title: 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.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, and.
authors.forename: Donya
authors.initials: D
authors.lastname: Moradi Manesh
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, and.
authors.forename: Jad
authors.initials: J
authors.lastname: El-Hoss
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, and.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Evans
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Richmond
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, and.
authors.forename: Cara E
authors.initials: CE
authors.lastname: Toscan
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, and.
authors.forename: Lauryn S
authors.initials: LS
authors.lastname: Bracken
authors.affiliation: School of Medical Sciences, University of New South Wales Australia, Sydney, NSW, Australia;
authors.forename: Ashlee
authors.initials: A
authors.lastname: Hedrick
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, and.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Sutton
authors.affiliation: Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia;
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.affiliation: Auckland Cancer Society Research Centre, The University of Auckland, Auckland, New Zealand;
authors.forename: William R
authors.initials: WR
authors.lastname: Wilson
authors.affiliation: Nationwide Children's Hospital, Columbus, OH;
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN; and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Billups
authors.affiliation: Nationwide Children's Hospital, Columbus, OH;
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, and.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.affiliation: Children's Cancer Institute, Lowy Cancer Research Centre, and.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000096:biosynthesis*; D000293:Adolescent; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000096:biosynthesis*; D015151:Immunoblotting; D008297:Male; D051379:Mice; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009588:Nitrogen Mustard Compounds; C524170:PR-104A; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3