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| Photo by Choreograph / Getty Images |
By Navdeep S. Chandel, Scientific American
On any given day, there are often more than 100 news
articles focused on cancer, many of which speak to new and promising
studies or breakthroughs in a research lab. The desperation for better
treatment options is palpable. And it is no wonder, since one in three people
will be diagnosed with cancer in their lifetime. While cancer research
and treatments have made great strides, cancer is still far too common,
which raises the question: What is missing?
Traditional cancer treatments such as chemotherapy,
radiation and immunotherapy have grown by leaps and bounds, but they
each have their limitations. Chemotherapy can be very effective and is
still the standard of care, but it shuts down the immune system in the
process and recurrence is often likely,
among many other concerns. Most types of radiation cannot reach all
parts of the body, and therefore cannot be used for cancers that have
spread. Finally, the medical community is increasingly hopeful about
advances made in immunotherapy, but it is still only 20 to 30 percent effective in some cancers, and completely ineffective in others.
There is another type of cancer treatment, however,
known as cell metabolic therapy, which has been researched and discussed
for decades without producing viable treatment options. Cell metabolic
therapy targets the mitochondria—energy producers—of cancer cells,
shutting down their growth and preventing them from spreading. If we
remove the energy source that these cells use to power their attack on
the body, we can stop the disease dead in its tracks.
There are many reasons why cell metabolic therapy
has failed in previous decades, but recent data are demonstrating that
it is finally turning a corner.
The mitochondria regulate the metabolism of most
cells in the body, giving them energy they need to perform. In the last
decade, our understanding of the role that mitochondria play in cancer
growth has developed exponentially. Scientists used to think that
mitochondria were dispensable because they did not seem to be active in
tumor cells. However, we now understand that the opposite is true.
Cellular metabolism is the set of chemical reactions
that occur in living organisms in order to maintain life, involving a
complex sequence of controlled biochemical reactions known as metabolic
pathways. Back in the 1920s, Otto Warburg observed that thin slices of
tumors consume more glucose than normal cells and convert most of the
glucose to lactic acid. This “Warburg effect” is the foundation of one
of the earliest concepts of cancer, which holds that at the root of
tumor formation and growth is a fundamental disturbance of cellular
metabolic activity.
Today, we understand that the metabolic
transformation from a healthy cell to a cancer cell involves
mitochondria, not only for generating energy but also to produce
biosynthetic intermediates, the building blocks used to support new cell
growth and proliferation. Therefore, by targeting the mitochondria of
cancerous cells, we can diminish their ability to grow—hitting cancer
where it hurts the most.
Developing a treatment that can do this effectively
is not so simple, however. While many labs have tried to create
therapies that target cancer-cell mitochondria, most have failed. Often,
the challenge has been selectively targeting the mitochondria of cancer
cells while sparing those of healthy cells. Another challenge is that
cancer cells quickly find ways to get around the therapy-induced
suppression of metabolic pathways. For decades, the field of cancer cell
metabolic therapy has remained a deserted island.
But all of that is changing. In fact, we are seeing a
renewed interest with researchers exploring the metabolic emergence of
cancer cells to facilitate the discovery and development of new
therapies. Metformin and hydroxychloroquine, for example, are two widely
used FDA-approved drugs that have been repurposed as anti-cancer drugs,
for cancer therapy. Metformin typically is used as a first-line agent
for diabetes treatment. Its anti-cancer effect is due in part to the way
it diminishes mitochondrial metabolic functions.
Currently, there are multiple trials using
metformin, including a large phase III clinical trial in breast cancer.
Hydroxychloroquine is an anti-malaria drug. Studies have shown that
hydroxychloroquine can decrease tumor growth by cutting off the fuels
that promote mitochondrial function. There are multiple phase I and II
trials testing the efficacy of hydroxychloroquine.
There are also newer drugs, developed in the past decade that diminish mitochondrial function.
One example is devimistat,
a clinical-stage drug that is being evaluated in phase I, II and III
trials. In a phase I trial, devimistat used in combination with a
chemotherapy regimen known as FOLFIRINOX increased survival in
pancreatic cancer patients. Devimistat inhibits enzymes in the
mitochondria, thus preventing mitochondria from producing macromolecules
for growth. Another clinical-stage drug is CB-839, which inhibits an
enzyme that provides fuel to mitochondria. CB-839 is in phase I and II
clinical trials.
Cancer metabolism is becoming an exciting and
promising area for the development of drugs to treat the disease,
especially with promising recent research showing that cell metabolic
therapy can selectively target the mitochondria of cancer cells. By
better understanding cancer-specific metabolic processes, researchers
can find new drugs to revolutionize cancer treatment and explore this
new alternative to traditional treatments.
Targeting cancer metabolism represents an
opportunity to develop novel, selective and broadly applicable drugs to
treat a multiplicity of cancer types. An exciting area that is being
explored is how metabolic therapy might enhance the efficacy of existing
therapies including immunotherapy. Within the next decade, the field of
therapy targeting cancer metabolism may join the mainstream cancer
treatments.
The views expressed are those of the author(s) and are not necessarily those of Scientific American.
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