Genes provide the instructions to synthesise the proteins in our cells. DNA contains the information to make all our proteins, RNA is the messenger that carries this information to the ribosomes, that serve as factories, were the proteins are made. Researchers can use various techniques to achieve and modify this central process in biology.
The major mutation observed in osteosarcoma affects the gene TP53. The protein P53, which is encoded by this gene, is considered the "guardian of the genome", as it facilitates the repair of mutations that otherwise will go unchecked.
TP53 loss has been identified in over 80% of osteosarcomas, it is followed by massive genome instability, leading to the further development and progression of tumours.
What were the aims of this research project?
The aim of this research was to restore TP53 in osteosarcoma cells, by using a messenger RNA (mRNA) technology similar to the one used to develop a vaccine against the COVID-19 virus. mRNA technology allows mRNA to enter cells and then deliver instructions to produce proteins. Not only that, but this method is also safe because it does not alter the DNA, and it is using mRNA rather than bacteria or viruses often used in vaccines to trigger an immune response. Once the cells have finished making the protein, they breakdown the mRNA. Additionally, and importantly, normal healthy cells would be unaffected, as they do not have the TP53 mutations seen in cancer cells.The researchers aimed to introduce TP53 mRNA to osteosarcoma cells missing the protein P53, hoping to trigger the production of the P53 protein which should result in cancer cell death, in cell models. They also aimed to research how to make many copies of the RNA in the osteosarcoma cells. Changes in both TP53 gene and P53 protein expression would be measured and investigated further to see if any restoration resulted in osteosarcoma cell death.
Results of the study
This research was trying to find out whether ‘fixing’ the TP53 loss-of-function in osteosarcoma via mRNA technology works, and if it would be a legitimate treatment option. They looked at TP53 levels in normal human bone cells, and in human osteosarcoma cells either missing TP53 or with abnormal (mutant) TP53. Firstly, they confirmed that the osteosarcoma cells had no TP53 or had mutant TP53 when compared to normal TP53 levels in healthy cells. They then produced TP53 mRNA and put them into the osteosarcoma cells. This resulted in these cells showing levels of TP53, as well as showing signs of tumour cell death. They were able to confirm that restoration of TP53 levels was due TP53 mRNA, and the results were reproducible and efficient.
Conclusions and outcomes for patients
The researchers have established TP53 restoration via mRNA technology in osteosarcoma cells, and that this induces cancer cell death in osteosarcoma cell models. This represents approximately 80-90% of patients with osteosarcoma, where TP53 has been shown to be lost. Further research is needed to expand this work and if the outcomes confirm these positive findings, TP53 restoration may be a viable, efficacious and non-toxic treatment for osteosarcoma.
Future plans
As well as publishing these findings, the researchers plan to continue these investigations in laboratory models, to provide further evidence that this may be a legitimate treatment for patients with osteosarcoma.
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