Scientists at the University of Illinois Chicago (UIC) have developed an innovative redesign of a treatment for acute lymphoblastic leukemia (ALL), the most common blood cancer in children. This groundbreaking treatment addresses a significant limitation of current therapies by minimizing severe side effects, such as blood clots and liver damage. The new treatment, if approved, could not only be tolerated by a broader range of leukemia patients but may also pave the way for treatments targeting other cancers.
The Development of a Novel Asparaginase Treatment
The UIC team, led by Arnon Lavie, a professor of biochemistry and molecular genetics, has redesigned the enzyme asparaginase, a crucial component in the treatment of ALL. Asparaginase works by depleting an essential amino acid called asparagine, which is necessary for the growth of cancer cells but is not produced by most normal cells. By starving the cancerous cells of asparagine, asparaginase effectively kills them while allowing healthy cells to survive.
Despite its effectiveness in treating ALL, traditional asparaginase comes with significant drawbacks. Asparaginase, which is derived from bacteria, often provokes a strong immune response in some patients, leading to allergic reactions and forcing treatment to be halted. Additionally, the enzyme has a short half-life, meaning it needs to be administered intravenously multiple times per week during treatment. This increases the treatment burden on patients, especially children, who are already dealing with the physical and emotional toll of cancer treatment.
Redesigning the Enzyme for Better Tolerance and Efficacy
The UIC team, including Amanda Schalk, a research assistant professor at UIC, and collaborators from Ghent University in Belgium, set out to improve the enzyme’s safety and efficacy by leveraging protein engineering. Their goal was to create a version of asparaginase that would be better tolerated by patients and require fewer treatments, all while maintaining its anticancer properties.
In the 1950s, asparaginase was originally discovered in the guinea pig, an animal whose enzymes are similar to those found in humans. The research team hypothesized that using a guinea pig-derived enzyme could result in fewer immune reactions compared to bacterial-based asparaginase. After screening several different asparaginases from guinea pigs, the team identified a promising enzyme with exceptional anticancer properties.
To further enhance the enzyme’s potential, the researchers took the next step of “humanizing” the guinea pig enzyme. This involved modifying its molecular structure to make it more similar to the version of asparaginase found in humans. The team used structural analysis to identify areas of the enzyme that could be altered without compromising its function or stability. By making these targeted changes, the team hoped to create a version of asparaginase that would be more compatible with the human immune system, thereby reducing the risk of adverse reactions.
A Fortuitous Discovery: Extending the Enzyme’s Half-Life
In an unexpected turn, the team’s redesign not only improved the enzyme’s compatibility with human patients but also extended its half-life—a critical factor in treatment. Traditional asparaginase requires frequent infusions because it is rapidly cleared from the body. By extending the enzyme’s half-life, the team effectively reduced the frequency of infusions, making the treatment more convenient and less burdensome for patients.
“This was a very happy accident,” said Arnon Lavie. “It turns out to be extremely important because it means you can treat the patient with a lower dose, and with a longer interval between treatments.”
This extended half-life is crucial for children and other patients who might be unable to tolerate frequent treatments. It also holds promise for improving patient compliance and overall outcomes.
Success in Preclinical Models: Leukemia and Beyond
The UIC team tested their redesigned asparaginase in various animal models, demonstrating its effectiveness in treating acute lymphoblastic leukemia. Mice treated with the new compound showed recovery comparable to those treated with traditional asparaginase, but without the dramatic weight loss and other signs of toxicity typically associated with the conventional treatment. These promising results suggest that the new enzyme is equally effective at killing leukemia cells, but without the severe side effects.
The team’s research also showed that the enzyme could effectively target other cancers, such as melanoma and liver cancer, which, like ALL, produce tumor cells that cannot make their own asparagine. In both cancer models, the redesigned enzyme successfully killed the cancer cells, further expanding the potential uses of the treatment beyond leukemia.
“It has been incredible to see the progress made from discovery to drug development over the past 13 years,” said Amanda Schalk. “It’s so exciting to be getting closer to the clinic and the possibility of providing life-changing benefits to patients.”
Moving Toward Clinical Trials
These preclinical successes provide strong evidence for the potential of this novel treatment, but the work is far from finished. The next step involves conducting toxicity, pharmacokinetic, and manufacturing studies to meet the necessary requirements for clinical trials. The team’s progress has already garnered the attention of the National Cancer Institute’s Experimental Therapeutics Program, which selected Lavie’s company, Enzyme by Design, to conduct the preclinical work required for approval to test the drug in humans.
Lavie expressed his excitement about the opportunity to translate years of academic research into a treatment that could directly benefit patients: “The reality is that the pharmaceutical industry is primarily interested in de-risked molecules, and our goal is to de-risk our novel asparaginase sufficiently so that it becomes an interesting therapeutic for a company.”
In 2023, the UIC team received approval to proceed with the essential preclinical studies, paving the way for future clinical trials. If successful, this redesigned enzyme could not only offer new hope for pediatric leukemia patients but also become a versatile cancer therapy for a broader range of cancers.
A Decade of Research and Dedication
The progress made by the UIC team has been a decade-long effort. From the early stages of enzyme discovery to protein engineering and testing in animal models, the team’s work has been a testament to perseverance and scientific innovation. Lavie, who has been dedicated to this research since the project’s inception, acknowledged the significant support from the University of Illinois and the broader scientific community in bringing this work to fruition.
“After more than a decade, we will finally get the chance to see how the drug performs in humans,” Lavie said. “The university has been very supportive of this project, and of me as a faculty member, to try to realize this dream of translating an academic discovery to something that could help patients.”
Conclusion: A Promising Future for Cancer Treatment
The redesigned asparaginase represents a promising new frontier in the treatment of acute lymphoblastic leukemia and potentially other cancers. By addressing the critical issue of side effects and improving the enzyme’s efficiency, the UIC team has created a treatment that could improve the lives of countless cancer patients. The results so far have been promising, and with further studies and clinical trials, this novel approach could soon offer a safer and more effective alternative to traditional cancer treatments.
This breakthrough exemplifies how academic research, supported by collaboration and innovation, can lead to significant advancements in medical treatments. As the research moves closer to clinical trials, it holds the potential to change the landscape of pediatric leukemia treatment and extend the possibilities for treating a wide range of cancers.
Reference: Maaike Van Trimpont et al, A human-like glutaminase-free asparaginase is highly efficacious in ASNSlow leukemia and solid cancer mouse xenograft models, Cancer Letters (2024). DOI: 10.1016/j.canlet.2024.217404