Cancer is most treatable in the early stages of the disease, and a biopsy is considered the gold standard in diagnosis. It involves directly sampling the suspected tumor by removing a small piece of tissue or a few cells and testing them in the lab to confirm if they are cancerous. But it is invasive and can be painful for the patient.1
The less painful and minimally invasive alternative is a liquid biopsy. This involves drawing a blood sample and separating it into blood cells and plasma. It is then run through a sequence of tests that look for circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA). Their presence can be used as evidence of a tumor, and to determine the type of cancer and what treatment may work best.1,2
Liquid biopsies may be offered if the patient has metastatic cancer or if treatments are no longer working. They can help determine prognosis and make treatment decisions, and are helpful if the tumor is hard to reach or the patient isn’t well enough for a traditional biopsy.1
Liquid biopsies are an active area of research and scientists are working to develop platforms that can catch cancer early, or even predict cancer before a tumor has formed. This article will focus on some of the advances currently being made in the field, from attempts to improve the sensitivity of tests, to using bodily fluids other than blood.
Overcoming the sensitivity challenge
Liquid biopsies work by detecting ctDNA or CTCs circulating in the bloodstream, but these only occur in small amounts and for the briefest of time before they are cleared by the body, so it is challenging to develop tests sensitive enough to detect them.2
“Diagnostics that use liquid biopsies require detecting very minute quantities of biological molecules associated with the disease or progression,” explained Professor J. Christopher Love, the Raymond A. and Helen E. St. Laurent Professor of Chemical Engineering at Massachusetts Institute of Technology (MIT), and a member of the Koch Institute and the Ragon Institute of MGH, MIT and Harvard.
“One example is cell-free DNA…Most cell-free DNA is released from dying cells and is degraded naturally by multiple mechanisms, including cellular uptake by liver cells and digestion by DNA nucleases. A small portion of this DNA can originate from tumors (usually ~ 1% or less); this DNA may contain mutations or variations that indicate the presence of cancer. One challenge for these tests is that the amount of tumor-derived DNA in one or two tubes of blood may be too small to detect reliably.”
Most efforts to improve the sensitivity of liquid biopsies tend to focus on developing new sequencing technologies to use after the blood is drawn.2 Professor Love and colleagues from MIT and the Broad Institute of MIT and Harvard have developed a way to significantly enhance the sensitivity of liquid biopsies by slowing down the clearance of tumor DNA from the bloodstream, before blood is drawn.
“Our work has explored a new idea similar to contrast agents used in other diagnostics like ultrasound and MRI. Our labs have developed two different ways to temporarily slow down the degradation of the cell-free DNA, and by doing so, boost the amount of DNA available in a tube of blood by 10–60x to make detection more robust,” Love said.
“One approach uses a form of ‘dummy’ nanoparticles that can distract the liver from collecting cell-free DNA in circulation. The other uses a monoclonal antibody, similar to many biopharmaceuticals used today for treating cancer, to bind and protect the cell-free DNA from degradation temporarily.”
The joint study focused specifically on lung cancer and mouse models has shown that the two priming agents can boost DNA levels enough that the percentage of detectable early-stage lung metastases leapt from less than 10% to over 75%.3
“We are excited that this concept for priming agents could help enhance the benefits of blood-based cancer diagnostics,” added Love.
“Boosting the levels of cell-free DNA prior to a blood draw could improve the ability to detect recurrence of disease, improve the selection of therapies for cancer patients, and ultimately, early detection of cancer.”
A key next step, Love explained, is to understand if this effect can be seen in humans and if this approach can be safe for patients in clinical trials, but with greater sensitivity, liquid biopsies could become more useful for far more patients.
Looking for dark matter
Daniel Kim, assistant professor of biomolecular engineering at the University of California Santa Cruz has taken a different approach to diagnosing cancer with liquid biopsies; his laboratory has been honing in on signals from “dark matter” RNA.
“RNA dark matter is RNA that does not encode for proteins, which is…
Read More: Advances in Liquid Biopsies: Improving Sensitivity and Earlier Detection