Groundbreaking Method to Improve Cancer Detection in Blood Tests Using Initiators

2024-03-23 20:30:38

A new way to recover significantly more circulating tumor DNA in a blood sample could improve the sensitivity of liquid biopsies used to detect, monitor and guide the treatment of tumors. Credit: MIT News; iStock

Researchers have created a groundbreaking method to improve cancer detection in blood tests by using initiators to increase circulating tumor DNA levels, offering promise for early diagnosis and accurate treatment decisions.

Tumors constantly shed DNA from dying cells, which briefly circulates in the patient’s bloodstream before rapidly breaking down. Many companies have created blood tests that can find out the DNA of this tumor, and may help doctors diagnose or monitor cancer or choose treatment.

However, the amount of circulating tumor DNA at any given time is extremely small, so it has been challenging to develop probes sensitive enough to pick up this tiny signal. A team of researchers from MIT and the Broad Institute of MIT and Harvard has now devised a way to significantly amplify this signal, by temporarily slowing the clearance of tumor DNA circulating in the bloodstream.

Breakthrough with agents of application

The researchers developed two different types of injectable molecules, which they call “priming agents,” that can temporarily interfere with the body’s ability to remove circulating tumor DNA from the bloodstream. In a mouse study, they showed that these agents could increase DNA levels enough that the percentage of detectable early-stage lung metastases jumped from less than 10% to more than 75%.

This approach could allow not only earlier diagnosis of cancer, but also more sensitive detection of tumor mutations that could be used to guide treatment. It can also help improve detection of cancer recurrence.

“You can give one of these agents an hour before the blood is drawn, and it makes things visible that weren’t there before. This means that we should be able to give anyone doing liquid biopsies, for any purpose, more molecules to work with,” says Sangata Bhatia, Professor G Wen and Dorothy Wilson Endowed Chair in Health Sciences and Technology and in Electrical Engineering and Computer Science at MIT, and a member of the MIT Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science.

Bhatia is one of the senior authors of the new study, along with J. Christopher Love, the Raymond A. and Helen A. St. Laurent Professor of Chemical Engineering at MIT and a member of the Koch Institute and the Ragon Institute of MGH, MIT, and Harvard, and Victor Edelsteinson, director of the Gerstner Center for Diagnostics Cancer at the Broad Institute.

Carmen Martin-Alonso PhD ’23, MIT and Broad Institute postdoctoral fellow Sherwin Tabrizi, and Broad Institute scientist Kan Xiong are lead authors of the paper, which was recently published in the journal knowledge.

Liquid biopsies: a way to improve cancer treatment

Liquid biopsies, which allow the detection of small amounts of DNA in blood samples, are now used in many cancer patients to identify mutations that can help guide treatment. However, with greater sensitivity, these tests could be useful for many more patients. Most efforts to improve the sensitivity of liquid biopsies have focused on the development of new sequencing technologies for use after blood aspiration.

While brainstorming ways to make liquid biopsies more informative, Bhatia, Love, Edelstein and their trainees came up with the idea of ​​trying to increase the amount of DNA in a patient’s bloodstream before taking the sample.

“A tumor always creates new cell-free DNA, and that’s the signal we’re trying to detect in the blood draw. Existing liquid biopsy technologies, however, are limited by the amount of material you collect in the blood tube,” Love says. “Where this work is trying to figure out how to inject something beforehand that will help amplify or increase the amount of signal available for collection in that small sample.”

The body uses two main strategies to remove circulating DNA from the bloodstream. Enzymes called DNases circulate in the blood and break down the DNA they encounter, while immune cells known as macrophages take up cell-free DNA as the blood is filtered through the liver.

The researchers decided to target each of these processes separately. To prevent DNases from breaking down DNA, they designed a monoclonal antibody that binds to circulating DNA and protects it from the enzymes.

“Antibodies are established biopharmaceutical agents, and they are safe in a number of different disease contexts, including cancer and autoimmune therapies,” Love says. “The idea was, can we use this type of antibody to help protect the DNA temporarily from degradation by the nucleases that are in circulation? And by doing that, we shift the balance to where the tumor is making DNA a little bit faster than it’s being degraded, increasing the concentration on drawing blood.”

The other breakthrough they developed is a nanoparticle designed to block macrophages from taking up cell-free DNA. These cells have a known tendency to eat synthetic nanoparticles.

“DNA is a biological nanoparticle, and it made sense that immune cells in the liver would probably pick it up just as they do synthetic nanoparticles. And if that were the case, which it turned out to be, then we could use a safe dummy nanoparticle to distract immune cells the vaccine and leave the circulating DNA alone so that it can be at a higher concentration,” says Bhatia.

A revolution in early cancer detection

The researchers tested their priming agents in mice that received transplants of cancer cells that tend to form tumors in the lungs. Two weeks after transplanting the cells, the researchers showed that these starters could increase the amount of circulating tumor DNA recovered in a blood sample by up to 60-fold.

After the blood sample is taken, it can be run through the same types of sequencing tests that are currently used on liquid biopsy samples. These tests can pick out the tumor’s DNA, including specific sequences used to determine the type of tumor and possibly which types of treatments will work best.

Early detection of cancer is another promising application for these initiators. The researchers found that when mice were given the nanoparticle booster before the blood draw, it allowed them to detect tumor DNA in the circulation of 75 percent of the mice with a low cancer burden, while none were detectable without the boost.

“One of the biggest obstacles to liquid biopsy testing of cancer has been the lack of circulating tumor DNA in a blood sample,” Edelsteinson says. “So it’s been encouraging to see the magnitude of the impact we’ve been able to achieve so far and to see what impact that can have on patients.”

After one of the primers is injected, it takes an hour or two for DNA levels to rise in the bloodstream, then they return to normal within about 24 hours.

“The ability to reach peak activity of these factors within a few hours, followed by their rapid approval, means that someone can go into a doctor’s office, receive such an agent, and then give their blood for the test itself, all within one visit,” says Love. “This feature bodes well for the potential to translate this concept into clinical use.”

The researchers launched a company called Amplifyer Bio that plans to further develop the technology, hoping to advance to clinical trials.

“A blood test is a much more accessible diagnosis than a colonoscopy or even a mammogram,” says Bhatia. “Ultimately, if these tools are truly predictive, then we should be able to get a lot more patients into the system who could benefit from cancer resection or better treatment.”

The study was funded by the Koch Institute Support Grant (Core) from the National Cancer Institute, the Marble Center for Cancer Nanomedicine, the Gerstner Family Foundation, the Ludwig Center at MIT, the Koch Institute’s Frontier Research Program through the Casey and Family Foundation, and the Bridge Project, a partnership between the Institute Koch to the Dana-Farber/Harvard Cancer Center.