New treatment strategies for refractory acute myelogenous leukemia (AML) are urgently needed. Dysregulation of the Bcl-2 family of apoptotic regulatory proteins and the PI3K/AKT/mTOR and MEK/ERK pathways occurs frequently in AML, and accumulating evidence indicates that interactions between Bcl-2 family members, in addition to their relative abundance, play key roles in determining cell fate. We now propose a mechanism-based anti-leukemic strategy combining PI3K/mTOR inhibitors with the BH3-mimetic ABT-737/263 in which these three important survival pathways are coordinately disrupted. This approach exploits our recent discovery that in AML, in contrast to other tumor types, PI3K/mTOR inhibitors, unlike other AKT pathway antagonists, inhibit both AKT and ERK. In the presence of BH3-mimetics, this leads to critical alterations in the association between pro-(e.g., Bim, Bak) and anti-(e.g., Mcl-1,Bcl-2/xL) apoptotic proteins, as well as perturbations in their expression (e.g., Mcl-1 down-regulation and Bim up-regulation).
In Specific Aim #1, we will employ genetic strategies (e.g., Bim AKT or ERK phosphorylation mutants, constitutively active or kinase-dead AKT or MEK mutants) to test our hypothesis that synergism stems from, in addition to Mcl-1 down-regulation, unleashing of up-regulated Bim (as well as Bak) from the inhibitory influence of Mcl-1/Bcl- 2/xL.
In Specific Aim 2, we will test the hypotheses that synergistic interactions will also occur in primary, genetically defined AML specimens, and that analogous mechanisms will be responsible. We will also test the hypothesis that PI3K/AKT pathway mutations, and particularly basal AKT activation status, can predict susceptibility to this strategy.
In Specific Aim #3, we will test the hypothesis that PI3K/mTOR inhibitors and BH3-mimetics, which individually target primitive leukemia-initiating cells (e.g., CD34+/CD38-/CD123+), will interact synergistically to eradicate this classically resistant population. We will also characterize, for the first time, AKT and ERK activation in these cells.
In Specific Aim #4, multiple in vivo systemic AML model systems will be employed to extrapolate in vitro findings to intact animals, and to determine whether similar mechanisms underlie anti-leukemic synergism. Fulfillment of these aims will provide the theoretical foundation needed to develop and implement a PI3K pathway inhibitor/BH3-mimetic anti-leukemic strategy, which represents the first to interrupt coordinately three mutually interactive leukemia-related pathways. It may also help to validate pharmacodynamic response determinants, and identify individual AML patients most likely to benefit from this strategy.
Acute myelogenous leukemia (AML) resistant to current therapy is a uniformly fatal disease. The goal of this proposal is to target coordinately the PI3K/AKT and MEK/ERK pathway in conjunction with Bcl-2 family proteins, all dysregulated in AML, with the goal of developing a novel anti-leukemic strategy that may prove particularly effective in the AML patients whose cells exhibit basal AKT activation. If successful, this proposal could lead to a new and more effective treatment strategy for AML patients who have no alternative therapeutic options.
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