An NCI-designated Comprehensive Cancer Center
By Katie Neith | June 25, 2018
Board of Governors - Rossi John Rossi, Ph.D.
For people with unresolved liver diseases — a growing worldwide epidemic — the result is often the development of fibrosis that can then lead to cirrhosis. Patients with cirrhosis are in danger of developing hepatocellular carcinoma (HCC), the most common type of liver cancer in adults and very hard to treat successfully.
In an effort to improve options for those with HCC, a group of researchers have identified a way of potentially treating a broad range of liver diseases and perhaps even other types of cancer.    
The international team found that small activating RNAs (saRNA) can be used as powerful activators of gene expression to target liver disease. They used saRNA to stimulate an increase of CCAAT/enhancer-binding protein alpha (CEBPA), a key regulatory protein that can activate a series of genes that then act as tumor suppressors by resetting the natural gene regulatory mechanism of liver cells to reduce fibrosis and reverse liver dysfunction.
In addition, CEBPA activates immune cell maturation, which in turn leads to an immune invasion of tumor microenvironments and ultimately to the reduction of tumor growth. The findings of the study are outlined in the paper, “Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer,” which was published in the journal Oncogene.
“We believe that this therapeutic approach can be used to block inflammation and treat a variety of cancers,” said John Rossi, Ph.D., the Lidow Family Research Chair at City of Hope and co-author of the paper. “Liver cancer and fatty liver disease are a major world health problem. Our small RNA drug is inexpensive to manufacture and has been proven to be safe in both animal models and human clinical trials.”

Promising Results

In the study, saRNAs aimed at upregulating CEBPA were encapsulated in SMARTICLES nanoparticles to deliver a treatment called MTL-CEBPA in multiple liver disease models. This represents the first development candidate to emerge from an RNA activation platform pioneered by MiNA Therapeutics, a biotechnology company for which Rossi is a co-founder and member of the scientific advisory board.
In a model of advanced liver cirrhosis, MTL-CEBPA significantly reversed liver fibrosis and liver dysfunction, enhancing survival. MTL-CEBPA also reversed the buildup of fat in a model of nonalcoholic fatty liver disease, improved liver function and reduced tumor size in a model of primary liver cancer.
“The combination of beneficial effects observed across a range of liver disease models supports a unique and promising role for MTL-CEBPA therapy in the treatment of liver diseases and liver cancer,” said Robert Habib, CEO of MiNA Therapeutics and another co-author of the Oncogene study, in a company press release. “This exciting preclinical data highlights the potential of saRNAs to upregulate gene expression and treat disease in radically new ways compared to conventional medicines.”
According to Rossi, research into the precise mechanism of action in CEBPA is currently under investigation in his laboratory.
“We believe that animal experiments underway in my lab and in the United Kingdom will provide valuable insight into the future use of this CEBPA activating drug in boosting immunity following chemotherapies,” he said.  
In addition to Rossi and Habib, additional researchers from Imperial College London, Queen Mary University of London, National Taiwan University, Norwegian University of Science and Technology, the Biomedical Research Foundation of the Academy of Athens (Greece), MiNA Therapeutics and BioTD Strategies LLC collaborated on the work.

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