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High-throughput Drug Screening Identifies Fluoxetine as a Potential Therapeutic Agent for Neuroendocrine Prostate Cancer

ABSTRACT: High-throughput Drug Screening Identifies Fluoxetine as a Potential Therapeutic Agent for Neuroendocrine Prostate Cancer

PROVIDER: PRJNA932252 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23360538_1.fastq.gz	Fastqsanger.gz
	SRR23360538_2.fastq.gz	Fastqsanger.gz
	SRR23360539_1.fastq.gz	Fastqsanger.gz
	SRR23360539_2.fastq.gz	Fastqsanger.gz
	SRR23360540_1.fastq.gz	Fastqsanger.gz

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High-throughput Drug Screening Identifies Fluoxetine as a Potential Therapeutic Agent for Neuroendocrine Prostate Cancer

Project description:Here, we performed a high-throughput drug screening and identified fluoxetine, originally an FDA-approved antidepressant, as candidate therapeutic agent for NEPC. In vitro experiments revealed that fluoxetine effectively curbed the neuroendocrine differentiation and inhibited the cell viability by targeting the AKT pathway. Altogether, this work repurposed fluoxetine for antitumor application, and supported its clinical development for NEPC therapy, which may provide a promising therapeutic strategy.

2023-04-05 | GSE224715 | GEO

High-throughput drug screening identifies fluoxetine as a potential therapeutic agent for neuroendocrine prostate cancer.

Project description:IntroductionNeuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis and resistance to hormone therapy, which has limited therapeutic approaches. Therefore, this study aimed to identify a novel treatment for NEPC and provide evidence of its inhibitory effects.MethodsWe performed a high-throughput drug screening and identified fluoxetine, originally an FDA-approved antidepressant, as candidate therapeutic agent for NEPC. We carried out both in vitro and in vivo experiments to demonstrate the inhibitory effects of fluoxetine on NEPC models and its mechanism in detail.ResultsOur results demonstrated that fluoxetine effectively curbed the neuroendocrine differentiation and inhibited cell viability by targeting the AKT pathway. Preclinical test in NEPC mice model (PBCre4: Ptenf/f; Trp53f/f; Rb1f/f) showed that fluoxetine effectively prolonged the overall survival and reduced the risk of tumor distant metastases.DiscussionThis work repurposed fluoxetine for antitumor application, and supported its clinical development for NEPC therapy, which may provide a promising therapeutic strategy.

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High-throughput Drug Screening Identifies Ketotifen as a Potential Therapeutic Agent for Neuroendocrine Prostate Cancer

Project description:We performed a high-throughput drug screening and identified Ketotifen, originally an FDA-approved antidepressant, as candidate therapeutic agent for NEPC. RNA-seq was performed of LASCPC-01 cells treated with Ketotifen or PBS.

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High-throughput Drug Screening Identifies Ketotifen as a Potential Therapeutic Agent for Neuroendocrine Prostate Cancer

Project description:High-throughput Drug Screening Identifies Ketotifen as a Potential Therapeutic Agent for Neuroendocrine Prostate Cancer

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Therapeutic opportunities for diffuse midline glioma identified from high-throughput combination drug screening

Project description:Diffuse midline gliomas (DMG) are a group of molecularly related malignancies occurring in midline structures of the childhood central nervous system, including thalamus, pons, and spinal cord. These cancers are characterized by high prevalence of the histone-3K27M mutation and are universally lethal, with median survival of only 9-11 months for pontine DMG (a.k.a. DIPG). In search of novel therapeutic options, we examined multiple cell models in sequential, quantitative high-throughput screens of approved and investigational drugs. This effort generated a total of 17,456 single-agent dose responses that inspired a subsequent series of HTS-enabled drug combination assessments encompassing a total of 8883 drug-drug examinations. Top combinations were validated across a panel of patient-derived cell lines representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-HDAC inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to the cellular unfolded protein response and key metabolic processes following treatment with panobinostat and marizomib. Rescue of drug induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking NAD+ production via NAMPT inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study represents the most comprehensive single-agent and combinatorial drug screen for DIPG reported to date and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores under-recognized metabolic vulnerabilities in DIPG. The combined screening outcomes represent a public resource for the DMG community.

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

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

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