One
gets the impressions that scientists are fighting tooth and nail for research
grants and that – in this atmosphere – more funding for research on global
problems like malaria is a hard sell. Right now, the NIH spends $170 million of
its $30 billion budget on malaria research. That’s $170 million for a disease
at which half the world is at risk.
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| Map of malaria risk (in red). Licensed under Public Domain via Wikimedia Commons |
Somewhere
between a half to 1 million people die from malaria every year and most of
these deaths are in children. I am well acquainted with these statistics as I
wrote them in the introduction of three first-author papers, several grants, and
countless presentations. The numbers served as a plea for the audience to care
about my research and a justification for the federal money spent on a disease
that doesn’t really affect Westerners.
Apparently
the fact that the malaria parasite is really freakin cool is not justification
enough. I mean Ebola – c’mon – it only has seven proteins! But the malaria
parasite encodes over 5,000 proteins, many of which have no similarity to any
known protein in other organisms and many of which are highly specialized for
invading cells inside your body and hiding from your immune system.
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| Malaria parasites (stained dark purple) inside red blood cells. By Department of Pathology, Calicut Medical College, via Wikimedia Commons. |
But
researchers at the University of Copenhagen (UC) and University of British
Columbia (UBC) published exciting new findings last month in Cancer Cell that will hopefully
bolster the argument for why global disease research can pay off!
When
the malaria parasite invades red blood cells inside the human body, it secretes
hundreds of its own proteins, leading to drastic remodeling of the red blood
cell: picture a saggy water balloon transforming into a rubber ball with
protrusions, or knobs. These knobs stick to molecules on the host’s endothelial
wall, sequestering the infected red blood cells and making it easier to acquire
nutrients while also avoiding clearance in the spleen.
One
of the malaria proteins in the knob, VAR2CSA, binds to highly complex chains of
sugars on the placenta of pregnant women, latching the infected red blood cells
onto the placenta and endangering both the mother and unborn child. It was
while trying to develop a vaccine against malaria for pregnant women, that Dr.
Ali Salanti of UC had an idea.
"For decades, scientists have been
searching for similarities between the growth of a placenta and a tumor. The
placenta is an organ, which within a few months grows from only few cells into
an organ weighing approx. two pounds, and it provides the embryo with oxygen
and nourishment in a relatively foreign environment. In a manner of speaking,
tumors do much the same, they grow aggressively in a relatively foreign
environment," Salanti said in a statement
to the university last month.
It turned out the complex sugar chain, chondroitin sulfate A
(CSA), which the parasite binds to, is found only on the placenta and many
types of tumors but not on other healthy cells. Salanti tested whether the
malaria protein could be exploited as a way to selectively deliver cancer drugs
to tumors.
Working with Dr. Mads Dausgaard at UBC, a prostate
cancer researcher, he found that fluorescently labeled VAR2CSA protein,
produced in the lab, not only bound tumor cells but was also internalized by
the cancerous cells. The researchers attached the protein to a toxin and found
that the fusion killed many types of tumor cells but not healthy cells, which
lacked the receptor for the VAR2CSA protein.
They next tested the toxin-VAR2 fusion
on mice with different types of tumors transplanted. Treatment with the fusion
drug essentially halted tumor growth in mice with non-Hodgkin’s lymphoma, while
tumors in mice treated with the toxin not fused to the malaria protein grew
four times the size. In mice transplanted with prostate cancer cells, treatment
reduced tumor size by over 50% compared to the control and two of the six mice
were even in remission 32 days after treatment. Finally, all mice with highly
aggressive metastatic breast cancer died when untreated or receiving the toxin
alone. In contrast five of the six mice that received the fusion drug survived
with no spreading of the cancer more than 50 days after drug treatment. Other
organs in the mice appeared normal and even high concentrations of toxin-VAR2 didn’t
affect healthy mice.
The University of Copenhagen, in collaboration with Salanti
and Dausgaard, has launched a biotech company to pursue their work further,
with hopes to test it in humans in the next four years. “The
biggest questions are whether it'll work in the human body, and if the human
body can tolerate the doses needed without developing side effects. But we're
optimistic because the protein appears to only attach itself to a carbohydrate
that is only found in the placenta and in cancer tumors in humans,"
Salanti concluded in his statement.
Reference:
Salanti, A. et al.
Targeting Human Cancer by a Glycosaminoglycan Binding Malaria Protein. Cancer
Cell, 2015; 28 (4): 500-514. DOI:
10.1016/j.ccell.2015.09.003.
