New Technology May Enable Earlier Cancer Diagnosis
Finding ways to diagnose cancer earlier could greatly improve the chances of survival for many patients. One way to do this is to look for specific proteins secreted by cancer cells that circulate in the bloodstream. However, the quantity of some of these biomarkers is so low that detecting them has proven difficult. Now, however, a technology developed at MIT may help to make biomarker detection much easier.
Sangeeta Bhatia, a project leader at the MIT-Harvard Center of Cancer Nanotechnology Excellence, led the team that developed nanoparticles that can home to a tumor and interact with cancer proteins to produce thousands of biomarkers, which can then be easily detected in the patient’s urine. This biomarker amplification system could also be used to monitor disease progression and track how tumors respond to treatment, says Dr. Bhatia. She and her collaborators published their findings in the journal Nature Biotechnology.
"There’s a desperate search for biomarkers, for early detection or disease prognosis, or looking at how the body responds to therapy," says Dr. 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 signatures.
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," Dr. Bhatia says. "That’s when we had this ‘aha’ moment: What if you could deliver something that could amplify that signal?" 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 fragments.
Cancer cells often produce large quantities of proteases known as matrix metalloproteins (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 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 spectrometry. 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 charge, making it possible to distinguish them with mass spectrometry. This should allow researchers to identify distinct signatures associated with different types of tumors. In situations where scientists want to detect tumors, and not determine distinct signatures, the peptides on the particles can be fluorescently tagged, making it easy to detect the peptides in urine when exposed to light.
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 even better than the currently used biomarkers.
This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, "Mass-encoded synthetic biomarkers for multiplexed urinary monitoring of disease." The full paper is available free of charge at the journal’s website.