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

  • Blood. 2015 Sep 3;126(10):1193-202. doi: 10.1182/blood-2014-12-618900.
Donya Moradi Manesh  1 ,  Jad El-Hoss  1 ,  Kathryn Evans  1 ,  Jennifer Richmond  1 ,  Cara E Toscan  1 ,  Lauryn S Bracken  1 ,  Ashlee Hedrick  2 ,  Rosemary Sutton  1 ,  Glenn M Marshall  3 ,  William R Wilson  4 ,  Raushan T Kurmasheva  5 ,  Catherine Billups  6 ,  Peter J Houghton  5 ,  Malcolm A Smith  7 ,  Hernan Carol  1 ,  Richard B Lock  1
Affiliations
  • 1. Children's Cancer Institute, Lowy Cancer Research Centre, and.
  • 2. School of Medical Sciences, University of New South Wales Australia, Sydney, NSW, Australia;
  • 3. Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia;
  • 4. Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand;
  • 5. Nationwide Children's Hospital, Columbus, OH;
  • 6. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN; and.
  • 7. Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.
PMID: 26116659 DOI: 10.1182/blood-2014-12-618900
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.

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