Creating a transient metabolic catastrophe for AML therapy

Proteasome inhibitors are effective in a small subset of malignancies, the most important one is multiple myeloma, a cancer of plasma cells. The underlying reasons for the exquisite sensitivity of myeloma to proteasome inhibitors are associated with the activation of higher stress conditions that ultimately promote apoptosis. Similar to myeloma, acute myeloid leukemia (AML) develops in the bone marrow and disseminates between bone marrows until becomes detectable in the bloodstream. The bone marrow microenvironment supports AML survival and promotes resistance to therapy. We have shown that a common feature associated with proteasome inhibition in vitro and in vivo is the suppression of mTORC1 activity, a kinase that controls cell metabolism and activation thereof is common to multiple cancers, including AML and myeloma. We reasoned that mTORC1 suppression is a key factor in promoting survival to proteasome inhibition and contributes to development of resistance. We developed a small molecule that activates mTORC1 and synergizes with PIs to kill AML in vitro and in vivo. When the molecule is combined with a proteasome inhibitor, mitochondrial respiration is strongly suppressed, and the membrane potential of the mitochondria is gradually lost. When the mTORC1 activator is added to quiescent AML cells, cell cycle resumes, and the cells regain sensitivity to chemotherapy. We will study the underlying mechanisms of both phenomena, mitochondrial damage, and reversal of quiescence. We will map the mitochondrial respiratory lesion, identify the predisposition of the mitochondria to stress and establish a connection with drug resistance. We will determine the translation mechanisms that reverse quiescence and evaluate the importance to AML therapy using in vitro and in vivo models. This study aims to establish a mechanistic understanding of the role of mTOR hyperactivation as a chemosensitizer of AML. These pharmacodynamic features should unravel novel metabolic vulnerabilities in AML that can be addressed pharmacologically.