Stealth tactic makes chemotherapy smarter

Chemotherapy faces a fundamental problem: The same drugs powerful enough to kill cancer cells can also damage healthy tissue.

UC Irvine researchers are trying to change that equation by essentially putting a safety lock on a highly potent cancer drug, a lock designed to be removed once the drug enters cancer cells with high levels of a specific protein-destroying activity.

The findings, published in Signal Transduction and Targeted Therapy, a Nature Portfolio journal, demonstrate a new way of turning a cell’s own protein-recycling machinery into a trigger for drug activation. The approach could eventually help scientists develop cancer treatments that deliver powerful drugs more selectively while reducing harmful effects elsewhere in the body.

At the center of the strategy is the immunoproteasome, a specialized form of the proteasome, the cellular mechanism responsible for breaking down proteins. Immunoproteasome activity can be elevated in inflammatory conditions and a variety of cancers.

Researchers designed an experimental prodrug – a pharmacologically inert compound that becomes active after administration – that takes advantage of that difference.

The team attached an extremely toxic anticancer agent called monomethyl auristatin E to a short peptide recognized by the immunoproteasome. While affixed, MMAE is essentially “caged,” limiting its ability to harm cells. When elevated immunoproteasome activity is detected inside a cancer cell, the peptide is cut and the active drug is released.

Think of it as giving chemotherapy a molecular lock and giving certain cancer cells the key.

“Our goal is to take advantage of something cancer cells are already doing differently and use that difference to activate a drug where we want it to be toxic,” says the study’s corresponding author, Darci Trader, UC Irvine associate professor of pharmaceutical sciences and vice chair of postgraduate studies in that department. “Rather than relying on traditional development of enzyme inhibitors, we’re harnessing the unique immunoproteasome activity as a prodrug trigger.”

Moving beyond a cancer cell’s address

Many targeted cancer therapies use antibodies to recognize specific proteins, or antigens, on the surface of cancer cells. The antibodies act as address labels, carrying a toxic drug directly to cells displaying that marker.

The approach has transformed treatment for some cancers, but it comes with an important limitation: Scientists first need to identify a suitable surface marker that’s abundant on cancer cells and sufficiently different from healthy tissue.

Not every cancer provides such a target.

The UC Irvine strategy takes another route. Instead of asking what marker sits on the surface of a cancer cell, researchers asked whether they could exploit what’s happening inside it.

Experiments showed that the immunoproteasome could recognize their specially designed peptide and release MMAE. Cancer cells with high immunoproteasome activity were highly sensitive to the prodrug, while healthy cells with low activity remained viable.

That distinction could potentially offer researchers another way to create a therapeutic window – attacking cancer while limiting the exposure of healthy tissue to the drug.

“This work expands the way we think about targeted therapy,” says study co-author Claudia Benavente, UC Irvine associate professor of pharmaceutical sciences and a member of the Chao Family Comprehensive Cancer Center. “Cancer cells are not defined only by what we see on their surface. There are important biological differences in how these cells function, and understanding those differences can reveal vulnerabilities that we may be able to target therapeutically.”

Putting the strategy to the test in lung cancer

The UC Irvine researchers next tested the approach in small cell lung cancer, an aggressive form of the disease for which treatment options remain limited.

In laboratory studies, the experimental prodrug retained strong cancer-killing activity in small cell lung cancer cells.

The team then moved into a preclinical model to determine whether the strategy could work in a living system, an important test of whether the prodrug could remain sufficiently masked as it traveled through the body and become active within the tumor.

The results were encouraging.

Treatment led to a significant reduction in tumor volume without significant toxicities. The findings provide early evidence that immunoproteasome activity can potentially serve as an internal switch for delivering highly potent drugs more selectively.

The work remains preclinical, and additional research will be necessary before the approach can be evaluated as a treatment for patients. Researchers also need to better understand which cancers have sufficiently high immunoproteasome activity to benefit from the strategy.

But because elevated immunoproteasome activity occurs across multiple cancer types, the researchers believe the concept could ultimately extend beyond small cell lung cancer.

Seed funding helps move an idea toward a cancer therapy

The research also highlights how early investment in basic and translational science can help unconventional ideas develop into potential therapeutic strategies.

The work was supported, in part, by startup funding from the UC Irvine School of Pharmacy & Pharmaceutical Sciences and the Chao Family Comprehensive Cancer Center, which provided resources that helped researchers investigate the immunoproteasome and build the scientific foundation for the approach.

The study brought together researchers across pharmaceutical sciences, cancer biology, physiology and biophysics, developmental and cell biology, and other areas at UC Irvine.

“What began with understanding and measuring the activity of this cellular machinery has developed into a strategy for controlling when a powerful drug becomes active,” Trader says. “That progression is important because it shows how fundamental discoveries can create entirely 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, Benavente and Trader.

In addition to support from the UC Irvine School of Pharmacy & Pharmaceutical Sciences and the Chao Family Comprehensive Cancer Center, the work received funding from the National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, and American Lung Association, as well as UC Irvine’s Vertex Diversity Graduate Research Program.