A research team at the University of Illinois Chicago (UIC) has achieved a significant breakthrough in cancer treatment by redesigning asparaginase, a crucial enzyme therapy for acute lymphoblastic leukemia (ALL), to eliminate its severe side effects while maintaining therapeutic efficacy.
The innovative approach, detailed in a recent paper published in Cancer Letters, addresses longstanding challenges with traditional asparaginase treatment, which can cause serious complications including blood clots and liver damage. The research was led by Dr. Arnon Lavie, professor of biochemistry and molecular genetics at UIC and member of the University of Illinois Cancer Center.
Engineering a Safer Treatment
The research team's novel approach involved returning to asparaginase's original source - the guinea pig - where the enzyme was first discovered in the 1950s. The scientists chose to work with mammalian enzymes due to their similarity to human proteins, potentially reducing immune responses in patients.
"We characterized several different asparaginases from the guinea pig to identify the one with highly unique anticancer properties," explained Amanda Schalk, a research assistant professor at UIC who has been involved in the project since its inception in 2011. "Then we re-engineered it to see if we could make that enzyme even better."
Promising Preclinical Results
In laboratory studies using mouse models of ALL, the redesigned enzyme demonstrated equivalent therapeutic effectiveness to traditional asparaginase but without causing significant weight loss - a common indicator of toxicity. The treatment also showed promising results against melanoma and liver cancer cells that share similar vulnerabilities to asparagine depletion.
A serendipitous discovery during the enzyme's modification process revealed an extended half-life, which could significantly reduce treatment frequency. "It was a very happy accident, which turns out to be extremely important," noted Dr. Lavie. "Ultimately, it means that you can treat the patient with a lower dose, and with a longer interval between treatments."
Advancing Toward Clinical Trials
The project has gained significant momentum, with Enzyme by Design, Dr. Lavie's company, receiving selection by the National Cancer Institute Experimental Therapeutics Program in 2023 to conduct necessary preclinical work. The research has secured nearly $4 million in funding and is progressing toward FDA approval for human clinical trials.
"After more than a decade, we will finally get the chance to see how the drug performs in humans," said Dr. Lavie. The team is currently conducting required toxicity, pharmacokinetic, and manufacturing studies to obtain FDA clearance for initial clinical trials.
The development represents a potential paradigm shift in leukemia treatment, particularly for patients who cannot tolerate current asparaginase therapies. If successful in clinical trials, this modified enzyme could not only improve ALL treatment but also expand therapeutic options for other cancer types.
