Penn Medicine, Philadelphia: Supercharged Liver Cancer Metabolism Offers New Treatment Strategy, Penn Study Suggests | India Education | Latest Education News | World Education News
Rapid growth of liver cancer leads to vulnerability in its energy-producing and cell-building processes that can be powerfully harnessed with a new combination treatment strategy, study by researchers at the University’s Perelman School of Medicine finds of Pennsylvania.
In the study, published Aug. 2 in Cell Metabolism, researchers found that the main type of primary liver cancer, hepatocellular carcinoma (HCC), alters its metabolism in ways that make it vulnerable to disruptions in liver function. supply of a key molecule, arginine. . This vulnerability to arginine, they found, is present in all HCC cancers, regardless of the specific genetic mutations that caused them.
Researchers have shown in preclinical tests that starving HCC tumors of arginine, and also blocking the resulting survival-promoting response, leaves HCC tumors in a non-growing, “senescent” 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 possibility of effectively treating these cancers, using drugs already approved or in development,” said study lead author Celeste Simon. PhD, Arthur H. Rubenstein, MBBCh Professor in the Department of Cell 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 accounts for about 80% of primary liver tumors – tumors that start in the liver instead of spreading there from other organs. HCC occurs in approximately 29,000 Americans each year, almost one million are detected worldwide and is thought to be caused by chronic inflammation of the liver due to hepatitis viruses, alcoholism and ‘obesity. The disease is rarely cured, as it tends to be diagnosed only after the possibility of surgical removal has passed. Also, liver transplants, which can cure mild disease, are often not available for patients with advanced HCC. Drug treatments for HCC are limited and almost never lead to cures. There is therefore an urgent need for new therapeutic strategies.
The approach taken by Simon and his team – targeting tumor metabolism – is one that cancer researchers have increasingly explored in recent years. Cancer cells typically find ways to alter their energy-producing and molecule-building processes to accommodate their rapid growth. These changes create vulnerabilities for cancer cells that can be found in all or nearly all cases of a given type of cancer. The challenge has been to identify these susceptibilities in different cancers and develop viable strategies to target them in ways that avoid metabolic redundancy and plasticity.
In the new study, Simon’s team first established from existing databases of cancer cell gene activity and from tests on patient tumor samples and cancer cell lines, that virtually all CHCs speed up their metabolism by suppressing a biochemical process called the urea cycle. The urea cycle normally produces, among other things, an amino acid called arginine, which is a building block of proteins and has many other important functions. The researchers showed that HCC cells compensate for their loss of internal arginine production in the urea cycle by importing arginine from their environment, mainly via a transport protein called SLC7A1.
The researchers tried to block SLC7A1 activity in HCC cells to deprive them of arginine. This, however, did not kill the HCC cells. Instead, arginine deprivation triggered a stress response that threw the cells into a slow, dormant growth mode from which they could recover if arginine became available again. The researchers then tried to block the stress response as well and found that the HCC cells were now forced into a deeper and more difficult to reverse state of non-growth called senescence.
The state of senescence is one in which many cells fall during normal aging. So-called senolytic drugs to kill these cells are being developed by pharmaceutical companies because the elimination of 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 results therefore point to the possibility of a three-part combination treatment – to starve HCC tumors of arginine, to block the ensuing stress response and induce senescence, and, finally, to kill the resulting senescent HCC cells. and stop 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 applications.
“It is conceivable that this type of combination treatment, if implemented correctly, would also make many patients more responsive to other treatments such as immunotherapies,” Simon said.