Pioneering method to tackle lethal liver cancer

GalNAc-conjugated siRNA aims at DNAJB1-PRKACA fusion in liver cancer.


Cell division is essential for life, but when it becomes uncontrolled, it can lead to deadly diseases like cancer. Researchers struggle to stop this process in oncogenes, genes that cause cancer when they mutate. 

However, Rockefeller University researchers found a new way to target the oncogene responsible for a rare and fatal liver disease. They employed small interfering RNAs or siRNAs to stop the detrimental effects of the oncogene and stop liver cancer cells from developing tumors.

According to Rockefeller University Ph.D. student Christoph Neumayer, siRNAs were utilized for the first time to slow down the growth of FLC. This finding is essential for FLC, tumors in other body parts, and other liver malignancies. The fusion of DNAJB1 and PRKACA creates a defective protein, which is the cause of FLC. However, how this fusion results in FLC still needs to be clarified.

Simon’s lab found in 2014 that the fusion of DNAJB1 and PRKACA genes causes FLC, which became more personal for Simon when his daughter Elana was diagnosed with liver disease. After Elana’s successful tumor removal, they collaborated on research published in Science.

Since then, they’ve studied the disease’s mechanisms and developed treatments using siRNAs, repurposed drugs, and PROTACs. The lab’s discoveries led to plans for a clinical trial and a $25 million grant for pediatric cancer treatments. Recently, they halted FLC tumor growth in mice using shRNAs, prompting further exploration of inhibiting kinase A activity, which drives tumor growth.

It was difficult to stop the hazardous kinase without harming healthy cells. To achieve this, they created siRNAs that specifically target the fusion. They needed a means of delivering the siRNA into the cells, and they did so by employing a binding protein called GalNAc to target a receptor called ASGR1, which is exclusive to liver cells. This strategy is comparable to treatments currently in use for other ailments. They aimed to halt the kinase responsible for FLC tumors using this technique.

To test their hypothesis, researchers examined the receptor in mice with different tumor models and human cell cultures by attaching a customized siRNA to its ligand. The treatment effectively penetrated cells and decreased the oncogene’s messenger RNA, stopping or reducing mouse tumor growth without causing liver damage.

Though they aimed to kill tumors, they observed tumor inhibition instead. They confirmed the siRNA’s specificity by injecting it into another liver cancer type’s tumor cells, which had no toxic effects. This suggests that siRNAs may treat tumors with high specificity beyond FLC, potentially revolutionizing genetic therapy.

The study introduces a new way to treat deadly liver cancer using siRNA therapy. This method could be promising for fibrolamellar hepatocellular carcinoma (FLC) and other types of cancer. It shows how genetic therapies could change how we treat cancer.

Journal reference:

  1. JOSHUA N. HONEYMAN, ELANA P. SIMON et al., Detection of a Recurrent DNAJB1-PRKACA Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma. Science. DOI: 10.1126/science.1249484.