Study points to a three-pronged approach that causes liver cancer cells to stop growing

The rapid growth of liver cancer leads to a vulnerability in energy production and cell-building processes that can be vigorously exploited with a new combination treatment strategy, according to a study by researchers at the Perelman School of Medicine at the University of Pennsylvania.

In the study, published Aug. 2 in cell metabolism, the researchers found that the main type of primary liver cancer, hepatocellular carcinoma (HCC), alters metabolism in such a way that it becomes susceptible to disruptions in the supply of a key molecule, arginine. This arginine vulnerability, they found, is present in all HCC cancers, regardless of the specific genetic mutations that led to them.

The researchers showed in preclinical tests that starving HCC tumors from arginine, as well as blocking the resulting survival-promoting response, leaves HCC tumors in a non-growing, “aging” state, in which they can be killed with a new class of drugs that target senescent cells.

“Essentially, we have identified a metabolic property of most liver cancers that offers the potential to effectively treat these cancers, using drugs that are already approved or in development.” said senior author Celeste Simon PhD, de Arthur H. Rubenstein, MBBCh professor in the Department of Cellular and Developmental Biology, and scientific director of the Abramson Family Cancer Research Institute at Penn Medicine.

HCC is the most common form of liver cancer in adults. According to the National Cancer Institute, it is responsible for about 80 percent of primary liver tumors — tumors that arise in the liver rather than spread there from other organs. HCC occurs in approximately 29,000 Americans each year, nearly a million are detected worldwide, and is thought to be caused by chronic liver inflammation due to hepatitis viruses, alcoholism, and obesity. The disease is rarely cured as it tends to be diagnosed only after it has progressed beyond the possibility of surgical removal. In addition, liver transplants, which can cure benign diseases, are often not available for advanced HCC patients. Drug treatments for HCC are limited and almost never lead to a cure. There is thus an urgent need for new treatment strategies.

Simon and her team’s approach — focusing on tumor metabolism — is one that cancer researchers have increasingly explored in recent years. Cancer cells usually find ways to adapt their energy production processes and molecules to enable their rapid growth. These modifications create vulnerabilities for the cancer cells that can be found in all or almost all cases of a particular cancer type. The challenge was to identify these susceptibilities in different cancers and develop viable strategies to address them in such a way as to avoid metabolic redundancies and plasticity.

In the new study, Simon’s team established for the first time from existing cancer cell gene activity databases and from tests on patient tumor samples and cancer cell lines, that virtually all HCCs increase their metabolism by suppressing a biochemical process called the urea cycle. The urea cycle normally produces an amino acid called arginine, among other things, which is a building block of proteins and has many other important functions. The researchers showed that HCC cells compensated for their loss of internal, urea cycle arginine production by importing arginine from their environment, primarily via a transport protein called SLC7A1.

The researchers tried to block SLC7A1 activity in HCC cells to starve them of arginine. However, this did not kill the HCC cells. Instead, starvation of arginine triggered a stress response that threw the cells into a dormant, slow-growth mode, from which they could recover if arginine became available again. The researchers then also tried to block the stress response and found that the HCC cells were now forced into a more profound and more difficult-to-reversible state of non-growth called senescence.

The senescent state is one that many cells fall into during normal aging. So-called senolytic drugs to kill these cells are being developed by pharmaceutical companies because removing senescent cells has been shown to have a rejuvenating effect in animal models of aging. Simon’s team used one of these experimental senolytic compounds, ABT-263, and found that it killed senescent HCC cells and caused very strong tumor regression in animal models of HCC.

The findings thus point to the possibility of a three-part combination treatment – to starve HCC tumors from arginine, block the ensuing stress response and induce aging, and finally, to kill the resulting senescent HCC cells and halt tumor growth. Simon said it’s possible all three of these effects could be achieved with drugs that are already in use or being studied for other uses.

It is conceivable that this type of combination treatment, if performed correctly, would also make many patients more sensitive to other treatments, such as immunotherapies.”


Celeste Simon, Study Senior Author and Arthur H. Rubenstein Professor, Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine

The study was funded by the National Cancer Institute (T32 CA09140, P01 CA104838, R35 CA197602) and by the Belgian American Educational Foundation.

Source:

Reference magazine:

Missiaen, R., et al. (2022) GCN2 inhibition sensitizes hepatocellular carcinoma cells lacking arginine to senolytic treatment. cell metabolism. doi.org/10.1016/j.cmet.2022.06.010.

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