Updated Death Receptor Agonist

More than 20 years ago, scientists discovered that the TRAIL protein drug can kill cancer cells without harming healthy ones, at least in the laboratory. The principle of the drug's action was to bind cancer cell proteins to specific receptors, called death receptors because they send a signal to the cell to self-destruct.

Initial experiments showed that the drug works with various cancer cell lines, including melanoma, lymphoma, pancreatic, prostate, lung and colon cancers, but unfortunately TRAIL and similar drugs were not successful in clinical trials.

Scientists began working to eliminate the reasons why the promising drug did not work: it was not powerful enough, it was excreted from the body too quickly, and some cancer cells were resistant to therapy.

The first stage of this process was to solve the problem of the limited functionality of TRAIL. Typically, cells have multiple death receptors, but a specific receptor called death receptor 5 (PC5) is more common in cancer cells. TRAIL, a three-component protein, bound to three death receptors, sending a signal to the cell to self-destruct. The drug could also bind to other death receptors and "false" receptors on normal cells.

Scientists have managed to create a highly effective death receptor agonist (APC) of six parts, which can bind 6 receptors and induce a much stronger self-destruction signal.

Then scientists began to prevent too rapid elimination of ARS from the body. They genetically fused APC with a temperature-sensitive protein called an elastin-like polypeptide, which forms a gel-like "depot" in solution at room temperature. After the solution is injected under the skin, it dissolves, releasing APC for a long period of time.

Next, the scientists switched off various genes in cancer cells using the CRISPR/Cas9 method until they determined which of them were responsible for resistance to TRAIL or APC. Then they selected drugs to target the proteins produced by these genes and paired them with a slow-release depot of APC.

With such a triple blow tool, it was possible to overcome internal resistance, suppress tumor growth and prolong survival in mice implanted with colorectal cancer cells from people resistant to TRAIL treatment.

Now the researchers are thinking about how they could apply this method to other protein and low-molecular-weight drugs that face similar problems in clinical trials.

Article by Manzari et al. Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models is published in the journal Science Advances.

Elena Panasyuk, portal "Eternal youth" http://vechnayamolodost.ru Based on Duke Pratt school of engineering: Genetic Targeting Gives Cancer Therapy a Better Shot at Success.