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Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML

James, Jenna R.; Curd, Johnathan; Ashworth, Jennifer C.; Abuhantash, Mays; Grundy, Martin; Seedhouse, Claire H.; Arkill, Kenton P.; Wright, Amanda J.; Merry, Catherine L. R.; Thompson, Alexander

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Authors

Jenna R. James

Johnathan Curd

Mays Abuhantash

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CATHY MERRY Cathy.Merry@nottingham.ac.uk
Professor of Stem Glycobiology



Abstract

In vivo models of acute myeloid leukemia (AML) are low throughput, and standard liquid culture models fail to recapitulate the mechanical and biochemical properties of the extracellular matrix-rich protective bone marrow niche that contributes to drug resistance. Candidate drug discovery in AML requires advanced synthetic platforms to improve our understanding of the impact of mechanical cues on drug sensitivity in AML. By use of a synthetic, self-assembling peptide hydrogel (SAPH) of modifiable stiffness and composition, a 3D model of the bone marrow niche to screen repurposed FDA-approved drugs has been developed and utilized. AML cell proliferation was dependent on SAPH stiffness, which was optimized to facilitate colony growth. Three candidate FDA-approved drugs were initially screened against the THP-1 cell line and mAF9 primary cells in liquid culture, and EC50 values were used to inform drug sensitivity assays in the peptide hydrogel models. Salinomycin demonstrated efficacy in both an ‘early-stage’ model in which treatment was added shortly after initiation of AML cell encapsulation, and an ‘established’ model in which time-encapsulated cells had started to form colonies. Sensitivity to Vidofludimus treatment was not observed in the hydrogel models, and Atorvastatin demonstrated increased sensitivity in the ‘established’ compared to the ‘early-stage’ model. AML patient samples were equally sensitive to Salinomycin in the 3D hydrogels and partially sensitive to Atorvastatin. Together, this confirms that AML cell sensitivity is drug- and context-specific and that advanced synthetic platforms for higher throughput are valuable tools for pre-clinical evaluation of candidate anti-AML drugs.

Citation

James, J. R., Curd, J., Ashworth, J. C., Abuhantash, M., Grundy, M., Seedhouse, C. H., …Thompson, A. (2023). Hydrogel-Based Pre-Clinical Evaluation of Repurposed FDA-Approved Drugs for AML. International Journal of Molecular Sciences, 24(4), Article 4235. https://doi.org/10.3390/ijms24044235

Journal Article Type Article
Acceptance Date Feb 10, 2023
Online Publication Date Feb 20, 2023
Publication Date Feb 2, 2023
Deposit Date Apr 12, 2023
Publicly Available Date Mar 29, 2024
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Electronic ISSN 1422-0067
Publisher MDPI AG
Peer Reviewed Peer Reviewed
Volume 24
Issue 4
Article Number 4235
DOI https://doi.org/10.3390/ijms24044235
Keywords acute myeloid leukemia; 3D peptide hydrogel model; candidate drugs
Public URL https://nottingham-repository.worktribe.com/output/17665136
Publisher URL https://www.mdpi.com/1422-0067/24/4/4235

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