New Approach to Treating Liver Cancer Holds Promise for Improved Therapies


A recent breakthrough in the understanding of the relationship between a naturally occurring enzyme and the liver cancer drug sorafenib could have significant implications for the treatment of liver cancer. Currently, sorafenib only extends the life of liver cancer patients by a mere two to three months. However, a study published in the journal Cell Death & Disease has shed light on the potential for a more effective therapy by combining existing anti-cancer drugs with treatments that stimulate the production of the enzyme DDX5.

The lead researcher, Ourania Andrisani, who is also a Distinguished Professor of Basic Medical Sciences at Purdue University, expressed optimism about the findings. She stated, “If we can find a way to continuously express DDX5 in the liver during treatment, then sorafenib and other multi-tyrosine kinase inhibitors have much better anti-tumor efficacy… This is a foundational discovery, and from this, we can think of new ways to develop effective therapies for liver cancer.”

Liver cancer remains a significant global health concern, with over three-quarters of a million people dying from the disease annually. Moreover, survival rates are dismal, ranging from less than 10% in certain European countries to 30% in Japan. Chronic infection with the hepatitis B virus (HBV) is responsible for more than half of all liver cancer cases worldwide. Andrisani’s research focuses on understanding the role of DDX5 in the synthesis of the HBV.

The study examined the relationship between DDX5 and sorafenib, a well-known liver cancer treatment that has limited effectiveness. The research team analyzed liver cancer cells and patient records and found that individuals with higher levels of DDX5 had longer survival rates compared to those with lower levels. Intriguingly, sorafenib was found to decrease DDX5 levels in liver cancer cells, while activating genes associated with the Wnt/β-catenin pathway, which is linked to liver cancer when overactivated.

To further investigate the role of DDX5, the researchers used engineered liver cancer cells that produced the enzyme when treated with the antibiotic doxycycline. Tumors generated from these cells were then treated with sorafenib either together with doxycycline or without it as a control. The results showed that the tumors treated with doxycycline were significantly smaller in weight compared to those that did not produce high levels of DDX5. The combination of sorafenib and doxycycline resulted in a 50% reduction in tumor weight, while both doxycycline alone and sorafenib alone had less impact.

Previous work by Andrisani’s team has shown that DDX5 inhibits HBV replication and helps repress the Wnt/β-catenin pathway. Based on the recent findings, a potential therapy could involve delivering mRNA to liver cells to stimulate the production of DDX5, similar to the approach used in the COVID-19 vaccine. Andrisani envisions a targeted treatment approach that focuses on cancer cells within the liver and continues only for the duration that the patient is taking sorafenib. Once the treatment is completed, the delivery of DDX5 mRNA would also cease.

These findings offer hope for the development of more effective therapies in the future, and Andrisani believes that they could pave the way for a “clean, neat approach” to treating liver cancer. By capitalizing on the mechanism uncovered in this study, researchers may be able to improve the efficacy of existing drugs and provide better outcomes for liver cancer patients


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