Science Translational Medicine: Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition

In a new study, using advances in nanotechnology, researchers have found that restoring p53 not only delays the growth of p53-deficient liver and lung cancer cells, but may also make cancer drugs symmetrically mTOR inhibitors more sensitive. The results were recently published in the journal Science Translational Medicine under the title “Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition”.

Tumor suppressor gene p53, also known as the guardian of the genome, plays a vital role in cancer prevention. Because of its powerful effect, it is one of the most commonly damaged genes in cancer. One reason cancer cells are so difficult to kill is that they often lack p53, a key tumor suppressor that promotes apoptosis. In preclinical trials, the researchers used synthetic mRNA nanoparticles to restore p53, making lung and liver cancer cells sensitive to existing cancer drugs.

Scientists have long been looking for a way to restore the activity of tumor suppressor genes such as p53. Recently, attention has turned to a method developed by Bregan Women’s Hospital to deliver synthetic messenger RNA (mRNA) using nanotechnology. Using advances in nanotechnology, the researchers found that restoring p53 not only delays the growth of p53-deficient liver and lung cancer cells but may also make tumors more sensitive to mTOR inhibitors.

“mTOR inhibitors have been approved for the treatment of certain types of cancer, but do not work well in clinical trials of many common cancers,” Dr. Jinjun Shi said. The evidence we provide in this new study suggests that the lipid-polymer hybrid mRNA nanoparticles platform we developed to restore p53 may make cancer cells sensitive to mTOR inhibitors. This represents a potentially powerful combination of cancer treatment. ”

The researchers used a platform of redox reactive nanoparticles to deliver synthetic mRNA that encodes p53. This synthesis of p53 leads to cell cycle arrest and cell death, and delays the growth of liver and lung cancer cells where p53 has been removed. In addition, this synthetic p53 makes these cancer cells more sensitive to everolimus, a mTOR inhibitor. They reported successful results in a variety of in vitro and in vivo models.

Previous Ivimus clinical trials have failed to show clinical benefits in patients with advanced liver cancer and lung cancer, but it has been found that responses to the drug vary widely among current patients. Existing studies have also found that p53 has changed in about 36% of hepatocellular carcinoma (the most common form of liver cancer) and 68% of non-small cell lung cancer.

Further preclinical development and evaluation will be needed to explore the clinical transformational potential and scalability of this approach, as well as its applicability to other p53 mutations and other cancers, the researchers noted. “We hope that this mRNA nanoparticles method can be applied to many other tumor suppressor genes and properly combined with other treatments to develop an effective combination therapy for cancer.”

 

References

Kong, N., Tao, W., Ling, X., Wang, J., Xiao, Y., Shi, S., … & Duda, D. G. (2019). Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition. Science Translational Medicine11(523).