Improving the Treatment of Acute Lymphoblastic Leukemia

L-asparaginase (EC 3.5.1.1) was first used as a component of combination drug therapies to treat acute lymphoblastic leukemia (ALL), a cancer of the blood and bone marrow, almost 50 years ago. Administering this enzyme to reduce asparagine levels in the blood is a cornerstone of modern clinical protocols for ALL; indeed, this remains the only successful example of a therapy targeted against a specific metabolic weakness in any form of cancer. Three problems, however, constrain the clinical use of L-asparaginase. First, a type II bacterial variant of L-asparaginase is administered to patients, the majority of whom are children, which produces an immune response thereby limiting the time over which the enzyme can be tolerated. Second, L-asparaginase is subject to proteolytic degradation in the blood. Third, toxic side effects are observed, which may be correlated with the L-glutaminase activity of the enzyme. This Perspective will outline how asparagine depletion negatively impacts the growth of leukemic blasts, discuss the structure and mechanism of L-asparaginase, and briefly describe the clinical use of chemically modified forms of clinically useful L-asparaginases, such as Asparlas®, which was recently given FDA approval for use in children (babies to young adults) as part of multi-drug treatments for ALL. Finally, we review ongoing efforts to engineer L-asparaginase variants with improved therapeutic properties and briefly detail emerging, alternate strategies to treat forms of ALL that are resistant to asparagine depletion.