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A Drug Repurposing Screen Identifies Fludarabine Phosphate as a Potential Therapeutic Agent for N-MYC Overexpressing Neuroendocrine Prostate Cancers

ABSTRACT: A Drug Repurposing Screen Identifies Fludarabine Phosphate as a Potential Therapeutic Agent for N-MYC Overexpressing Neuroendocrine Prostate Cancers

PROVIDER: PRJNA750746 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15296015_1.fastq.gz	Fastqsanger.gz
	SRR15296015_2.fastq.gz	Fastqsanger.gz
	SRR15296016_1.fastq.gz	Fastqsanger.gz
	SRR15296016_2.fastq.gz	Fastqsanger.gz
	SRR15296017_1.fastq.gz	Fastqsanger.gz

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A Drug Repurposing Screen Identifies Fludarabine Phosphate as a Potential Therapeutic Agent for N-MYC Overexpressing Neuroendocrine Prostate Cancers

Project description:Neuroendocrine prostate cancer (NEPC) represents a highly aggressive form of prostate tumors. NEPC results from trans-differentiated castration-resistant prostate cancer (CRPC) with increasing evidence indicating that the incidence of NEPC often results from the adaptive response to androgen deprivation therapy. Recent studies have shown that a subset of NEPC exhibits overexpression of the MYCN oncogene along with the loss of tumor suppressing TP53 and RB1 activities. N-MYC is structurally disordered with no binding pockets available on its surface and so far, no clinically approved drug is available. We adopted a drug-repurposing strategy, screened ~1800 drug molecules and identified Fludarabine Phosphate to preferentially inhibit proliferation of N-MYC overexpressing NEPC cells by inducing ROS. We also show that Fludarabine phosphate affects N-MYC protein levels and N-MYC transcriptional targets in NEPC cells. Moreover, enhanced ROS production destabilizes N-MYC protein by inhibiting AKT signaling and is responsible for the reduced survival of NEPC cells and tumors. Our results indicate that increasing ROS production by administration of Fludarabine Phosphate may represent an effective treatment option for patients with N-MYC overexpressing NEPC tumors.

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A Drug Repurposing Screen Identifies Fludarabine Phosphate as a Potential Therapeutic Agent for N-MYC Overexpressing Neuroendocrine Prostate Cancers.

Project description: Not available

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Project description:RATIONALE: Placing a gene into T cells may improve the body’s ability to recognize cancer cells and build an immune response to fight cancer. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Biological therapies, such as aldesleukin, may stimulate the immune system in different ways and stop cancer cells from growing. Giving specially treated T cells together with cyclophosphamide, fludarabine phosphate, and aldesleukin may kill more tumor cells. PURPOSE: This phase I clinical trial is studying the side effects and best dose of treated T cells when given together with cyclophosphamide, fludarabine phosphate, and aldesleukin in treating patients with cancer.

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