Achm-025: Targeting AKR1C3 to Overcome Aggressive T-Cell Leukemia in Preclinical Studies

A novel prodrug, ACHM-025, was developed to target T-cell acute lymphoblastic leukemia (T-ALL), which has a high expression of the enzyme AKR1C3. This enzyme selectively activates ACHM-025, forming a potent DNA alkylating agent that aims to reduce toxicity compared to current treatments like cyclophosphamide (CPM). The drug's efficacy and selectivity were tested on 25 pediatric T-ALL patient-derived xenografts (PDXs) using various methods, including RNA-seq and flow cytometry.

Orthotopic models in immune-deficient NSG mice were used to evaluate in vivo efficacy, with treatment starting when a certain threshold of human CD45+ cells was reached. The drug's effectiveness was measured by mouse event-free survival (EFS) and objective response rates. ACHM-025 was administered weekly for three weeks in a single mouse trial format, comparing it to a vehicle control.

The results showed that ACHM-025 was well tolerated and had a significant impact on T-ALL PDXs, with 7 out of 25 not relapsing over 250 days and 22 showing an objective response. AKR1C3 expression was a strong predictor of efficacy, with higher expression levels correlating with better drug response. ACHM-025 outperformed CPM both as a single agent and in combination with cytarabine and 6-mercaptopurine, doubling survival time.

Furthermore, ACHM-025 was more effective than nelarabine, the only FDA-approved treatment for relapsed/refractory T-ALL, and showed no signs of resistance upon re-treatment. The combination of ACHM-025 with nelarabine was curative in treating chemoresistant T-ALL PDXs in vivo.

Overall, ACHM-025 demonstrated profound in vivo efficacy against T-ALL PDXs and was significantly more effective than standard treatments, with its efficacy directly linked to AKR1C3 expression levels, indicating its potential as a targeted therapy for aggressive T-ALL.