Earlier Detection of Cancer May Be Enhanced by MIT
Discovery with Biomarkers Collected in Urine
Nanoparticles amplify tumor signals, making them much
easier to detect in urine
These nanoparticles created by
MIT engineers can act as synthetic biomarkers for disease. The
particles (brown) are coated with peptides (blue) that are
cleaved by enzymes (green) found at the disease site. The
peptides then accumulate in the urine, where they can be
detected using mass spectrometry. Image:
Justin H. Lo
Dec. 17, 2012 – Most senior citizens live with a
fear of cancer, since the oldest are the most likely targets for many of
the deadliest cancers. Certainly most have wished for a simple way to
detect cancer in its earliest stage, when surgery or other treatments
are most likely to end the threat. A simple blood test has not been the
solution because the protein biomarkers secreted by cancer are so few
that they are hard to detect. MIT researchers, however, may have found a
solution to make detection much easier.
The researchers, led by Sangeeta Bhatia, have
developed nanoparticles that can locate a tumor and interact with cancer
proteins to produce thousands of biomarkers, which can then be easily
detected in the patient’s urine - a process even easier for most
patients than a blood test.
This biomarker amplification system could also be
used to monitor disease progression and track how tumors respond to
treatment, says Bhatia, the John and Dorothy Wilson Professor of Health
Sciences and Technology and Electrical Engineering and Computer Science
“There’s a desperate search for biomarkers, for
early detection or disease prognosis, or looking at how the body
responds to therapy,” says Bhatia, who is also a member of MIT’s David
H. Koch Institute for Integrative Cancer Research.
She adds that the search has been complicated
because genomic studies have revealed that many cancers, such as breast
cancer, are actually groups of several diseases with different genetic
The MIT team, working with researchers from Beth
Israel Deaconess Medical Center, described the new technology in a paper
appearing in Nature Biotechnology on Dec. 16. Lead author of the paper
is Gabriel Kwong, a postdoc in MIT’s Institute for Medical Engineering
and Science and the Koch Institute.
Amplifying cancer signals
Cancer cells produce many proteins not found in
healthy cells. However, these proteins are often so diluted in the
bloodstream that they are nearly impossible to identify. A recent study
from Stanford University researchers found that even using the best
existing biomarkers for ovarian cancer, and the best technology to
detect them, an ovarian tumor would not be found until eight to 10 years
after it formed.
“The cell is making biomarkers, but it has limited
production capacity,” Bhatia says. “That’s when we had this ‘aha’
moment: What if you could deliver something that could amplify that
Serendipitously, Bhatia’s lab was already working
on nanoparticles that could be put to use detecting cancer biomarkers.
Originally intended as imaging agents for tumors, the particles interact
with enzymes known as proteases, which cleave proteins into smaller
Cancer cells often produce large quantities of
proteases known as MMPs. These proteases help cancer cells escape their
original locations and spread uncontrollably by cutting through proteins
of the extracellular matrix, which normally holds cells in place.
The researchers coated their nanoparticles with
peptides (short protein fragments) targeted by several of the MMP
proteases. The treated nanoparticles accumulate at tumor sites, making
their way through the leaky blood vessels that typically surround
tumors. There, the proteases cleave hundreds of peptides from the
nanoparticles, releasing them into the bloodstream.
The peptides rapidly accumulate in the kidneys and
are excreted in the urine, where they can be detected using mass
This new system is an exciting approach to
overcoming the problem of biomarker scarcity in the body, says Sanjiv
Gambhir, chairman of the Department of Radiology at Stanford University
School of Medicine. “Instead of being dependent on the body to naturally
shed biomarkers, you’re sampling the site of interest and causing
biomarkers that you engineered to be released,” says Gambhir, who was
not part of the research team.
To make the biomarker readings as precise as
possible, the researchers designed their particles to express 10
different peptides, each of which is cleaved by a different one of the
dozens of MMP proteases. Each of these peptides is a different size,
making it possible to distinguish them with mass spectrometry. This
should allow researchers to identify distinct signatures associated with
different types of tumors.
In this study, the researchers tested their
nanoparticles’ ability to detect the early stages of colorectal cancer
in mice, and to monitor the progression of liver fibrosis.
Liver fibrosis is an accumulation of scarring in
response to liver injury or chronic liver disease. Patients with this
condition have to be regularly monitored by biopsy, which is expensive
and invasive, to make sure they are getting the right treatment. In
mice, the researchers found that the nanoparticles could offer much more
rapid feedback than biopsies.
They also found that the nanoparticles could
accurately reveal the early formation of colorectal tumors. In ongoing
studies, the team is studying the particles’ ability to measure tumor
response to chemotherapy and to detect metastasis.
The research was funded by the National Institutes
of Health and the Kathy and Curt Marble Cancer Research Fund.
>> Original report by Anne Trafton of the MIT
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