Cancer-associated genes are many genes tied to cancer that are regulated by cancer-associated proteins (CAR), which are proteins that bind to cancer cells by signaling in the cell’s immune system. In a team of scientists, the discovery of new gene-silencing has helped reduce the chemical exposure of cancer cells to groups of CARs that are known to cause leukemia, lymphomas and sarcoma, and in mice, show improvement in their ability to survive.
The study, published in Nature Chemistry, is the first to identify gene silencing as an intrinsically chemo-treatable cancer-associated protein-regulated mechanism that can limit the persistence of cancer cells.
“The cancer-associated CAR-T cell surface is very well understood, but tumors can also secrete toxic substances into the environment, which are previously thought to act as endogenous tumors or ligand precursors of tumor development. Because of several clinical observations, clinicians have shown that the presence of cancer-associated CARs and the activation of CAR-T cells has a role in cancer progression. Therefore, we hypothesized that the presence of chemically-redundant groups of CARs may contribute to tumor survival, at least in some disease states,” said Jiao Yan, who heads CNBM’s Chemical and Biological Signal Composition Team and led the study.
The researchers primarily focused on a gene that is regulated by the human epidermal growth factor receptor (EGFR), a protein that regulates hair growth in skin, hair and other types of skin. They found that a small group of proteins that, while deficient in their natural self-renewing state, are drug-resistant to targeted CAR, indicating that these proteins may act as surrogate CARs to suppress tumor progression.
Using cells grown in petri dishes filled with CAR-T cells that are chemically inactive and EGRF deregulated to elicit low (trimethoprim-iodine) toxicity, the researchers cleaned their cell lines of CAR-T cells and also in mouse models injected with MSCs that carry CAR-T cells. The results were shown to be in line with experiments in animal models.
The scientists then conducted studies with gene editing models that had been depleted of CAR-T cells and compared them to non-car that were depleted and normal mice. In the case of CAR-T cells without CAR-T cells, the researchers harvested stem cells and used them to produce mice with CAR-T cells but without them. Transplanted into the back of the hind feet of affected mice, these CAR-T cells treated with drugs that control CAR-T cell growth resulted in striations that were extinguished.
These striations were present in both mouse and human tumor samples. “Initially, the animals were treated with NMDA, which is often targeted at tumor cells sensitive to NMDA receptors. Rare CAR-T cells did not respond to NMDA-mediated cell death and lysis and elimination in tumors. Nevertheless, in analyses of cell viability, we proved that eGRF can reactivate to NMDA and therefore act as CARs in cancer,” said Wangfu Huang, first author of the study and a CNBM group leader in the Chemical and Biological Signaling Departments.