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Drug repurposing identifies a synergistic high-order drug combination to treat sunitinib-resistant renal cell carcinoma

ABSTRACT: Drug repurposing identifies a synergistic high-order drug combination to treat sunitinib-resistant renal cell carcinoma

PROVIDER: PRJNA731385 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14599967.fastq.gz	Fastqsanger.gz
	SRR14599968.fastq.gz	Fastqsanger.gz
	SRR14599969.fastq.gz	Fastqsanger.gz
	SRR14599970.fastq.gz	Fastqsanger.gz
	SRR14599971.fastq.gz	Fastqsanger.gz

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Drug repurposing identifies a synergistic high-order drug combination to treat sunitinib-resistant renal cell carcinoma

Project description:We report that in response to combination treatment with a synergistic low-dose four-drug combination, human Caki-1 cells resistant to sunitinib alter their pheno- and genotype. We detected that the metabolism of these cells is altered. Gene expression analysis revealed significant differential expression of genes related to mitosis, apoptosis and cell attachment. We detected regulation changes in enzymes mediating the ceramide and sphingolipid metabolism.

2021-05-21 | GSE174740 | GEO

Drug Repurposing to Identify a Synergistic High-Order Drug Combination to Treat Sunitinib-Resistant Renal Cell Carcinoma.

Project description:Repurposed drugs have been evaluated for the management of clear cell renal cell carcinoma (ccRCC), but only a few have influenced the overall survival of patients with advanced disease. To combine repurposed non-oncology with oncological drugs, we applied our validated phenotypic method, which consisted of a reduced experimental part and data modeling. A synergistic optimized multidrug combination (ODC) was identified to significantly reduce the energy levels in cancer remaining inactive in non-cancerous cells. The ODC consisted of Rapta-C, erlotinib, metformin and parthenolide and low doses. Molecular and functional analysis of ODC revealed a loss of adhesiveness and induction of apoptosis. Gene-expression network analysis displayed significant alterations in the cellular metabolism, confirmed by LC-MS based metabolomic analysis, highlighting significant changes in the lipid classes. We used heterotypic in vitro 3D co-cultures and ex vivo organoids to validate the activity of the ODC, maintaining an efficacy of over 70%. Our results show that repurposed drugs can be combined to target cancer cells selectively with prominent activity. The strong impact on cell adherence and metabolism indicates a favorable mechanism of action of the ODC to treat ccRCC.

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Project description:Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. In this study, we profile 80 FDA-approved and clinically tested drugs in neural cell cultures, with the goal of producing a ranked list of possible repurposing candidates.

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REPURPOSING OF GLATIRAMER ACETATE TO TREAT CARDIAC ISCHEMIA IN ANIMAL MODELS

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