Amplifying the signal
CAMBRIDGE, Mass.—Biomarkers are one of the leading beaus in several therapeutic indications for their potential in determining the efficacy of treatments in patients, but some of the latest work to come out of the Massachusetts Institute of Technology (MIT) is focusing on how to increase biomarker production to enable easier, earlier cancer diagnoses.
Diagnosis via biomarkers focuses on proteins secreted by cancer cells, but the cancer cells release so few of the biomarkers that detection is difficult. However, researchers at MIT led by Sangeeta Bhatia have developed a new set of nanoparticles capable of homing in on a tumor and interacting with cancer proteins, thereby stimulating the production of thousands of biomarkers. The produced biomarkers allow for easy detection in urine samples.
"There 's a desperate search for biomarkers, for early detection or disease prognosis, or looking at how the body responds to therapy," said Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT, in a press release. In fact, Stanford University researchers published a recent study that revealed that even with the best technology and existing ovarian cancer biomarkers, an ovarian tumor would not be found until eight to 10 years after its formation.
The idea for this new technology came from an "a-ha" moment, according to Bhatia, a member of MIT's David H. Koch Institute for Integrative Cancer Research. Cancer cells have "limited production capacity," she noted, but "What if you could deliver something that could amplify that signal?"
One of the many products of cancer cells are large amounts of proteases known as matrix metalloproteinases (MMPs), which help cancer cells spread beyond their original birth points by cutting through proteins of the extracellular matrix. According to EMD Millipore, MMPs are "secreted or transmembrane proteolytic endopeptidases that process and degrade extracellular matrix proteins. MMPs play critical roles in many normal growth and developmental aspects of tissue remodeling, wound healing and angiogenesis. In a pathological context, MMPs are associated with cell migration, invasion, arthritis and cancer tumor progression."
The team coated the nanoparticles—ones that interact with proteases and which the lab had been working on originally as imaging agents for tumors—with peptides that are targeted by several MMP proteases. The nanoparticles gather at tumor sites, traveling via the leaky blood vessels that generally surround and are put out by tumors, and once there, the proteases cleave hundreds of peptides from the nanoparticles. Once cleaved, the nanoparticles are released into the bloodstream, where they are then carried to and accumulate in the kidneys and excreted in urine, at which point they can be detected with mass spectrometry.
For more precise biomarker readings, the nanoparticles were designed to express 10 different peptides, with each one cleaved by a different MMP protease. In addition, the peptides are all differently sized, allowing for easier differentiation with mass spectrometry.
The amplification system could be used to monitor disease progression and track the response of tumors to treatment as well, Bhatia noted. She added that researchers' search for biomarkers has become more complicated of late due to the recent discovery that many cancer types, including breast cancer, actually consist of groups of several diseases with different genetic signatures.
For this study, the nanoparticles were tested in mouse models to detect the early stages of colorectal cancer as well as for monitoring the progression of liver fibrosis (progressive scarring as a result of liver injury or liver disease). The mouse models demonstrated that the nanoparticles provided feedback much faster than biopsies in the case of liver fibrosis. In addition, the nanoparticles were also able to accurately reveal the early formation of colorectal tumors. Moving forward, the nanoparticles will be studied to determine their ability to gauge tumor response to chemotherapy as well as metastasis.
The MIT researchers, working alongside a team from Beth Israel Deaconess Medical Center, reported the nanoparticle technology in a Nature Biotechnology paper on Dec. 16, 2012. Gabriel Kwong, a postdoctoral in the MIT Institute for Medical Engineering and Science and the Koch Institute, was lead author of the paper, titled "Mass- encoded synthetic biomarkers for multiplexed urinary monitoring of disease."