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In a new study, taking advantage of advances in nanotechnology, researchers from research institutions such as Brigham and Women’s Hospital in the United States, Zhejiang University in China, and Hangzhou Normal University found that restoring p53 not only delays the liver cancer cells and lung cancer cells lacking p53, it also makes tumors more sensitive to cancer drugs called mTOR inhibitors. Related research results were recently published in the journal Science Translational Medicine, and the title of the paper is Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition.
In preclinical experiments, these researchers restored p53 using synthetic mRNA nanoparticles, making lung cancer cells and liver cancer cells sensitive to existing cancer drugs. The tumor suppressor gene p53, also known as the guardian of the genome, plays a vital role in preventing cancer. Because of its powerful effect, it is one of the most commonly disrupted genes in cancer.
Scientists have long been searching for a way to restore the activity of tumor suppressor genes such as p53. Recently, attention has been turned to a method developed by Brigham and Women’s Hospital that uses nanotechnology to deliver synthetic messenger RNA (mRNA). With advances in nanotechnology, these researchers have found that restoring p53 not only delays the growth of liver cancer cells and lung cancer cells lacking p53, but also makes tumors more sensitive to mTOR inhibitors.
The co-corresponding author of the paper, Dr. Jinjun Shi of the Brigham and Women’s Hospital Nanomedicine Center, said that mTOR inhibitors have been approved to treat certain types of cancer, but they have not worked well in clinical trials for many common cancers; the evidence provided in this new study suggests that the lipid-polymer hybrid mRNA nanoparticle platform they developed to restore p53 may sensitize cancer cells to mTOR inhibitors. This represents a potentially powerful cancer Treatment combination.
Shi and colleagues, including co-corresponding authors of the paper, Dr. Omid Farokhzad, Dr. Wei Tao, and lead author of the paper, Dr. Na Kong, used a redox-reactive nanoparticle platform to deliver synthetic mRNA encoding p53. This synthetic p53 causes cell cycle arrest and cell death, and delays the growth of liver cancer and lung cancer cells where p53 has been knocked out. In addition, this synthetic p53 makes these cancer cells more sensitive to everolimus (an mTOR inhibitor drug). They have reported successful results in a variety of in vitro and in vivo models.
Past clinical trials of everolimus failed to show clinical benefit in patients with advanced liver cancer and lung cancer, but found that the response of this drug to different patients was very different. Existing studies have also found that p53 is altered in approximately 36% of hepatocellular carcinoma (the most common form of liver cancer) and 68% of non-small cell lung cancers. These researchers point out that further preclinical development and evaluation will be needed to explore the clinical transformation potential and scalability of this method, as well as its applicability to other p53 mutations and other cancers. The researchers wrote that they hope this mRNA nanoparticle approach can be applied to many other tumor suppressor genes and reasonably combined with other treatment modalities to develop effective combination cancer treatments.
References：
1. Na Kong et al. Synthetic mRNA nanoparticle-mediated restoration of p53 tumor suppressor sensitizes p53-deficient cancers to mTOR inhibition. Science Translational Medicine, 2019, doi:10.1126/scitranslmed.aaw1565.
2. Nanoparticle therapeutic restores tumor suppressor, sensitizes cancer cells to treatment, https://medicalxpress.com/news/2019-12-nanoparticle-therapeutic-tumor-suppressor-sensitizes.html.