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Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

ABSTRACT: Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

PROVIDER: PRJNA740252 | ENA |

REPOSITORIES: ENA

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Organoid-based drug screening reveals neddylation as therapeutic target for malignant rhabdoid tumors

Project description:Malignant rhabdoid tumors (MRT) represent one of the most aggressive childhood malignancies. No effective treatment options are available, and prognosis is therefore dismal. Previous studies have demonstrated that tumor organoids capture the heterogeneity of patient tumors and can be used to predict patient therapy response. Here, we perform drug screening on patient-derived normal and tumor organoids to identify MRT-specific therapeutic vulnerabilities. We identify neddylation inhibitor MLN4924 as a potential therapeutic agent. Mechanistically, we find increased neddylation in MRT organoids and tissues and show that MLN4924 induces a cytotoxic response via upregulation of the unfolded protein response. Lastly, we demonstrate in vivo efficacy in an MRT PDX mouse model, in which single agent MLN4924 treatment significantly extends survival. Our study demonstrates that organoids can be used to find drugs selectively targeting tumor cells while leaving healthy cells unharmed and proposes neddylation inhibition as therapeutic strategy in MRT.

2021-06-24 | GSE178737 | GEO

Methylation profiling of Malignant Rhabdoid Tumours

Project description:An observational experiment to methylation profile 79 SMARCB1 negative primary tumours from patients diagnosed with Malignant Rhabdoid Tumours.

2020-07-15 | E-MTAB-6708 | biostudies-arrayexpress

MDM2 and MDM4 are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors

Project description:MDM2 and MDM4 are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors

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Analysis of gene expression in human malignant rhabdoid cells following prolonged treatment with the histone deacetylase inhibitor, Panobinostat

Project description:We hypothesized that prolonged treatment of malignant rhabdoid tumor cells with low-dose HDACi will drive cellular differentiation. We assessed changes in gene expression following 21 days treatment with the HDACi, Panobinostat, versus a DMSO vehcile control in three human MRT cell lines. Total RNA obtained from three human malignant rhabdoid tumor cell lines (G401, SJSC, STM91-01) cultured for 21 days in the presence of low-dose Panobinostat was compared to 21-day treated DMSO control cells. All treatments and cell lines were performed in triplicate.

2016-03-01 | E-GEOD-76664 | biostudies-arrayexpress

DNA methylation profiling of SMARCB1 reconstitution in malignant rhabdoid tumor organoids

Project description:We have generated DNA methylation profiles for patient-derived malignant rhabdoid tumor organoids and re-expressed SMARCB1 to assess SMARCB1-dependent changes in DNA methylation

2021-01-13 | GSE161814 | GEO

An Organoid Biobank for Childhood Kidney Cancers that Captures Disease and Tissue Heterogeneity

Project description:Kidney tumours are among the most common solid tumours in children, comprising several distinct subtypes differing in many aspects, including cell-of-origin, genetics, and pathology. Pre-clinical cell models capturing the disease heterogeneity are currently lacking. Here, we describe the first paediatric cancer organoid biobank. It contains tumour and matching normal kidney organoids from over 50 children with different subtypes of kidney cancer, including Wilms tumours, malignant rhabdoid tumours, renal cell carcinomas, and congenital mesoblastic nephromas. The malignant rhabdoid tumour organoids represent the first organoid model for tumours of non-epithelial origin. The tumour organoids retain key properties of native tumours, useful for revealing patient-specific drug vulnerabilities. We further demonstrate that organoid cultures derived from Wilms tumours consist of multiple different cell types, including epithelial, stromal and blastemal-like. Our organoid biobank captures the cellular heterogeneity of paediatric kidney tumours, providing a representative collection of well-characterized models for basic cancer research, drug-screening, and personalized medicine.

2019-09-18 | GSE137544 | GEO

MDM2 and MDM4 are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors

Project description:Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. We screened several MRT cell lines each with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin and ATSP-7041, we show that MRT cells are more sensitive than other p53 wild-type cancer cell lines to MDM2 and dual MDM2/4 inhibition in vitro. These compounds cause significant upregulation of the p53 pathway in MRT cells, and sensitivity is ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRT, sensitizes cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a five-day idasanutlin pulse causing marked regression of all xenografts including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene p53, and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer.

2019-02-04 | GSE124508 | GEO

The difference of gene expression signatures between CD146+ and CD146- cells in malignant rhabdoid tumor

Project description:To uncover the molecular mechanisms by which CD146+ malignant rhabdoid tumor cells exhibited higher tumorigenic potential, microarray analysis was carried out to compare gene expression profiles between CD146+ and CD146− cells isolated from three cell lines

2014-11-01 | GSE59025 | GEO

High-Throughput Drug Screening identifies Pazopanib and Clofilium tosylate as effective treatments for malignant rhabdoid tumors

Project description:We used microarrays to compared gene re-expression of SMARCB1 in I2A SMARCB1-deficient rhabdoid tumor cell line.

2017-11-02 | GSE98277 | GEO

Neddylation Status Determines the Therapeutic Sensitivity of BCR-ABL1-targeting Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

Project description:BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) dominate the treatment of chronic myeloid leukemia (CML) over the past decades. In this study, we reported an unexpected role of neddylation inhibitors in desensitizing the therapeutic efficacy of BCR-ABL1-targeting TKIs in CML. Unlike their function in reducing drug resistance in many solid tumors, we revealed that neddylation inhibitors counteracted the cytotoxicity of TKIs against CML cells, both in cellular experiments and in animal model. Conversely, neddylation agonist sensitized the function of TKIs. RNA sequencing data revealed that neddylation inhibitor reversed the transcriptomic changes induced by TKI. Co-immunoprecipitation (co-IP) assay identified ABL1 kinase domain as a novel substrate for neddylation. Furthermore, an artificial intelligence (AI) 3-Dimensional spatial structure binding technology was employed to predict the impact of neddylation on the structure of ABL1 kinase domain. Finally, we provided potential evidence showing that TKI therapy decreased the expression of neddylation enzymes in the bone marrow of CML patients. Hence, our study offers new insights into the post-translational modification (PTM)-mediated drug resistance, and highlights the potential clinical benefits of neddylation agonists in improving the responsiveness of BCR-ABL1 TKIs in CML.

2024-09-15 | GSE275701 | GEO

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