Repurposing anthelmintic agents to eradicate resistant leukemia

Area of Science:

• Hematology
• Oncology
• Pharmacology

Background:

• Genomic profiling in acute lymphoblastic leukemia (ALL) has advanced, yet identifying drug targets and predicting treatment response remains difficult.
• Discovering novel therapeutic strategies is crucial for overcoming drug resistance and improving outcomes in ALL.

Purpose of the Study:

• To identify novel anti-leukemia vulnerabilities in acute lymphoblastic leukemia (ALL) through drug repurposing.
• To evaluate the efficacy of FDA-approved compounds, particularly anthelmintic agents, against primary ALL cells.

Main Methods:

• A drug screen of 2487 FDA-approved compounds was conducted on primary human ALL samples within a bone marrow microenvironment model.
• High-content image analysis was used to assess drug efficacy.
• Ex vivo validation was performed on 55 primary ALL samples, including refractory and relapsed cases.

Main Results:

• Macrocyclic lactone anthelmintic agents demonstrated potent anti-leukemia activity, comparable to current induction chemotherapy agents.
• Anthelmintic agents increased intracellular chloride levels, leading to mitochondrial depolarization and cell death in leukemia cells.
• Synergistic anti-leukemia effects were observed when combining anthelmintic agents with navitoclax or dexamethasone.

Conclusions:

• Anthelmintic agents possess significant anti-leukemia activity and represent a promising avenue for drug repurposing in ALL treatment.
• Targeting cell death pathways with anthelmintic agents, especially in combination therapies, holds potential for eradicating refractory leukemia.