Biomarker of sensitivity to PR-104 in leukemia.

Acute lymphoblastic leukemia (ALL) represents the most common childhood malignancy. Because patients with T-ALL are more likely to experience induction therapy failure and early relapse compared with the B-cell precursor subtype (BCPALL), there is a high medical need to develop novel treatment strategies for these patients. PR-104, a pre-prodrug currently tested in adult early clinical trials for the treatment of cancer, is converted in vivo to the nitrogen mustard prodrug PR-104A and subsequently activated via hypoxiadependent reductases or independently of hypoxia by AKR1C3. Because AKR1C3 is frequently overexpressed in human cancers, including leukemia, PR-104 is considered a promising targeted drug for cancers with high AKR1C3 expression. Testing of PR-104 in a panel of primary pediatric cancer xenografts in immune-deficient mice has previously revealed high in vivo efficacy in childhood leukemia, inparticular againstT-ALL compared with BCP-ALL, when tested at doses providingplasmapharmacokinetics achievable in humans. However, the underlyingmechanism for this differential sensitivity of ALL subtypes remained elusive. Against this background, the aim of this study was to test whether AKR1C3 is a predictive biomarker of in vivo PR-104 sensitivity. To investigate whether PR-104 exhibits lineage-specific in vivo efficacy against T-ALL,MoradiManesh et al extended the evaluation of PR-104 to a panel of patientderived pediatric ALL xenografts. PR-104 exerted significantly greater antileukemic efficacy against T-ALL xenografts than BCP-ALL. Comparison of PR-104 with an induction-type regimen consisting of vincristine, dexamethasone, and L-asparaginase revealed that single-agent PR-104 was more efficacious against T-ALL xenografts than this standard-of-care regimen. To identify a biomarker for PR-104 sensitivity the authors performed gene expression profiling comparing PR-104A–sensitive and PR-104A–resistant xenografts. This analysis revealed AKR1C3 as one of the top 2 differentially expressed genes, andAKR1C3 expression correlatedwith PR-104/PR-104A sensitivity in vivo and in vitro. A causal relationship between AKR1C3 expression and sensitivity to PR-104 was then demonstrated by overexpression of AKR1C3 in a resistant BCP-ALL xenograft, which led to increased sensitivity to PR-104 in vivo. To validate their results, the authors went on to test ex vivo sensitivity to PR-104A against patient-derived leukemic blasts. Primary T-ALL cells proved to be more sensitive than BCP-ALL to PR-104A in vitro, and this sensitivity correlated with AKR1C3 expression. Together, these findings indicate that PR-104 represents a promising novel therapeutic for refractory and relapsed T-ALL and that AKR1C3 expression could serve as a biomarker to select patients who will most likely benefit from treatment with PR-104 in prospective clinical trials. This study has important clinical implications. In line with the present study showing the safety of PR-104 in preclinical mouse xenograft models with no toxicityrelated events, PR-104 proved to be well tolerated in early-phase clinical trials in adult solid tumors and hematologic malignancies. PR-104 may be of particular interest for refractory and relapsed cases of T-ALL, as PR-104 has been shown to specifically target hypoxic regions of leukemia infiltration (eg, in the bone marrow), which are considered as important contributors to chemoresistance and relapse in ALL. Nevertheless, there are also a number of open questions. Although in the study by Moradi Manesh et al, AKR1C3 expression levels proved to be a strong predictor of response to PR-104 independently of hypoxia in ALL, AKR1C3 expression levels did not significantly correlate with overall tumor responsiveness to PR-104 across a panel of solid and hematologic pediatric cancers in another study. Furthermore, ex vivo testing of primary T-ALL blasts in the present study revealed 1 case with low AKR1C3 expression but high sensitivity to PR-104. Although the molecular basis of this outlier is currently not well understood, this observation suggests that AKR1C3maynot universally serve as a suitable biomarker to select patients who may benefit from PR-104. Moreover, the underlying mechanisms responsible for the reported increased expression levels of AKR1C3 in T-ALL compared with BCP-ALL remain subject to further investigation. Also clinically relevant is the question as to whether or not PR-104 is active against biologically distinct subgroups of T-ALL at high risk of treatment resistance and relapse that have recently been identified, such as early T-cell precursor ALL. Another issue relates to PR-104–based drug combinations to exploit synergistic drug interactions or to overcome resistance toPR-104. Because DNA interstrand cross-link repair proficiency, in addition to hypoxia and reductase activity, has been reported to determine sensitivity to the alkylating agent PR-104, evaluation of PR-104 together with DNA repair inhibitors might be of special interest. In sum, the present study supports the further investigation of PR-104 for refractory or relapsedT-ALLpatients that are selected by high AKR1C3 expression in their leukemic blasts as a biomarker. Conflict-of-interest disclosure: The author declares no competing financial interests. n