Study shows senotherapy blunts the progression of liver tumors

According to a new study performed by researchers, “senotherapy” blunts the progression of liver tumors in animal models. Senotherapy is a type of treatment in which small molecule drugs are used to target the “senescent” cells or those cells in which cell division no longer takes place.

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The research team was headed by Celeste Simon, Ph.D., scientific director of the Abramson Family Cancer Research Institute and a professor of Cell and Developmental Biology in the Perelman School of Medicine at the University of Pennsylvania. The study was published in the Nature Cell Biology journal.

This kind of therapy is not something that has been tried before with liver cancer. And in our models, so-called ‘senolytic’ therapy greatly reduced disease burden, even in cases with advanced disease.”

Celeste Simon, PhD, Professor of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania

Tumor growth is considerably increased when human liver cells lack the FBP1 enzyme. Earlier studies have demonstrated that FBP1 concentrations are reduced in stage 1 tumors and further decreases with the progression of the disease.

In this analysis, RNA-sequencing data was used by Simon and her research team to detect the FBP1 enzyme, which is universally under-expressed in the hepatocellular carcinoma—the most common form of liver cancer—irrespective of the underlying causes like hepatitis, alcoholism, and obesity.

The loss of the FBP1 enzyme in human liver cells triggers the adjacent hepatic “stellate cells”—which constitute 10% of liver mass—leading to tissue scarring or fibrosis and subsequent stellate cell senescence; both these medical conditions encourage the growth of tumors.

The scientists discovered that senolytics, including Navitoclax (which is already being used in clinical trials for other disorders, like hematological malignancies) can selectively target these senescent stellate cells to blunt the progression of tumors fueled by the loss of FBP1 enzyme specific to liver cells.

The researchers offered the first genetic proof that FBP1 is a true metabolic tumor suppressor in the liver and its loss in the liver cells encourages tumor growth because of the impacts on other cells present inside the tumor microenvironment.

With the help of genetically engineered mouse models, the researchers removed the FBP1 enzyme and observed that the disease advanced more quickly and the burden of the tumor increased considerably in dietary, carcinogen-mediated, and other forms of hepatocellular carcinoma.

The case with liver cancer is very dire, once you get beyond a certain stage there are limited, if any, treatments available. As obesity rates continue to increase and viral infections continue to be a problem, there is going to be an increasing surge of liver cancer which currently has few treatment options.”

Celeste Simon, PhD, Professor of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania

Simon continued, “And since FBP1 activity is also lost in renal cancer, FBP1 depletion may be generally applicable to a number of human cancers. What’s unique about our senotherapy approach is that we are specifically targeting other cells in the liver tumor environment rather than the cancer cells themselves.”

According to the team, the next steps will be to test these new treatments in a clinical setting.