“How RNA-altering drugs might improve anticancer immunotherapies” Sabin Russel (Fred Hutch Article)
A research team comprised of members of scientists at the Fred Hutchinson Cancer Research Center in Seattle and the Memorial Sloan Kettering Cancer Center in New York have recently found that changing the mRNA of cancer cells produces nonfunctional, foreign proteins called neoantigens that are produced on the cell membrane. These proteins are then more easily identified as foreign and potentially harmful by immune cells, thus creating an effective way to kill more cancer cells without also killing normal cells. One of the created drugs has gone through multiple clinical trials and has been successful in transforming the mRNA of tumor cells.
Cancer cells are a result of genetic mutations that allow uncontrolled cell division and growth. Cancers such as melanoma that have a large amount of DNA mutations are easier to develop immunotherapies to battle because if the DNA is mutated, the mRNA that is transcribed is also transcribing mutated genes. Therefore, previous “checkpoint blockade immunotherapies” are more effective because the mechanisms by which the cell checks if it’s fit to go through the cell cycle are more likely to detect DNA damage. However, cancers such as breast cancer that only have a 5% mutation rate offer a challenge in that traditional “checkpoint blockade immunotherapies” can’t detect the genetic mutations and subsequently cause cell death of the tumor cell.
So, scientists wanted to tackle the problem of how cancer cells can “disguise” themselves from immune cells and are thus able to keep growing without detection from the body and may even metastasize to other portions of the body. In response, they wanted to make the cancer cells more “noticeable” to immune cells by changing cancer cell mRNAs to produce neoantigens that trigger an immune response.
This mRNA-transforming drug works alongside the Pfizer Covid-19 vaccine in that it changes the mRNA, which delivers the coded genetic instructions from the nucleus to create enzymes and other proteins in the scientific process called the “Central Dogma” or protein synthesis. Both changed mRNAs from the Pfizer vaccine and this new cancer drug produce harmless surface proteins that cause the human body to start creating antibodies to start killing the real threat. The new cancer drug alters the mRNA by altering something called the spliceosome, a key enzyme in RNA splicing. The initial “draft” of the nucleus’ mRNA has a lot of DNA that doesn’t actually code for the protein and needs to be spliced out, which is the spliceosome’s job. The newly developed drugs, indisulam and MS023, interrupt the spliceosome’s job and cause the mRNA to be filled with mistakes and non-coding segments of DNA. Therefore, a foreign protein is produced once the mRNA is translated into amino acids, which is detected by the immune system.
This technology can revolutionize cancer treatment because it provides alternate solutions to traditional “checkpoint blockade immunotherapies” and can target cancers that have a relatively low mutation rate but still can be fatal such as breast cancer.
Image Credit: Claudia Flandoli
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