PO-028 Effective targeting of nad+biosynthesis in patient-derived xenograft models of high-risk paediatric acute lymphoblastic leukaemia
2018
Introduction Children diagnosed with high-risk acute lymphoblastic leukaemia (ALL) have a dismal prognosis. For those patients who survive treatment, currently used chemotherapeutics are associated with severe health problems, indicating the urgent need for safer and more potent therapeutic strategies. We have therefore investigated the therapeutic potential of a newly developed inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), OT-82, which has previously shown efficacy within a safe therapeutic window against a range of preclinical haematopoietic malignancy models. Material and methods The therapeutic potency of OT-82 against high-risk ALL was evaluated in a panel of well characterised paediatric patient-derived xenograft (PDX) models that accurately recapitulate the cellular and molecular features of the original disease and for which in vivo responses to chemotherapeutic agents were significantly correlated with the clinical outcome of the patients from whom the PDX were derived. The PDX panel comprised MLL-rearranged ALL (n=6), B-Cell Precursor ALL (n=9), including Philadelphia chromosome positive (Ph + ) and Ph-like ALL, as well as T-cell ALL (n=6) including early T cell precursor ALL. Response to treatment was assessed by event-free survival and stringent objective response criteria modelled after the clinical setting. Results and discussions OT-82 was well tolerated and demonstrated impressive single agent in vivo activity against the high-risk ALL PDX panel, achieving significant leukaemia growth delay in 95% (20/21) and objective responses in 86% (18/21) of PDX. In addition, OT-82 enhanced the in vivo efficacy of targeted therapy dasatinib, used in the treatment of Ph + ALL patients, and chemosensitised two highly resistant MLL-rearranged ALL PDX to chemotherapeutic cytarabine. Confirming its action as a NAMPT inhibitor, OT-82 depleted leukaemia cell NAD + levels thereby decreasing the amount of available ATP and inhibiting the NAD + -requiring DNA damage repair enzyme PARP-1, culminating in apoptosis induction. The previously identified markers for in vitro susceptibility to other NAMPT inhibitors such as baseline NAD + and NAMPT levels, did not predict in vivo responsiveness of high-risk ALL PDX to OT-82. Conclusion Our study provides evidence that the NAMPT inhibitor OT-82 is a promising new therapeutic strategy for a broad spectrum of high-risk and poor outcome paediatric ALL for which novel therapeutic options are urgently needed.
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