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

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: Apr 20, 2023
• Journal: International Journal of Molecular Sciences
• Print ISSN: 1661-6596
• Electronic ISSN: 1422-0067
• Publisher: MDPI
• 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