The emergence of acid ceramidase as a therapeutic target for acute myeloid leukemia

ABSTRACT

Introduction: Acute myeloid leukemia (AML) is the most common adult leukemia. Only a fraction of AML patients will survive with existing chemotherapy regimens. Hence, there is an urgent and unmet need to identify novel targets and develop better therapeutics in AML. In the past decade, the field of sphingolipid metabolism has emerged into the forefront of cancer biology due to its importance in cancer cell proliferation and survival. In particular, acid ceramidase (AC) has emerged as a promising therapeutic target due to its role in neutralizing the pro-death effects of ceramide.

Areas covered: This review highlights key information about AML biology as well as current knowledge on dysregulated sphingolipid metabolism in cancer and AML. We describe AC function and dysregulation in cancer, followed by a review of studies that report elevated AC in AML and compounds known to inhibit the enzyme.

Expert opinion: AML has a great need for new drug targets and better therapeutic agents. The finding of elevated AC in AML supports the concept that this enzyme represents a novel and realistic therapeutic target for this common leukemia. More effort is needed towards developing better AC inhibitors for clinical use and combination treatment with existing AML therapies.

KEYWORDS:

• Acid ceramidase
• ceramide
• sphingosine 1-phosphate
• acute myeloid leukemia

Article highlights

• Novel therapeutics for AML are greatly needed due to lack of treatment advances

• Sphingolipid metabolism is dysregulated in AML and contributes to blast survival

• Acid ceramidase is upregulated in AML and elevated activity correlates with reduced patient survival

• Acid ceramidase inhibitors exhibit preclinical efficacy against AML in vitro and in vivo

• Optimized acid ceramidase inhibitors are needed for advancement to clinical trials

This box summarizes key points contained in the article.

Acknowledgments

We apologize to any investigators whose important work was not included due to space limitations. The authors gratefully acknowledge the collaborative support and discussions of all members of the projects and cores within our funded Program Project (P01) “Targeted Sphingolipid Metabolism for Treatment of AML”. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the National Cancer Institute of the National Institutes of Health [P01CA171983 and T32-GM007055].