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

Elhasasna, Hussain; Khan, Raymond; Bhanumathy, Kalpana K.; Vizeacoumar, Frederick S.; Walke, Prachi; Bautista, Maricris; Dahiya, Dinesh Kumar; Maranda, Vincent; Patel, Hiren; Amrutha, Balagopal; Alli, Nezeka; Krishnan, Anand; Freywald, Andrew; Vizeacoumar, Franco J.

doi:10.3390/cells11142246

Cited by 9 publications

(6 citation statements)

References 73 publications

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“…Our study revealed that treatment with fludarabine elicited the most pronounced transcriptional changes, exhibiting a large number of differentially expressed genes that converge on p53 pathway signaling and Myc transcription factor activity. Fludarabine treatment is known to induce a p53-dependent transcriptional responses in chronic lymphocytic leukemia (45,46), and our study highlights a similar mechanism of action in an additional hematological malignancy model. Although we observed only minimal overlap in differentially expressed genes between the scRNA-seq method, of the genes identified, DDB2 , was consistently detected by all three methods and is known to be induced by p53.…”

Section: Discussionsupporting

confidence: 67%

“…We additionally detected a consistent downregulation of Myc transcriptional targets in fludarabine-treated cells. A recent drug repurposing effort found fludarabine phosphate to suppress MYCN signaling in neuroendocrine prostate cancers (46). These findings motivate further exploration of MYC transcriptional activity as a biomarker of response to fludarabine and other DNA synthesis inhibitors.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of High-Throughput Single-Cell Rna-Seq Methods for Ex Vivo Drug Screening

Gezelius,

Enblad,

Lundmark

et al. 2023

Preprint

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Functional precision medicine (FPM) aims to optimize patient-specific drug selection based on the unique characteristics of their cancer cells. Recent advancements in high throughputex vivodrug profiling have accelerated interest in FPM. Here, we present a proof-of-concept study for an integrated experimental system that incorporatesex vivotreatment response with a single-cell gene expression output enabling barcoding of several drug conditions in one single-cell sequencing experiment. We demonstrate this through a proof-of-concept investigation focusing on the glucocorticoid-resistant acute lymphoblastic leukemia (ALL) E/R+ Reh cell line. Three different single-cell transcriptome sequencing (scRNA-seq) approaches were evaluated, each exhibiting high cell recovery and accurate tagging of distinct drug conditions. Notably, our comprehensive analysis revealed variations in library complexity, sensitivity (gene detection), and differential gene expression detection across the methods. Despite these differences, we identified a substantial transcriptional response to fludarabine, a highly relevant drug for treating high-risk ALL, which was consistently recapitulated by all three methods. These findings highlight the potential of our integrated approach for studying drug responses at the single-cell level and emphasize the importance of method selection in scRNA-seq studies. Finally, our data encompassing 27,327 cells are freely available to extend to future scRNA-seq methodological comparisons.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Comparison of High-Throughput Single-Cell Rna-Seq Methods for Ex Vivo Drug Screening

Gezelius,

Enblad,

Lundmark

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…We additionally detected a consistent downregulation of Myc transcriptional targets in fludarabine-treated cells with the MULTI-seq and 10x Fixed approaches. A recent drug repurposing effort found fludarabine phosphate to suppress MYCN signaling in neuroendocrine prostate cancers ( 49 ). These findings motivate further exploration of MYC transcriptional activity as a biomarker of response to fludarabine and other DNA synthesis inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Comparison of high-throughput single-cell RNA-seq methods for ex vivo drug screening

Gezelius,

Enblad,

Lundmark

et al. 2024

NAR Genomics and Bioinformatics

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Functional precision medicine (FPM) aims to optimize patient-specific drug selection based on the unique characteristics of their cancer cells. Recent advancements in high throughput ex vivo drug profiling have accelerated interest in FPM. Here, we present a proof-of-concept study for an integrated experimental system that incorporates ex vivo treatment response with a single-cell gene expression output enabling barcoding of several drug conditions in one single-cell sequencing experiment. We demonstrate this through a proof-of-concept investigation focusing on the glucocorticoid-resistant acute lymphoblastic leukemia (ALL) E/R+ Reh cell line. Three different single-cell transcriptome sequencing (scRNA-seq) approaches were evaluated, each exhibiting high cell recovery and accurate tagging of distinct drug conditions. Notably, our comprehensive analysis revealed variations in library complexity, sensitivity (gene detection), and differential gene expression detection across the methods. Despite these differences, we identified a substantial transcriptional response to fludarabine, a highly relevant drug for treating high-risk ALL, which was consistently recapitulated by all three methods. These findings highlight the potential of our integrated approach for studying drug responses at the single-cell level and emphasize the importance of method selection in scRNA-seq studies. Finally, our data encompassing 27 327 cells are freely available to extend to future scRNA-seq methodological comparisons.

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“…For instance, KRAS signaling mediated by the phosphatidylinositol 3-kinase (PI3K) effector pathway leads to activation of the AKT kinase and subsequent inactivation of GSK3, thereby stabilizing MYC ( 79 ). Consequently, AKT signaling inhibition leads to MYC protein destabilization as shown with the drug fludarabine phosphate, which was identified in a drug-repurposing screen on neuroendocrine prostate cancer cells ( 94 ). These cells are derived from a highly aggressive prostate cancer form featured by MYCN overexpression and loss of the tumor suppressors TP53 and RB1.…”

Section: Myc: An Oncogenic Transcription Factor With Pleiotropic Func...mentioning

confidence: 99%

“…These cells are derived from a highly aggressive prostate cancer form featured by MYCN overexpression and loss of the tumor suppressors TP53 and RB1. Fludarabine phosphate was identified to inhibit cell proliferation by inducing reactive oxygen species (ROS) and by inhibiting AKT signaling, thereby affecting NMYC protein stability and the expression of NMYC target genes ( 94 ).…”

Section: Myc: An Oncogenic Transcription Factor With Pleiotropic Func...mentioning

confidence: 99%

Strategies to target the cancer driver MYC in tumor cells

Weber

Hartl

2023

Front. Oncol.

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The MYC oncoprotein functions as a master regulator of cellular transcription and executes non-transcriptional tasks relevant to DNA replication and cell cycle regulation, thereby interacting with multiple proteins. MYC is required for fundamental cellular processes triggering proliferation, growth, differentiation, or apoptosis and also represents a major cancer driver being aberrantly activated in most human tumors. Due to its non-enzymatic biochemical functions and largely unstructured surface, MYC has remained difficult for specific inhibitor compounds to directly address, and consequently, alternative approaches leading to indirect MYC inhibition have evolved. Nowadays, multiple organic compounds, nucleic acids, or peptides specifically interfering with MYC activities are in preclinical or early-stage clinical studies, but none of them have been approved so far for the pharmacological treatment of cancer patients. In addition, specific and efficient delivery technologies to deliver MYC-inhibiting agents into MYC-dependent tumor cells are just beginning to emerge. In this review, an overview of direct and indirect MYC-inhibiting agents and their modes of MYC inhibition is given. Furthermore, we summarize current possibilities to deliver appropriate drugs into cancer cells containing derailed MYC using viral vectors or appropriate nanoparticles. Finding the right formulation to target MYC-dependent cancers and to achieve a high intracellular concentration of compounds blocking or attenuating oncogenic MYC activities could be as important as the development of novel MYC-inhibiting principles.

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

Cited by 9 publications

References 73 publications

Comparison of High-Throughput Single-Cell Rna-Seq Methods for Ex Vivo Drug Screening

Comparison of High-Throughput Single-Cell Rna-Seq Methods for Ex Vivo Drug Screening

Comparison of high-throughput single-cell RNA-seq methods for ex vivo drug screening

Strategies to target the cancer driver MYC in tumor cells

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