AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia.

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.

• Authors: Donya Moradi Manesh, Jad El-Hoss, Kathryn Evans, Jennifer Richmond, Cara E Toscan, Lauryn S Bracken, Ashlee Hedrick, Rosemary Sutton, Glenn M Marshall, William R Wilson, Raushan T Kurmasheva, Catherine Billups, Peter J Houghton, Malcolm A Smith, Hernan Carol, Richard B Lock
• Journal: Blood (Blood) Vol. 126 Issue 10 Pg. 1193-202 (Sep 03 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 26116659 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Biomarkers, Tumor
• Nitrogen Mustard Compounds
• PR-104A
• 3-Hydroxysteroid Dehydrogenases
• Hydroxyprostaglandin Dehydrogenases
• AKR1C3 protein, human
• Aldo-Keto Reductase Family 1 Member C3

Topics

• 3-Hydroxysteroid Dehydrogenases (biosynthesis)
• Adolescent
• Aldo-Keto Reductase Family 1 Member C3
• Animals
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (analysis)
• Cell Survival (drug effects)
• Child
• Child, Preschool
• Female
• Humans
• Hydroxyprostaglandin Dehydrogenases (biosynthesis)
• Immunoblotting
• Male
• Mice
• Nitrogen Mustard Compounds (pharmacology)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (metabolism, pathology)
• Real-Time Polymerase Chain Reaction
• Xenograft Model Antitumor Assays