Targeting Acid Ceramidase in Acute Myeloid Leukemia 323 views

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by expansion of myeloid blasts. These immature cells overpopulate the blood and bone marrow leading to anemia, neutropenia and thrombocytopenia associated with increased risk of infection. AML progresses rapidly and many patients relapse after treatment. Only about 25% of patients survive five years past diagnosis. Although our understanding of the disease has evolved significantly, many of the latest therapeutics do not dramatically improve survival. One major challenge in treating AML is genetic heterogeneity among patients. For this reason, we aim to characterize and target a common biochemical dependence in AML cells. Dysregulation of sphingolipid metabolism is an emerging area of study in several cancers including AML. Generally, patients have increased levels of enzymes that form pro-survival sphingosine 1-phosphate and decreased levels of enzymes that form pro-death ceramides. These enzymes are crucial for regulating cell fate, and identifying compounds that target these enzymes creates an opportunity to restore this balance. In these studies, we identify and characterize SACLAC an inhibitor of one of these enzymes, acid ceramidase (AC). AC detoxifies pro-death ceramides, and blocking AC causes accumulation of these pro-death signals. AC is elevated in AML patients and is associated with poor prognosis, highlighting its potential as a therapeutic target. We found that SACLAC potently inhibits AC and increases ceramide levels. SACLAC induces apoptosis through altered splicing of Mcl-1. Importantly, we demonstrate that SACLAC reduces leukemic burden at the cellular level in two mouse models of AML. However, SACLAC delivery is limited by poor solubility. To address this, we formulated a nanoliposomal SACLAC (nanoSACLAC) to improve delivery and safety in vivo. We found that nanoSACLAC has reduced potency due to serum interactions, but this can be attenuated by adding cholesterol into the nanoliposome. Since SACLAC targets Mcl-1, we also explored the potential for co-treatment with therapeutics with known Mcl-1-mediated resistance. In fact, AML cells that were resistant to Bcl-2 inhibitor ABT-199—currently approved to treat older adults with AML—were sensitized when they were co-treated with SACLAC. Together, these studies highlight SACLAC as an interesting novel therapeutic with potential to inform further investigation of sphingolipid-based therapies for AML.

PHD (Doctor of Philosophy)

sphingolipids; acid ceramidase; splicing; ceramide; apoptosis; acute myeloid leukemia; drug characterization

English

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2019-11-25