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

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

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1193-1202
Number of pages10
JournalBlood
Volume126
Issue number10
DOIs
StatePublished - Sep 3 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Manesh, D. M., El-Hoss, J., Evans, K., Richmond, J., Toscan, C. E., Bracken, L. S., Hedrick, A., Sutton, R., Marshall, G. M., Wilson, W. R., Kurmasheva, R. T., Billups, C., Houghton, P. J., Smith, M. A., Carol, H., & Lock, R. B. (2015). AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. Blood, 126(10), 1193-1202. https://doi.org/10.1182/blood-2014-12-618900