The Fiscal Year 2018 (FY18) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas to be addressed by this research project are Liver Cancer and Immunotherapy.

The objective of this research proposal is to develop a novel and effective therapeutic strategy for treatment of hepatocellular carcinoma (HCC), the most common type of liver cancer. The loss/mutation of tumor suppressors (e.g., p53) is a driving force of the development and progression of various cancers including HCC. The very recent clinical data from The Cancer Genome Atlas (TCGA) reveal the mutation of tumor suppressor gene p53 in 31% of HCC patients, ranking the top among those altered genes. Our study and the TCGA data also show that HCC patients with high expression of p53 mRNA have significantly longer overall and progression-free survival than those with low p53 expression. Additionally, p53 mutation is correlated with the immune suppression in the tumor microenvironment. We therefore hypothesize that restoration of p53 function will lead to apoptotic death of p53-decifient HCC cells and the activation of anti-tumor immunity.

In this project, we will leverage advances in mRNA and nanotechnology for restoration of tumor suppressor p53 in HCC with p53 loss/mutation. Compared to plasmid DNA, the use of therapeutic mRNA has recently attracted considerable attention, since it does not require nuclear entry for transfection activity and has a negligible chance of integrating into the host genome, thus excluding potentially detrimental genotoxicity. In our recent studies, we have demonstrated the first proof-of-principle of using nanotechnology to delivery tumor suppressor mRNA into tumor cells in vitro and in vivo. When the nanotechnology is used for p53 mRNA delivery, we noticed drastic cell death of p53-deficient HCC cells that could also induce effective anti-tumor immune responses, while no obvious toxicity with normal liver cells. We thus expect that the combination of our p53 mRNA nanotechnology with anti-PD-1 immunotherapy (recently approved for advanced HCC) will lead to highly effective treatment of HCC.

The successful completion of this research project will lead to the generation of an effective and safe mRNA nanotherapy candidate that could benefit HCC patients with p53 loss/mutation. In addition, it is worth noting that this platform nanotechnology will not be limited to p53 mRNA delivery and could be readily expanded to delivery of other tumor suppressor mRNAs or therapeutic mRNAs in general, thus potentially benefiting more HCC patients. Moreover, this project will study the mechanisms of anti-tumor immune responses induced by p53 restoration in HCC models, which could contribute to better understanding of cancer immunotherapy.

With a recent study supporting that male United States (U.S.) military Veterans had an increased frequency of HCC at autopsy compared with the general population, we expect the proposed research to benefit HCC patients in general but have a particularly profound impact on the health of U.S. military Veterans – one of the FY18 PRCRP Military Relevance Focus Areas.