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Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in HPB-ALL cells

ABSTRACT: We used microarrays to study the transcriptional networks controlled by CB-103 in HPB-ALL human cell line.

ORGANISM(S): Homo sapiens

PROVIDER: GSE142406 | GEO | 2020/12/19

REPOSITORIES: GEO

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Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in KOPT-K1 cells

Project description:We used microarrays to study the transcriptional networks controlled by CB-103 in KOPT-K1 human cell line.

2020-12-19 | GSE142407 | GEO

Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in HPB-ALL cells

Project description:Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in HPB-ALL cells

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Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103

Project description:Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103

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Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-12-19 | GSE142408 | GEO

Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in KOPT-K1 cells

Project description:Targeting of the NOTCH transcription complex by a novel small molecule inhibitor CB-103 in KOPT-K1 cells

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CRISPR/Cas9 screen of T-ALL cells (DND-41) in the presence of DMSO, CB-103 or GSI (DAPT).

Project description:The efficacy of targeted therapies for treatment of cancer patients is often limited by development of drug resistance. Potential resistance mechanisms to pharmacological Notch1 inhibition mediated by GSI or CB-103 in T-ALL are currently unclear. Thus, we performed a genome-wide loss-of-function (LoF) CRISPR/Cas9 screen to identify genes responsible for resistance to Notch inhibition and novel combination therapies for efficient treatment of human T-ALL. We used a Notch-dependent human T-ALL cell line, DND-41, which responds moderately to both GSI and CB-103 treatment in vitro. DND-41 cells stably expressing Cas9 were infected with human GeCKO v2 CRIPSR libraries, containing 123,411 sgRNAs targeting 19,050 genes and treated with either vehicle, GSI or CB-103 for 21 days enabling both positive and negative selection of sgRNAs.

2023-06-26 | GSE221576 | GEO

Study of CB-103 in Adult Patients With Advanced or Metastatic Solid Tumours and Haematological Malignancies

Project description:This is a phase I/II, non randomized, open-label, dose escalation study to investigate the safety, tolerability and preliminary efficacy of CB-103.

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The Efficacy of CB-103, a First-in-Class Transcriptional Notch Inhibitor, in Preclinical Models of Breast Cancer.

Project description:BackgroundThe efficacy of CB-103 was evaluated in preclinical models of both ER+ and TNBC. Furthermore, the therapeutic efficacy of combining CB-103 with fulvestrant in ER+ BC and paclitaxel in TNBC was determined.MethodsCB-103 was screened in combination with a panel of anti-neoplastic drugs. We evaluated the anti-tumor activity of CB-103 with fulvestrant in ESR1-mutant (Y537S), endocrine-resistant BC xenografts. In the same model, we examined anti-CSC activity in mammosphere formation assays for CB-103 alone or in combination with fulvestrant or palbociclib. We also evaluated the effect of CB-103 plus paclitaxel on primary tumors and CSC in a GSI-resistant TNBC model HCC1187. Comparisons between groups were performed with a two-sided unpaired Students' t-test. A one-way or two-way ANOVA followed by Tukey's post-analysis was performed to analyze the in vivo efficacy study results.The resultsCB-103 showed synergism with fulvestrant in ER+ cells and paclitaxel in TNBC cells. CB-103 combined with fulvestrant or paclitaxel potently inhibited mammosphere formation in both models. Combination of CB-103 and fulvestrant significantly reduced tumor volume in an ESR1-mutant, the endocrine-resistant BC model. In a GSI-resistant TNBC model, CB-103 plus paclitaxel significantly delayed tumor growth compared to paclitaxel alone.Conclusionour data indicate that CB-103 is an attractive candidate for clinical investigation in endocrine-resistant, recurrent breast cancers with biomarker-confirmed Notch activity in combination with SERDs and/or CDKis and in TNBCs with biomarker-confirmed Notch activity in combination with taxane-containing chemotherapy regimens.

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Pharmacological disruption of the Notch transcription factor complex

Project description:Notch pathway signaling is implicated in several human cancers. Aberrant activation and mutations of Notch signaling components are linked to tumor initiation, maintenance and resistance to cancer therapy. Several strategies, such as monoclonal antibodies (MAbs) against Notch ligands and receptors, as well as small molecule -secretase inhibitors (GSIs), have been developed to interfere with Notch receptor activation at proximal points in the pathway. However, the use of drug-like small molecules to target the downstream mediators of Notch signaling, the Notch transcription activation complex, remains largely unexplored. Using a Notch signaling dependent co-culture system, we developed a high-throughput small molecule screening assay. Herein we report the discovery of an orally active small molecule inhibitor (termed CB-103) of the Notch transcription activation complex. We show that CB-103 inhibits Notch signaling in primary human T-ALL and other Notch-dependent human tumor cell lines, and concomitantly induces cell cycle arrest, thereby impairing proliferation. Notably, CB-103 has the ability to downregulate Notch signaling in GSI-resistant human tumor cell lines that harbor chromosomal translocations and rearrangements in Notch genes. CB-103 mimics Notch loss-of-function phenotypes in flies and mice, retarding tumor growth in xenograft models of breast cancer and patient-derived xenograft models of human leukemia, notably without causing the frequently observed dose-limiting intestinal toxicity induced by other Notch inhibitors. In summary, we describe a pharmacological strategy to interfere with Notch signaling by disrupting the transcriptional regulatory complex it assembles, with therapeutic potential for the treatment of human tumors.

2020-12-19 | GSE148228 | GEO

Transcriptome analysis of Intestinal epithelial cells after Heligmosomoides polygyrus bakeri (Hpb) infection

Project description:RNAseq on intestinal epithelial cells 24hrs after Hpb inoculation in WT- villinCre and VillinCre-A2BARfl/fl mice

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