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Published on: October 11, 2018
AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia
Donya Moradi Manesh1, Jad El-Hoss1, Kathryn Evans1
1Children's Cancer Institute, Lowy Cancer Research Centre, and.
Abstract:
PR-104, a phosphate ester of the nitrogen mustard prodrug PR-104A, has shown evidence of efficacy in adult leukemia clinical trials. Originally designed to target hypoxic cells, PR-104A is independently activated by aldo-keto-reductase 1C3 (AKR1C3). The aim of this study was to test whether AKR1C3 is a predictive biomarker of in vivo PR-104 sensitivity. In a panel of 7 patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts, PR-104 showed significantly greater efficacy against T-lineage ALL (T-ALL) than B-cell-precursor ALL (BCP-ALL) xenografts. Single-agent PR-104 was more efficacious against T-ALL xenografts compared with a combination regimen of vincristine, dexamethasone, and l-asparaginase. Expression of AKR1C3 was significantly higher in T-ALL xenografts compared with BCP-ALL, and correlated with PR-104/PR-104A sensitivity in vivo and in vitro. Overexpression of AKR1C3 in a resistant BCP-ALL xenograft resulted in dramatic sensitization to PR-104 in vivo. Testing leukemic blasts from 11 patients confirmed that T-ALL cells were more sensitive than BCP-ALL to PR-104A in vitro, and that sensitivity correlated with AKR1C3 expression. Collectively, these results indicate that PR-104 shows promise as a novel therapy for relapsed/refractory T-ALL, and that AKR1C3 expression could be used as a biomarker to select patients most likely to benefit from such treatment in prospective clinical trials.
Insights
Aldo-keto-reductase 1C3 (AKR1C3) expression predicts sensitivity to the novel leukemia drug PR-104. Higher AKR1C3 levels in T-cell acute lymphoblastic leukemia (T-ALL) correlate with better PR-104 efficacy, suggesting AKR1C3 as a predictive biomarker.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- PR-104 is a nitrogen mustard prodrug activated by aldo-keto-reductase 1C3 (AKR1C3).
- PR-104 has shown efficacy in adult leukemia, with potential for pediatric applications.
- AKR1C3 is a key enzyme in the activation of PR-104.
Purpose of the Study:
- To determine if AKR1C3 expression can serve as a predictive biomarker for PR-104 sensitivity in pediatric acute lymphoblastic leukemia (ALL).
- To evaluate the efficacy of PR-104 in different subtypes of pediatric ALL.
Main Methods:
- Testing PR-104 efficacy in patient-derived pediatric ALL xenografts (T-ALL vs. BCP-ALL).
- Measuring AKR1C3 expression levels in xenografts and patient samples.
- Assessing PR-104 sensitivity in vitro and in vivo in relation to AKR1C3 expression.
Main Results:
- PR-104 demonstrated significantly greater efficacy against T-ALL xenografts compared to BCP-ALL xenografts.
- AKR1C3 expression was higher in T-ALL and correlated with PR-104 sensitivity.
- Overexpression of AKR1C3 sensitized resistant BCP-ALL xenografts to PR-104.
- Patient-derived T-ALL cells showed greater in vitro sensitivity to PR-104A than BCP-ALL cells, correlating with AKR1C3 levels.
Conclusions:
- PR-104 shows promise as a novel therapeutic for relapsed/refractory T-ALL.
- AKR1C3 expression is a potential predictive biomarker for selecting patients likely to benefit from PR-104 treatment.
- This study supports the use of AKR1C3 as a biomarker in future clinical trials for PR-104.
