“Caged Glycan-Antibody Conjugates for Tumor-Selective Activation of Lysosome-Targeting Chimeras”
Journal of Medicinal Chemistry
Although there are many cancer treatments available today that effectively eliminate abnormal cells, these therapies may also damage healthy cells, leading to unwanted side effects. Now, researchers publishing in ACS’ Journal of Medicinal Chemistry have developed a new therapeutic that is kept “locked” unless it finds itself within a tumor cell. In mice, the treatment significantly reduced tumor size without accumulating in the liver, which suggests adverse exposures could be reduced and treatment safety improved.
By using the intrinsic tumor microenvironment as a molecular switch, this strategy enables more precise and safer targeted protein degradation therapy.” – Peng Shi
Traditional chemotherapy impacts all fast-growing cells in the body. So, scientists are investigating targeted therapies, which aim to focus on specific molecular components within cancer cells. One type of targeted therapy involves modifying the cancer cells so that the body’s immune system recognizes and eliminates the cancer cells more efficiently. But sometimes these therapies impact healthy cells, too. Peng Shi, Mohan Chen and colleagues wanted to employ a different strategy: keep their treatment compounds “locked” until they reach the tumor cells. “By using the intrinsic tumor microenvironment as a molecular switch, this strategy enables more precise and safer targeted protein degradation therapy,” Shi explains.
The team developed a cancer therapeutic, abbreviated as Pro-LYTAC, that’s activated by glutathione — a peptide found in elevated concentrations in tumors. Once activated, Pro-LYTAC targets a protein exploited by cancer cells to evade immune recognition. Pro-LYTAC directs this protein to the cell’s natural cleanup crew, the lysosomes, and the protein gets taken apart. “This degradation removes this protective shield, restoring immune recognition of tumor cells and facilitating a more effective antitumor immune response,” Chen explains.
In studies with mouse models of triple-negative breast cancer conducted over two weeks, the researchers found that the Pro-LYTAC therapeutic suppressed tumors better compared with a control group that was given saline. Importantly, they also found that the Pro-LYTAC was concentrated in the tumors, and only small amounts were present in the animals’ livers. This result suggested that keeping the therapeutic “locked” outside of the tumor prevented it from accumulating in the liver and should reduce unwanted side effects, such as liver damage. Though Pro-LYTAC is still in early stages, the researchers hope it represents a path toward safer and more precise cancer therapy.
The authors acknowledge funding from the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province, and the GJYC program of Guangzhou.
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