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t may be feasible to treat
pancreatic cancer by using one drug to get the cancer cells to depend on a
single source of energy, and another drug to take it away from them.
Using two types of drugs at once
may combat hard-to-treat pancreatic cancer.
The
approach looks promising after a recent study successfully tested it on pancreatic cancercells and mice in the
laboratory.
The
researchers who led the study work at the Lineberger Comprehensive Cancer
Center in the University of North Carolina (UNC) at Chapel Hill.
They hope that the findings will generate new
options for treating pancreatic cancer, a disease that typically has a poor
prognosis.
In
the United States, only around 8.5 percent
of people live more than 5 years after a diagnosis of pancreatic
cancer.
The
journal Nature Medicine has
recently published a paper on the new findings.
First
author Kirsten Bryant, Ph.D., who is a research assistant professor at UNC,
says that it is early days and there is still a lot of work to do. There are
questions to address and human clinical trials of drug safety and effectiveness
to conduct.
However,
she remains cautiously optimistic, especially as another team has recently come
to a similar conclusion in a different
study.
"This
may not cure pancreatic cancer, but it's another step toward more treatment
options," Bryant remarks.
Pancreatic cancer and autophagy
The
pancreas is a large, flat organ that sits deep inside the abdomen behind the
stomach. It produces enzymes and hormones that help to digest food and control
blood sugar.
According
to the Centers for Disease Control and Prevention (CDC), pancreatic cancer is
one of the "10 most
common cancers" that arise in both men and women in the U.S.,
and it is responsible for around 7 percent of all deaths to cancer.
Pancreatic
cancer is difficult to detect in its early stages. The deep location of the
organ inside the body means that tumors and lumps are not easy to spot in
routine exams. Often, by the time symptoms emerge, cancer has already spread,
which makes it challenging to treat.
The
new study focuses on autophagy, which is a term that literally means
"self-eating." It is the process by which cells recycle spent
materials, releasing energy as a result.
The researchers devised and tested a strategy
whereby they got pancreatic cancer cells to rely on autophagy as their main
fuel source and then blocked it.
They
used one compound to stop the cancer cells from being able to use other sources
of energy, making them rely heavily on autophagy, and then they used another
compound that indirectly blocked that as well.
"What
we found," says senior study author Channing J. Der, who is a professor of
pharmacology at UNC, "is, if you cripple perhaps the most significant
pathway for energy – glycolysis – the cancer cell really starts to suffer, and
it ratchets up autophagy."
Increasing potency of autophagy inhibitors
In
effect, the strategy that Prof. Der and his colleagues have developed could
potentially increase the potency of autophagy inhibitors as a pancreatic cancer
treatment.
Previous
studies have revealed that a key driver of pancreatic cancer is a mutation in
the KRASgene. However, when researchers have tried
to develop treatments that target the mutation, they have not met with much
success.
In
the meantime, other studies have also found that autophagy is more active in
pancreatic cancers with a mutated KRAS gene.
But attempts to block autophagy indirectly with the inhibitor
hydroxychloroquine also resulted in disappointment.
Prof.
Der suggests that the reason that trials with hydroxychloroquine failed was
that the cancer cells switched to another energy source.
"Cancer cells have many options for energy — we
know of at least four or five," he explains.
Der
and his colleagues tested some ideas on human pancreatic cells and in mice.
They found that silencing KRAS made
cells more dependent on autophagy; it effectively "crippled" their
ability to use other energy sources. This was one way to weaken them.
The
team then found that combining a compound that blocks signals
"downstream" of KRAS with
the autophagy inhibitor hydroxychloroquine worked even better. The two
compounds helped each other.
"I'm going to keep improving
this combination for future use and looking for other treatment strategies that
could benefit pancreatic cancer patients
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