Project Details
Description
ABSTRACT
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 1α (HIF-1α). 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-1α 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.
Status | Active |
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Effective start/end date | 6/14/19 → 5/31/24 |
Funding
- National Cancer Institute: $625,201.00
- National Cancer Institute: $469,082.00
- National Cancer Institute: $587,548.00
- National Cancer Institute: $618,721.00
- National Cancer Institute: $287,375.00
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