Now that researchers have made a breakthrough in understanding the relationship between naturally-occurring enzymes and the liver cancer drug sorafenib, which may hold the promise of improving the effectiveness of the drug, which currently only extends the lives of liver cancer patients by 2-3 months, a recent article published in the international journal Cell Death & Disease entitled "RNA helicase DDX5 modulates sorafenib sensitivity in hepatocellular carcinoma via the Wnt/β-catenin-ferroptosis axis ", scientists from Purdue University and other institutions have revealed an association between the enzyme DDX5 and the liver cancer drug sorafenib, which may hold promise for combining existing anticancer drugs with therapies that stimulate the production of DDX5 to serve as an effective liver cancer treatment.
If we can find a way to consistently express DDX5 in the liver during treatment, then sorafenib and other polytyrosine kinase inhibitors may have better anti-tumor efficacy, which may be a fundamental finding that could lead to the development of novel therapies to effectively treat liver cancer," said researcher Ourania Andrisani. More than 750,000 people die of liver cancer worldwide each year, and even in wealthy countries the survival rate of liver cancer patients is low, ranging from less than 10% in several European countries to 30% in Japan. More than half of all liver cancer cases worldwide are caused by chronic infections due to the hepatitis B virus, and now researchers are shedding light on the key role in viral biosynthesis played by DDX5, a special class of proteins called RNA deconjugating enzymes, which modifies the structure of RNA and is involved in all aspects of RNA biology.
In this latest study, researchers addressed the link between DDX5 and sorafenib, a drug recognized to treat liver cancer but with short-lived efficacy. In an analysis of liver cancer cells and medical records of patients treated with sorafenib, the researchers found that patients with higher levels of DDX5 in their organisms tended to live longer than those with lower levels; it was conscious that sorafenib itself was able to Reduce levels of DDX5 in liver cancer cells and animal models of liver cancer, and RNA sequencing showed that the drug activates genes essential to the Wnt/β-linker pathway, a series of molecular steps that are normally activated during liver embryonic development, and which when inappropriately activated tend to be directly linked to hepatocarcinogenesis.
Scientists are expected to develop novel therapies to treat human liver cancer.
Image from: Cell Death & Disease (2023). DOI:10.1038/s41419-023-06302-0
Subsequently, the researchers conducted a study using engineered liver cancer cells and found that enhancing the levels of DDX5 protein may improve the efficiency of sorafenib in reducing liver tumor growth, and then the researchers modified their liver cancer cells to produce DDX5 protein when treated with the antibiotic doxycycline treatment. Subsequently, the researchers utilized therapies of sorafenib in combination with or without doxycycline to treat tumors produced by engineered cells implanted into the organism of mice and as a control, and found that the tumors treated with doxycycline were significantly smaller in weight than those that had not been stimulated to produce high levels of DDX5, and during the two-week duration of the therapies that utilized sorafenib and doxycycline to make DDX5, the the weight of the tumors in the mouse organisms was reduced by an average of 50 percent, while the use of millicarbamycin alone or perhaps sorafenib alone did not have a significant effect on the weight of the tumors.
In previous studies, researchers have found that DDX5 inhibits HBV replication and that DDX5 levels decline with chronic hepatitis B infection, and now they've found that DDX5 can help inhibit the Wnt/beta-catenin pathway; potential therapies based on this new discovery, says researcher Andrisani, might primarily involve transporting mRNA into liver cells and inducing their produce the DDX5 protein, similar to the use of mRNA in the COVID-19 vaccine to instruct cells to make viral proteins.
The researchers hope that this finding will inspire the development of novel therapies that utilize this mechanism, which may be a clean means of targeting cancer cells in the liver, and that the treatment will continue as long as the patient is taking sorafenib, and that once the therapy is over, the transport of DDX5 will also stop. Thus, overexpression of DDX5 in combination with a multi-tyrosine kinase inhibitor may hold promise as a novel therapeutic strategy for the treatment of human hepatocellular carcinoma.
