PFKL is an enzyme in cancer cells that
metabolizes sugar. This image shows the protein structure of PFKL bound to two
parts of the experimental cancer drug XJ-4-85 (blue and orange). When XJ-4-85
binds the sites K677 and K315 on PFKL (inset), it boosts sugar metabolism and
releases a payload (not shown) that shuts down fatty acid metabolism. Credit:
Eric Lynch (University of Washington) and Xiaoding Jiang (University of Texas
at Austin).
Cancer cells have a voracious
appetite for sugar—using it to fuel their rapid growth. This is why many
scientists have tried to develop drugs that block cancer cells' metabolism by
cutting off their sugar supply.
Now a team led by researchers at
The University of Texas at Austin report in Nature Chemical Biology that they have found a completely different
approach. Instead of starving cancer cells, they trick them into consuming even
more sugar than usual. At the same time, the drug blocks their backup fuel
source—fat.
By attacking both fuel sources at
once, the experimental drug puts cancer cells under so much stress that many of
them die. They demonstrated the drug's effectiveness in treating an aggressive
form of melanoma in mice.
"I like to think of this
technology like a two-headed dragon," said Xiaolu (Lulu) Lim Ang
Cambronne, an associate professor of molecular biosciences at UT and
co-corresponding author. "We are putting one part of the cell into
overdrive while simultaneously weakening another part. It appears to be
extremely potent."
A chemical alternative to ADCs
In lab experiments, the drug was
effective against several types of human cancer cells, including melanoma,
leukemia, breast cancer, lung cancer, liver cancer and neuroblastoma. In mice
with melanoma, most cancer cells died, while noncancerous cells were much less
affected.
Drugs that attack cancer with this
kind of one-two punch are not entirely new. A growing class of compounds
called antibody-drug conjugates (ADCs) use an antibody to target cancer cells, then
deliver a payload of chemotherapy directly to the tumor. But ADCs have many
limitations.
"Antibodies are difficult to
make, and because they're so large, they're only able to target proteins on the
surface of cancer cells," said Ken Hsu, an associate professor of
chemistry at UT and co-corresponding author. "We think of this new
compound as a fully chemical counterpart to ADCs. They are much easier to
manufacture. And because they are smaller, they are able to target even
proteins that are inside cells."
How the two-part drug works
The drug has two parts. The
targeting agent, a molecule called XJ-4-85, acts on an enzyme called PFKL,
speeding up glycolysis (the breakdown of sugar) inside cancer cells. After
XJ-4-85 binds, it releases its payload, a compound that acts on another enzyme
called CPT2. CPT2 normally helps cells break down fatty acids for energy. By
disrupting both of the cells' major energy sources at the same time, it shuts
down cancer growth.
"The way this drug works was
totally unexpected," said Xiaoding Jiang, a postdoctoral fellow in the Hsu
Lab, who designed the molecule. "A lot of research was required to figure
out what it was doing on the molecular level. We were also surprised to see how
selectively it binds to cancer cells."
Early promise, broader potential
The research is still in its early
stages. Although the results are promising, much more laboratory testing is
needed before the drug can be studied in people.
Beyond this particular drug, the
researchers say the research also illustrates a broader approach for designing
these two-part medicines, which they call "electrophile-drug
conjugates" or EDCs. "They have the potential to be useful beyond cancer,
for other kinds of diseases as well," Cambronne said.
The team members emphasize the importance of collaboration in making this discovery possible, bringing together experts from across UT—and beyond. "This project took a village," Hsu said.
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