Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression profiles of desmoid tumor cells treated with gamma-secretase inhibitor

ABSTRACT: Desmoid tumors (DTs) are rare mesenchymal monoclonal lesions that have a high risk of local recurrence but lack metastatic potential. Since the Notch pathway appears to be important in the carcinogenesis of several tumor types, in the past few years Î³-secretase inhibitors (GSIs) have emerged as a potential therapeutic treatment by inhibiting cancer cell Notch signaling through NICD cleavage blockade. To investigate the antitumor effect of PF-03084014, a Î³-secretase inhibitor, in DT models, cells treated with PF-03084014 were characterized by gene array analysis. Three cell strains of Desmoid tumors (Desm14, Desm27 and Desm39b) were subjected to either no treatment (control, called G-0) or treatment with 10Î¼M of PF-03084014 (called G-10). The regimen for each treatment was ~8 days and ~30 days; multiple group comparison

ORGANISM(S): Homo sapiens

SUBMITTER: Chad Creighton

PROVIDER: E-GEOD-61097 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors.

Shang Hui H Braggio Danielle D Lee Ya-Jung YJ Al Sannaa Ghadah A GA Creighton Chad J CJ Bolshakov Svetlana S Lazar Alexander J F AJ Lev Dina D Pollock Raphael E RE

Cancer 20150908 22

<h4>Background</h4>Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/β-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment.<h4>Methods</h4>The expr ...[more]

PMID: 26349011

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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.

Project description:Triple-negative breast cancer (TNBC) is defined as pathologically negative for estrogen receptor α (ER-), progesterone receptor (PR-), and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy, recently supplemented by immunotherapy [37296893]. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including gamma secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs. We confirmed that SS, a known gamma secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, the anti-tumor effects of SS were significantly enhanced when combined with α-PD1 immunotherapy in our TNBC organoids and in vivo. Our data support further investigation of SS for the treatment of TNBC, in conjunction with standard of care chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option solution for a patient population in need of effective therapies.

Project description:Î³-secretase is an intra-membrane-cleaving aspartyl protease implicated in the processing of a wide range of type I membrane proteins including the Notch receptor and the amyloid-Î² precursor protein (APP). It thus regulates a diverse array of cellular and biological processes including the differentiation of neuronal embryonic stem cells, or intestinal stem cells, with the latter controlling the self-renewing of the intestinal epithelium. Indeed, proteolysis of these proteins by Î³-secretase triggers signaling cascades by releasing intracellular domains (ICDs) which, following association with adaptor proteins and nuclear translocation, modulate the transcription of different genes by binding directly to their promoters. The pronounced proliferative and regenerative effects of Notch signaling and its implication in the generation of the AÎ²-peptides, makes Î³-secretase a therapeutic target for several types of cancer and for Alzheimerâs disease. To investigate the broad effects of Î³-secretase activity onto the cellular transcriptome, Chinese hamster ovary (CHO) cells with enhanced Î³-secretase were compared to cells with abolished Î³-secretase activity via a microarray designed for a genetically close species, mouse. Our findings will potentially help to decipher the biology of Î³-secretase, including a better understanding of the roles of this enzyme in gene transcription. We compared the transcriptomes of two CHO cell lines displaying extreme differences in Î³-secretase activity. The S-1 cell line overexpressed the four components of Î³-secretase (NCT, APH1aL, PS1, and PEN2) and was characterized by a marked increase in the level of PS1 heterodimers associated with 8-fold increased Î³-secretase activity compared to untransfected controls. The other cell line consisted of wild type CHO cells incubated with DAPT, a well-known Î³-secretase inhibitor. The two cell lines were used in combination with a mouse microarray to analyze gene transcription under enhanced Î³-secretase. Two samples, S1 and DAPT treated CHO- were used in biological triplicates each.

Dataset Information

Gene expression profiles of desmoid tumor cells treated with gamma-secretase inhibitor

Publications

Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors.

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