UC Irvine researchers have developed a new approach to chemotherapy that aims to reduce damage to healthy tissues by activating potent cancer drugs only within cancer cells. The findings, published in the Nature Portfolio journal *Signal Transduction and Targeted Therapy*, detail a method that uses a cell's own protein-recycling machinery as a trigger for drug activation.
The challenge with traditional chemotherapy is that the same drugs capable of killing cancer cells can also harm healthy tissue throughout the body.
To address this, UC Irvine researchers designed an experimental prodrug, which is a pharmacologically inert compound that becomes active after administration. This prodrug incorporates an extremely toxic anticancer agent called monomethyl auristatin E (MMAE), which is temporarily "caged" by a short peptide. While affixed, MMAE's ability to harm cells is limited.
The key to this strategy lies in the immunoproteasome, a specialized form of the proteasome, which is the cellular mechanism responsible for breaking down proteins. Immunoproteasome activity can be elevated in various cancers and inflammatory conditions. The prodrug is engineered so that when elevated immunoproteasome activity is detected inside a cancer cell, the attached peptide is cut, and the active drug, MMAE, is released.
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 a difference in cancer cell activity to activate the drug precisely where toxicity is desired. Trader noted that this approach harnesses unique immunoproteasome activity as a prodrug trigger, rather than relying on traditional enzyme inhibitor development.
Many existing targeted cancer therapies use antibodies to identify specific proteins on the surface of cancer cells, acting as carriers to deliver toxic drugs. While this has transformed treatment for some cancers, it requires identifying suitable surface markers abundant on cancer cells and distinct from healthy tissue—a target not all cancers provide. The UC Irvine strategy takes a different path, focusing on exploiting internal cellular processes rather than surface markers.
Claudia Benavente, UC Irvine associate professor of pharmaceutical sciences and a member of the Chao Family Comprehensive Cancer Center, commented that this work expands how targeted therapy is considered. Benavente added that understanding the biological differences in how cancer cells function, beyond what is visible on their surface, can reveal vulnerabilities for therapeutic targeting.
Experiments showed that the immunoproteasome could recognize the 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 offers a potential way to create a therapeutic window by attacking cancer while limiting the drug's exposure to healthy tissue.
The researchers then tested the approach in small cell lung cancer, an aggressive disease with limited treatment options. In laboratory studies, the experimental prodrug maintained strong cancer-killing activity in these cancer cells.
Moving to a preclinical model, the team assessed whether the strategy would work in a living system. This test aimed to confirm that the prodrug could remain masked while traveling through the body and then become active within the tumor. Treatment in this model led to a significant reduction in tumor volume without significant toxicities, providing early evidence that immunoproteasome activity could serve as an internal switch for selective drug delivery.
This work remains preclinical, and further research is necessary before the approach can be evaluated as a treatment for patients. Researchers also need to better understand which specific cancers possess sufficiently high immunoproteasome activity to benefit from this strategy. However, because elevated immunoproteasome activity occurs across multiple cancer types, the researchers believe the concept could extend beyond small cell lung cancer.
The 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, in part, from startup funding provided by the UC Irvine School of Pharmacy & Pharmaceutical Sciences and the Chao Family Comprehensive Cancer Center, which offered resources to investigate the immunoproteasome and build the scientific foundation for the approach. Additional funding came from the National Institutes of Health, the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, the American Lung Association, and UC Irvine’s Vertex Diversity Graduate Research Program.
This study involved researchers from various fields at UC Irvine, including pharmaceutical sciences, cancer biology, physiology and biophysics, and developmental and cell biology. Darci Trader noted that the progression from understanding cellular machinery to controlling drug activation demonstrates how fundamental discoveries can create new possibilities for drug development.
The study was led by Cody A. Loy, who earned a Ph.D. in pharmaceutical sciences earlier this year, and involved UC Irvine researchers Yijun Gu, Samuel C. Kim, Mariam V. Mohagheghi, Noah B. Trask, Marina Suarez-Pizarro, Lisa E. Wagar, Claudia Benavente, and Darci Trader.
