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Starve it to death by depriving it of what appears
to be a favorite food: HDL cholesterol.
Northwestern Medicine® researchers discovered this
with a new nanoparticle that acts like a secret
double agent. It appears to the cancerous lymphoma
cell like a preferred meal -- natural HDL. But when
the particle engages the cell, it actually plugs it
up and blocks cholesterol from entering. Deprived of
an essential nutrient, the cell eventually dies.
A new study by C. Shad Thaxton, M.D., and Leo I.
Gordon, M.D. shows that synthetic HDL nanoparticles
killed B-cell lymphoma, the most common form of the
disease, in cultured human cells, and inhibited
human B-cell lymphoma tumor growth in mice.
The paper will be published Jan. 21 in the journal
Proceedings of the National Academy of Sciences.
"This has the potential to eventually become a
nontoxic treatment for B-cell lymphoma which does
not involve chemotherapy," said Gordon, a
co-corresponding author with Thaxton on the paper. "It's
an exciting preliminary finding."
Gordon is a professor of medicine in hematology/oncology
and Thaxton is an assistant professor of urology,
both at Northwestern University Feinberg School of
Medicine.
Gordon also is co-director of the hematologic
malignancy program at the Robert H. Lurie
Comprehensive Cancer Center of Northwestern
University and a physician at Northwestern Memorial
Hospital. Thaxton is also a member of the Lurie
Cancer Center.
The lymphoma research showed Thaxton that the HDL
nanoparticle had more than one trick up its golden
sleeve.
"At first I was heavily focused on developing
nanoparticles that could remove cholesterol from
cells, especially those involved in heart disease,"
Thaxton said. "The lymphoma work has broadened this
focus to how the HDL nanoparticles impact both the
removal and uptake of cholesterol by cells. We
discovered the particles are multi-taskers."
After developing the HDL nanoparticle, Thaxton gave
a lecture in 2010 to Feinberg faculty. Gordon was in
the audience. He knew that patients with advanced
forms of B-cell lymphoma sometimes have dropping
levels of cholesterol. A long-time lymphoma
researcher and oncologist, Gordon was looking for
new methods to deliver drugs to patients. He
contacted Thaxton and they began to collaborate.
They tested the HDL nanoparticle alone and the HDL
nanoparticle transporting cancer drugs. Surprisingly,
the nanoparticle without drugs was just as effective
at killing the B-cell lymphoma cells.
"We thought, 'That's odd. Why don't we need the
drug?'" Gordon recalled.
That's when the scientists began delving into the
mechanism by which the HDL nanoparticles were
sticking to the HDL receptors on the lymphoma cell
and manipulating cholesterol transport. In addition,
patient samples analyzed by collaborators at Duke
University for the study showed that lymphoma cells
in patients had an overproduction of these HDL
receptors compared to normal lymphocytes.
The National Cancer Institutes reports that in 2012
there were about 70,000 new cases of non-Hodgkin
lymphoma in the U.S. with nearly 19,000 deaths.
About 90 percent of those new cases were B-cell
lymphoma. Non-Hodgkin lymphoma is a cancer that
starts in cells called lymphocytes, which are part
of the body's immune system.
"Gold has a good track record of being compatible
with biologic systems," Thaxton said.
Thaxton and Gordon are encouraged by their early
data showing that the HDL nanoparticles do not
appear toxic to other human cells normally targeted
by HDLs, normal human lymphocytes or to mice. Also,
because gold nanoparticles can be made in a discreet
size and shape, they are excellent scaffolds for
creating synthetic HDLs that closely mimic those
found in nature.
"Like every new drug candidate, the HDL nanoparticle
will need to undergo further testing," Thaxton noted.
The co-first authors of the paper are Shuo Yang and
Marina Damiano. Shuo is a research associate in
medicine in Gordon's laboratory in the division of
hematology/oncology at the Feinberg School and
Marina is a graduate student in the department of
chemistry at Weinberg College of Arts and Sciences.
For more information
www.northwestern.edu/
(MDN)
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