UC Irvine researchers have developed a new method to precisely activate chemotherapy drugs, a strategy intended to deliver potent cancer treatments while minimizing harm to healthy tissue. The findings, published in *Signal Transduction and Targeted Therapy*, demonstrate a novel way to use a cell’s own protein-recycling machinery to trigger drug activation.
The challenge with traditional chemotherapy is that the same powerful drugs that kill cancer cells can also damage healthy tissue. To address this, UC Irvine researchers designed an experimental prodrug, a compound that is pharmacologically inert until it becomes active within the body.
This new approach essentially puts a safety lock on a highly potent anticancer agent called monomethyl auristatin E (MMAE). While affixed to a short peptide, MMAE is “caged,” which limits its ability to harm healthy cells. This lock is designed to be removed once the drug enters cancer cells that exhibit high levels of a specific protein-destroying activity.
At the core of this strategy is the immunoproteasome, a specialized form of the proteasome, which is the cellular mechanism responsible for breaking down proteins. Activity of the immunoproteasome can be elevated in various inflammatory conditions and numerous cancers. The researchers designed the prodrug to take advantage of this difference.
Darci Trader, UC Irvine associate professor of pharmaceutical sciences and vice chair of postgraduate studies in that department, stated that the goal is to leverage something cancer cells are already doing differently and use that difference to activate a drug where toxicity is desired. Trader noted that this method harnesses unique immunoproteasome activity as a prodrug trigger, rather than relying on traditional enzyme inhibitor development.
Many existing targeted cancer therapies use antibodies to recognize specific proteins, or antigens, on the surface of cancer cells, acting as address labels to deliver drugs directly to those cells. While effective for some cancers, this approach requires identifying a suitable surface marker that is abundant on cancer cells and distinct from healthy tissue, a target not available for all cancers.
The UC Irvine strategy explores an alternative route. Instead of focusing on surface markers, researchers investigated whether they could exploit processes occurring inside cancer cells. Claudia Benavente, UC Irvine associate professor of pharmaceutical sciences and a member of the Chao Family Comprehensive Cancer Center, explained that this work expands how targeted therapy is considered. Benavente added that cancer cells are defined not only by their surface but also by important biological differences in their function, which can reveal vulnerabilities for therapeutic targeting.
Initial experiments confirmed that the immunoproteasome could recognize their specially designed peptide and release MMAE. Cancer cells exhibiting high immunoproteasome activity were highly sensitive to the prodrug, while healthy cells with low activity remained viable. This distinction suggests a potential method for creating a therapeutic window, allowing for attack on cancer while limiting healthy tissue exposure to the drug.
The research team then tested this approach in small cell lung cancer, an aggressive form of the disease with limited treatment options. In laboratory studies, the experimental prodrug maintained strong cancer-killing activity in small cell lung cancer cells. Further testing in a preclinical model demonstrated that the strategy could function in a living system, confirming the prodrug remained masked during transit through the body and became active within the tumor. Treatment in this model led to a significant reduction in tumor volume without significant toxicities.
These findings provide early evidence that immunoproteasome activity could serve as an internal switch for more selectively delivering potent drugs. The work is currently preclinical, and additional research is necessary before the approach can be evaluated as a treatment for patients. Researchers also need to better understand which specific cancers have sufficiently high immunoproteasome activity to benefit from this strategy. However, given that elevated immunoproteasome activity occurs across multiple cancer types, the researchers believe the concept could extend beyond small cell lung cancer.
This research highlights how early investment in basic and translational science can lead to the development of unconventional ideas into potential therapeutic strategies. The work received support from various sources, including startup funding from the UC Irvine School of Pharmacy & Pharmaceutical Sciences and the Chao Family Comprehensive Cancer Center. Additional funding came from the National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, the American Lung Association, and UC Irvine’s Vertex Diversity Graduate Research Program.
The study involved researchers across pharmaceutical sciences, cancer biology, physiology and biophysics, developmental and cell biology, and other areas at UC Irvine. The research was led by Cody A. Loy, who earned a Ph.D. in pharmaceutical sciences this year, and included UC Irvine researchers Yijun Gu, Samuel C. Kim, Mariam V. Mohagheghi, Noah B. Trask, Marina Suarez-Pizarro, Lisa E. Wagar, Benavente, and Trader. Darci Trader noted that understanding and measuring the activity of cellular machinery has progressed into a strategy for controlling when a powerful drug becomes active, emphasizing how fundamental discoveries can create new possibilities for drug development.
