed (4 samples evaluated in duplicate and 5 samples investigated singly).
2009-03-24 | E-GEOD-11635 | biostudies-arrayexpress