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ABSTRACT:
PROVIDER: PRJNA98469 | ENA |
REPOSITORIES: ENA
Publications
Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia.
Real Pedro J PJ Tosello Valeria V Palomero Teresa T Castillo Mireia M Hernando Eva E de Stanchina Elisa E Sulis Maria Luisa ML Barnes Kelly K Sawai Catherine C Homminga Irene I Meijerink Jules J Aifantis Iannis I Basso Giuseppe G Cordon-Cardo Carlos C Ai Walden W Ferrando Adolfo A
Nature medicine 20081221 1
Gamma-secretase inhibitors (GSIs) block the activation of the oncogenic protein Notch homolog-1 (NOTCH1) in T cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid ...[more]
Similar Datasets
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of gamma-secretase inhibitors (GSIs). Here, we characterized the interaction between PF-03084014, a clinically-relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Molecular characterization of the response to PF-03084014 plus glucocorticoids through gene expression profiling revealed transcriptional upregulation of the glucocorticoid receptor as the mechanism mediating the enhanced glucocorticoid response. Moreover, treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment was highly effective at reversing PF-03084014-induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results suggest that combination of PF-03084014 treatment with glucocorticoids may be well-tolerated and highly active for the treatment of glucorticoid-resistant T-ALL. Overall design: Duplicate samples of the CUTLL1 T-ALL cell line were treated with vehicle only (DMSO), the gamma-secretase inhibitor PF-03084014 (1 microM), dexamethasone (1 microM), or PF-03084014 (1 microM). plus dexamethasone (1 microM) for 48 hours. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (PF-03084014) or the combination of both treatments.
2011-11-09 | GSE33562 | GEO
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of gamma-secretase inhibitors (GSIs). Here, we characterized the interaction between PF-03084014, a clinically-relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Molecular characterization of the response to PF-03084014 plus glucocorticoids through gene expression profiling revealed transcriptional upregulation of the glucocorticoid receptor as the mechanism mediating the enhanced glucocorticoid response. Moreover, treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment was highly effective at reversing PF-03084014-induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results suggest that combination of PF-03084014 treatment with glucocorticoids may be well-tolerated and highly active for the treatment of glucorticoid-resistant T-ALL. Duplicate samples of the CUTLL1 T-ALL cell line were treated with vehicle only (DMSO), the gamma-secretase inhibitor PF-03084014 (1 microM), dexamethasone (1 microM), or PF-03084014 (1 microM). plus dexamethasone (1 microM) for 48 hours. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (PF-03084014) or the combination of both treatments.
2011-11-09 | E-GEOD-33562 | ArrayExpress
Project description:Glucocorticoids are an essential component of the treatment of lymphoid malignancies and resistance to glucocorticoid therapy constitutes a prominent clinical problem in relapsed and refractory lymphoblastic leukemias. Constitutively active NOTCH signaling is involved in the pathogenesis of over 50% of T-cell lymphoblastic leukemia (T-ALL) which harbor activating mutations in the NOTCH1 gene. Aberrant NOTCH1 signaling has been shown to protect normal thymocytes from glucocorticoid induced cell death. Here we analyzed the interaction of glucocorticoid therapy with inhibition of NOTCH signaling in the treatment of T-ALL. Gamma-secretase inhibitors (GSI), which block the activation of NOTCH receptors, amplified the transcriptional changes induced by glucocorticoid treatment, including glucocorticoid receptor autoinduction and restored sensitivity to dexamethasone in glucocorticoid-resistant T-ALL cells. Apoptosis induction upon inhibition of NOTCH signaling and activation of the glucocorticoid receptor was dependent on transcriptional upregulation of BIM and subsequent activation of the mitochondrial/intrinsic cell death pathway. Finally, we used a mouse xenograft model of T-ALL to demonstrate that combined treatment with dexamethasone and a GSI results in improved antileukemic effects in vivo. These studies provide insight in the mechanisms of glucocorticoid resistance and serve as rationale for the use of glucocorticoid and GSIs in combination in the treatment of T-ALL. Experiment Overall Design: Duplicate samples (biologic replicas) from CUTLL1 cells were treated for 24 hours with vehicle only (DMSO), dexamethasone (1microM), a gamma-secretase inhibitor (CompE 100nM) and a combination of dexamethasome plus gamma secretase inhibitor at the same concentrations indicated before. Gene expression profiling was analyzed to identify gene expression signatures assocuated with glucocorticoid treatment (dexamethasone), inhibition of NOTCH1 by gamma secretase inhibitor (CompE) or the combination of both treatments.
2009-01-13 | E-GEOD-7067 | ArrayExpress
Project description:Gamma-secretase inhibitor plus fludarabine in CLL
| PRJNA219743 | ENA
Project description:Purpose: Although significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted in mutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease.Experimental Design: We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment. We then tested the combination of LEE011 with dexamethasone or everolimus in three orthotopic mouse models and measured on-target drug activity.Results: We first determined that both NOTCH1-mutant and wild-type T-ALL are highly sensitive to pharmacologic inhibition of CDK4/6 when wild-type RB is expressed. Next, we determined that CDK4/6 inhibitors are antagonistic when used either concurrently or in sequence with many of the drugs used to treat relapsed T-ALL (methotrexate, mercaptopurine, asparaginase, and doxorubicin) but are synergistic with glucocorticoids, an mTOR inhibitor, and gamma secretase inhibitor. The combinations of LEE011 with the glucocorticoid dexamethasone or the mTOR inhibitor everolimus were tested in vivo and prolonged survival in three orthotopic mouse models of T-ALL. On-target activity was measured in peripheral blood and tissue of treated mice.Conclusions: We conclude that LEE011 is active in T-ALL and that combination therapy with corticosteroids and/or mTOR inhibitors warrants further investigation. Clin Cancer Res; 23(4); 1012-24. ©2016 AACRSee related commentary by Carroll et al., p. 873.
| S-EPMC5432118 | BioStudies
Project description:Gamma-secretase inhibitors (GSIs), which block the activation of NOTCH receptors, are being tested in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Thus far, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. Additionally, cotreatment with glucocorticoids induced Ccnd2 upregulation in the gut which protected mice from the intestinal secretory metaplasia typically induced by loss of NOTCH signaling. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL. Experiment Overall Design: Experiments analyzing the interacition of dexamethasone and the gamma-secretase inhibitor DBZ were carried out in 6-week-old C57/Black6 female mice (Jackson Laboratory). In these studies we treated mice with vehicle (DMSO) (n=2), dexamethasone (15 mg/kg) (n=2), DBZ (10 micromol/kg) (n=2) and dexamethasone (15 mg/kg) plus DBZ (10 micromol/kg) (n=2) daily by intraperitoneal injection for 5 days. At the end of the treatment, animals were euthanized and segments of the small intestine were collected and processed for RNA extraction, histological and immunohistochemical analysis.
2009-04-10 | E-GEOD-11184 | ArrayExpress
Project description:Presenilin heterodimers apparently contain the active site of gamma-secretase, a polytopic aspartyl protease involved in the transmembrane processing of both the Notch receptor and the amyloid-beta precursor protein. Although critical to embryonic development and the pathogenesis of Alzheimer's disease, this protease is difficult to characterize, primarily because it is a multicomponent complex of integral membrane proteins. Here the functional gamma-secretase complex was isolated by using an immobilized active site-directed inhibitor of the protease. Presenilin heterodimers and nicastrin bound specifically to this inhibitor under conditions tightly correlating with protease activity, whereas several other presenilin-interacting proteins (beta-catenin, calsenilin, and presenilin-associated protein) did not bind. Moreover, anti-nicastrin antibodies immunoprecipitated gamma-secretase activity from detergent-solubilized microsomes. Unexpectedly, C83, the major endogenous amyloid-beta precursor protein substrate of gamma-secretase, was also quantitatively associated with the complex. These results provide direct biochemical evidence that nicastrin is a member of the active gamma-secretase complex, indicate that beta-catenin, calsenilin, and presenilin-associated protein are not required for gamma activity, and suggest an unprecedented mechanism of substrate-protease interaction.
| S-EPMC122414 | BioStudies
Project description:Preclinical analysis of the gamma secretase inhibitor PF-030840214 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia
| PRJNA148585 | ENA
Project description:Gamma-secretase inhibitors (GSIs), which block the activation of NOTCH receptors, are being tested in the treatment of T-cell acute lymphoblastic leukemia (T-ALL). Thus far, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. Additionally, cotreatment with glucocorticoids induced Ccnd2 upregulation in the gut which protected mice from the intestinal secretory metaplasia typically induced by loss of NOTCH signaling. These results support a role for glucocorticoids plus GSIs in the treatment of glucocorticoid-resistant T-ALL. Keywords: drug treatment in vivo, dibenzazepine DBZ, T-ALL, glucocorticoid Overall design: Experiments analyzing the interacition of dexamethasone and the gamma-secretase inhibitor DBZ were carried out in 6-week-old C57/Black6 female mice (Jackson Laboratory). In these studies we treated mice with vehicle (DMSO) (n=2), dexamethasone (15 mg/kg) (n=2), DBZ (10 micromol/kg) (n=2) and dexamethasone (15 mg/kg) plus DBZ (10 micromol/kg) (n=2) daily by intraperitoneal injection for 5 days. At the end of the treatment, animals were euthanized and segments of the small intestine were collected and processed for RNA extraction, histological and immunohistochemical analysis.
2008-12-04 | GSE11184 | GEO
Project description:T-cell acute lymphoblastic leukemias (T-ALL) and lymphomas are aggressive hematologic cancers frequently associated with activating mutations in NOTCH1. Early studies identified NOTCH1 as an attractive therapeutic target for the treatment of T-ALL through the use of ?-secretase inhibitors (GSI). Here, we characterized the interaction between PF-03084014, a clinically relevant GSI, and dexamethasone in preclinical models of glucocorticoid-resistant T-ALL. Combination treatment of the GSI PF-03084014 with glucocorticoids induced a synergistic antileukemic effect in human T-ALL cell lines and primary human T-ALL patient samples. Mechanistically PF-03084014 plus glucocorticoid treatment induced increased transcriptional upregulation of the glucocorticoid receptor and glucocorticoid target genes. Treatment with PF-03084014 and glucocorticoids in combination was highly efficacious in vivo, with enhanced reduction of tumor burden in a xenograft model of T-ALL. Finally, glucocorticoid treatment effectively reversed PF-03084014-induced gastrointestinal toxicity via inhibition of goblet cell metaplasia. These results warrant the analysis of PF-03084014 and glucocorticoids in combination for the treatment of glucocorticoid-resistant T-ALL.
2012-01-01 | S-EPMC3392513 | BioStudies