T-cell acute lymphocytic leukemia (T-ALL) is an aggressive hematological malignancy. Despite successes in curing pediatric T-ALL with intensive chemotherapy, the majority of adult T-ALL patients will relapse and die of their disease. We and others have demonstrated that in T-ALL, oxidative phosphorylation (OxPhos) generates energy and metabolic intermediates necessary to promote growth and support survival, by regulation of mitochondrial Complex I (CI). This unique metabolic and mitochondrial biology makes T-ALL vulnerable to strategies that target OxPhos. We have identified a first-in-class nanomolar-potent inhibitor of OxPhos (OxPhosi), IACS-010759, that inhibits CI of the OxPhos respiratory chain, blocks oxygen consumption, and destabilizes Hypoxia-Inducible Factor 1? (HIF-1?). Our data demonstrated profound growth-inhibitory effects of this agent in T-ALL cell lines and primary ALL cells at low nM concentrations, with minimal toxicity against normal BM cells. OxPhos blockade in vivo was tolerable as a single agent, yet had only a modest therapeutic benefit. However, targeting the OxPhos-driven biology of T-ALL is likely to be effective in the right combinations. We have demonstrated synergy of IACS-010759 with standard chemotherapy agents used in T-ALL, both in vitro and in the in vivo T-ALL PDX models. We will translate these findings in our Aim 3, by a Phase I/II clinical trial of IACS-010759 combined with a modified hyperCVAD/L-asparaginase regimen in relapsed/refractory ALL patients, using the recommended Phase 2 dose of IACS-010759 from the ongoing AML trial. Matching pre-clinical studies on T-ALL PDX models in Aim 1 will develop biomarkers of response in ways not possible in human subjects. We have further identified a synthetically lethal combination in T-ALL cells of OxPhosi with an inhibitor of the lactate transporter MCT1 (AZD3965, now in Phase 2 trials), and in Aim 2 will investigate mechanisms of this synergy. We will also characterize the effect of HIF-1? blockade by IACS-010759 on T-ALL cells using in vivo two-photon imaging of metabolic NADH and oxygen sensing by phosphorescence lifetime microscopy. Finally, we will conduct further screening with a novel high-content metabolomic drug library to identify other combinations with IACS-010759 that are toxic to T-ALL cells but not normal cells, for future therapeutic applications. We believe that the proposed studies will provide mechanistic insights into the newfound vulnerability of T-ALL to OxPhosi; identify candidate predictive biomarkers for the combination of IACS-010759 with chemotherapy or MCT1 inhibitor; and develop combinations for the next generation of OxPhosi trials for T-ALL.
A leukemia called T-ALL cannot be cured by current treatments in more than half of adult patients. This project will test novel experimental drug affecting tumor metabolism, alone and in combinations, for suppression of ALL disease development in laboratory models. Phase I/II clinical trial will examine safety and efficacy of combinations with standard chemotherapy in relapsed/refractory ALL.
