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Protein neddylation as a therapeutic target in pulomonary and extrapulonary small cell carcinomas [FHSC39]

ABSTRACT: Protein neddylation as a therapeutic target in pulomonary and extrapulonary small cell carcinomas [FHSC39]

PROVIDER: PRJNA718867 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14119409.fastq.gz	Fastqsanger.gz
	SRR14119410.fastq.gz	Fastqsanger.gz
	SRR14119411.fastq.gz	Fastqsanger.gz
	SRR14119412.fastq.gz	Fastqsanger.gz
	SRR14119413.fastq.gz	Fastqsanger.gz

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Protein neddylation as a therapeutic target in pulomonary and extrapulonary small cell carcinomas

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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.

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