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.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
