Saint-Louis: For decades, scientists have tried to halt cancer by blocking
nutrients from reaching tumor cells, in essence starving tumor cells of
the fuel needed to grow and proliferate. Such attempts often have
disappointed because cancer cells are nimble, relying on numerous backup
routes to continue growing. Now, scientists at Washington University School of Medicine in St.
Louis have exploited a common weak point in cancer cell metabolism,
forcing tumor cells to reveal the backup fuel supply routes they rely on
when this weak point is compromised. Mapping these secondary routes,
the researchers also identified drugs that block them. They now are
planning a small clinical trial in cancer patients to evaluate this
treatment strategy.
The research is published Jan. 24 in Cell Reports.
Studying human cancer cells and mice implanted with patients’ tumor
samples, the researchers demonstrate that a double hit — knocking out
the weak point and one of the tumor cells’ backup routes — shows promise
against many hard-to-treat cancers. Though present in multiple cancer
types, the weak point is particularly common in sarcomas — rare cancers
of fat, muscle, bone, cartilage and connective tissues. Doctors treat
sarcomas primarily with traditional surgery, radiation and chemotherapy,
but such treatments often are not effective.
“We have determined that this metabolic defect is present in 90 percent of sarcomas,” said senior author Brian A. Van Tine, MD, PhD,
an associate professor of medicine. “Healthy cells don’t have this
weakness. We have been trying to create a therapy that takes advantage
of the metabolic defect because, in theory, it should target only the
tumor. Basically, the defect allows us to force the tumor cells to
starve.”
To grow and proliferate, tumor cells must have basic building
materials. The researchers’ strategy relies on the fact that the vast
majority of sarcomas have lost the ability to manufacture their own
arginine, a protein building block that cells need to make more of
themselves. Lacking this ability, the cells must harvest arginine from
the surrounding environment. The supply of arginine in the blood is
abundant, and cancer cells have no trouble scavenging it. But remove
this environmental supply of arginine and the cells have a problem.
“When we use a drug to deplete arginine in the blood, the cancer
cells panic because they’ve lost their fuel supply,” Van Tine said. “So
they rewire themselves to try to survive. In this study, we used that
rewiring to identify drugs that block the secondary routes.”
Unlike most cancer therapies, depleting arginine in the blood does
not affect healthy cells. Normal cells don’t rely on external sources of
arginine because they don’t have the cancer’s metabolic defect. They
continue to make their own arginine, so there is no induced starvation
in normal cells even when there is no arginine in the blood. Van Tine
said this strategy is based on the properties of a tumor — it shuts down
tumor metabolism specifically and nothing else.
Unable to make or obtain external arginine, the tumor cells’ fuel
supply routes are forced inward. The cells must begin to metabolize
their internal supply of arginine in a process called autophagy, or
“self-eating.” In the case of sarcomas, this state slows or pauses
cancer growth but does not kill the cell. During this period, tumor
cells appear to be buying time to find yet another internal work-around.
“Cancer doesn’t die when you halt its primary fuel supply,” Van Tine
said. “Instead, it turns on all these salvage pathways. In this paper,
we identified the salvage pathways. Then we showed that when you drug
them, too, you kill cells. Our study showed that tumors actually shrink
under these conditions. This is the first time tumors have been shown to
shrink using just metabolism drugs and no other anti-cancer
strategies.”
The arginine-depleting drug is currently in clinical trials
investigating its safety and effectiveness against liver, lung,
pancreatic, breast and other cancers. But so far, it has been
ineffective likely because it has activated the salvage pathways
allowing cancer growth to continue. The researchers said the drug may
yet become a vital metabolic therapy for cancer as long as it is used in
combination with other drugs targeting the backup pathways.
Van Tine and the study’s first author, Jeff C. Kremer, a PhD student
in Van Tine’s lab, explained that when cancer cells with this metabolic
defect are deprived of environmental arginine, they are forced to shift
from a system that burns glucose to a system that burns a different fuel
called glutamine. They showed that adding a glutamine inhibitor to the
arginine-depleting drug is lethal to the cells. Eliminating arginine
from the blood also rewires serine biology, another backup fuel, so
adding serine inhibitors also causes cell death.
This strategy could be applied beyond rare sarcoma tumors because the
metabolic defect is often present in other cancers, including certain
types of breast, colon, lung, brain and bone tumors, the researchers
said. The new study includes data showing similar anti-tumor responses
in cell lines from these cancer types. Van Tine also pointed out that
all of the drugs used in the study are either already approved by the
U.S. Food and Drug Administration for other conditions or in ongoing
clinical trials investigating cancer drugs.
Based on this study and related research, Van Tine and his colleagues at Siteman Cancer Center
at Barnes-Jewish Hospital and Washington University School of Medicine
are planning a clinical trial of the arginine-depleting drug in patients
with sarcomas.
“We will start with a baseline trial testing the arginine-depleting
drug against sarcomas with this defect, and then we can begin layering
additional drugs on top of that therapy,” Van Tine said. “Unlike breast
cancer, for example, sarcomas currently have no targeted therapies. If
this strategy is effective, it could transform the treatment of 90
percent of sarcoma tumors.”