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

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Drug Discovery

Background:

• In vivo models for acute myeloid leukemia (AML) are low throughput.
• Standard liquid cultures do not replicate the bone marrow niche's mechanical and biochemical properties, impacting drug resistance.
• Advanced synthetic platforms are needed to study mechanical cues' effect on AML drug sensitivity.

Purpose of the Study:

• To develop and utilize a 3D synthetic peptide hydrogel (SAPH) model of the bone marrow niche.
• To screen repurposed FDA-approved drugs for anti-AML activity.
• To investigate the impact of mechanical cues on drug sensitivity in AML.

Main Methods:

• Fabrication of a tunable stiffness and composition SAPH.
• Optimization of SAPH stiffness for AML cell colony growth.
• Screening of FDA-approved drugs (Salinomycin, Vidofludimus, Atorvastatin) in 3D hydrogel models and comparison with liquid culture data.

Main Results:

• AML cell proliferation depended on SAPH stiffness.
• Salinomycin showed efficacy in both early and established AML models.
• Atorvastatin sensitivity increased in the established model, while Vidofludimus showed no efficacy.
• AML patient samples exhibited context-specific drug sensitivity in 3D hydrogels.

Conclusions:

• The SAPH model effectively recapitulates aspects of the bone marrow niche.
• Drug sensitivity in AML is both drug- and context-specific.
• Advanced synthetic platforms offer valuable tools for higher-throughput pre-clinical evaluation of anti-AML drugs.