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European Consortium Developing Bimodal Liquid Biopsy Test for Colorectal Cancer


NEW YORK (GenomeWeb) – A European Union-sponsored research project that integrates DNA, microRNA, and protein-based tumor autoantibody detection may lead to a liquid biopsy in vitro diagnostic test for colorectal cancer in 2018.

The project dubbed ULTRAPLACAD, for ultrasensitive plasmonic devices for early cancer diagnosis, is being developed by a multination consortium involving 13 entities. They include research organizations, companies, and the Regina Elena Italian National Cancer Institute, which are collaborating to make available what they believe will be a one-of-a-kind test to people in Europe.

"When the project is completed, an industrial prototype will be made available that works in a bimodal fashion," Giuseppe Spoto, a professor of chemical sciences at the University of Catania in Italy and project coordinator, said in an interview.

The system leverages plasmonics — an optical effect — that combines the transmission of light to gold nanoparticles on a chip, and measures light reflecting from the chip. "You can easily detect biomolecules because when they are close to the nanostructures, they produce a change in the way light interacts with the structure, and you can detect that change," he said.

The system detects the change in light "at very low concentrations of the molecule" and can single out the molecules you are targeting, Spoto said. As a result, the system detects protein-based tumor autoantibodies and recognizes specific DNA and microRNA mutations, eliminating the requirement for preliminary amplification of nucleic acid sequences.

The researchers said that they have demonstrated attomolar-level detection of all-RAS mutations and femtomolar detection of microRNAs. And the system is being designed to detect protein antibodies "with an improved sensitivity with respect to conventional fluorescence detection platforms," they added.

The research, sponsored by a European Union Horizon 2020 research and innovation program grant valued at €6.0 million ($6.5 million), has brought together entities with expertise and capabilities throughout the in vitro diagnostics value chain.

The prototype in development consists of disposable chips that "integrate nanostructures and microfluidics that are suitable for large-scale and low-cost production," Spoto said, adding that the grant materialized because the test uses liquid biopsies, which he believes is among "the most important emerging applications in diagnostics."

The project may yield a "radical change" in detecting colorectal cancer using biomarkers circulating in the blood, Elena Turco, a project manager for ULTRAPLACAD and for Amires, a Prague-based consulting company for research, development, and innovation projects, said in an interview.

"At the moment, most of the hospitals that are dealing with the detection of colorectal cancer are using invasive techniques such as colonoscopies or even more invasive analyses," Turco said. "From the user point of view, the biggest advantage of the new system is that it relies on the use of liquid biopsies and the detection of biomarkers," she added.

The research and development team expects that the platform will not only provide early diagnostic testing for colorectal cancer, but will also enable more specific selection of patients for therapy and facilitate therapy monitoring from liquid biopsies.

The platform could "relatively easily" be adapted for other kinds of testing, including performing prenatal liquid biopsies, Spoto said.

"We selected colorectal cancer as our target, but this principle can be applied to many other cancers," Spoto said. "With colorectal cancer, a colonoscopy facilitates taking a tissue biopsy if needed, but with other cancers it may not be possible to access the tissue depending on its location in the body," he said.

The project team started by identifying technical specifications of ULTRAPLACAD's final industrial prototype.

In the first 18 months, it identified nanostructure geometries for the surface plasmon resonance imaging and plasmon-enhanced fluorescence sensing technologies.

The first version of plasmonic reader laboratory prototypes has been completed, Spoto said. The group is now developing automated fabrication processes suitable for low-cost mass production, and it has demonstrated high-volume fabrication of nanostructured disposable chips.

It is also selecting the most suitable plasmonic nanostructures and integrating the plasmonic readers into a single device for the development of the industrial prototype. A high-volume manufacturing process for the chips and assays is being developed, after which clinical project partners will validate the industrial prototype.   

Turco and her colleagues have conducted background intellectual property research. She said that she could not find "any commercially available system that is able to provide all of the features that ULTRAPLACAD is developing."

Researchers in general are employing a few techniques to analyze tumor DNA, including analyzing whole tumor cells, capturing and analyzing vesicles that are released by tumors, and analyzing circulating tumor DNA.

Alexander Baraniskin, a researcher in the department of medicine, hematology, and oncology at Ruhr-University of Bochum in Germany, noted in an interview that having the ability to conduct liquid biopsies is important for the diagnosis and monitoring of colorectal cancer patients. 

Baraniskin and his colleagues use Sysmex Beaming Digital PCR and Bio-Rad droplet digital PCR technologies to conduct liquid biopsy-based analysis of RAS mutations within cell-free circulating tumor DNA in patients with colorectal cancer.

In a recent project reported in Case Reports in Oncological Medicine, Baraniskin and his team concluded that liquid biopsy provides a rapid genotype result that accurately reproduces the current mutation status of tumor tissue, and it enables close monitoring of the onset of secondary resistance to anti-EGFR therapy.

"There are two clinical aspects we need to consider concerning the RAS tests — diagnosis and monitoring the disease," Baraniskin said. In diagnosing patients that have many tumor masses, liquid biopsies are particularly important because the technique provides insight into all RAS mutations in the body, while tissue diagnostics may provide the RAS status of one location in the tumor tissue only, he said.

In colorectal cancer screening, liquid biopsies are important because they not only reduce the number of invasive procedures required to obtain and test cancer tissue, but they also allow for precise prescription of therapies, he noted.

"Liquid biopsies in screening of colorectal patients is vital because we know that all patients that are being treated with anti-EGFR monoclonal antibodies will relapse, and around 50 percent of these patients will relapse because of new RAS mutations," he said. "You can detect these mutations early on with liquid biopsies, and you can adopt your therapy to respond to the new RAS status."

The collaborators participating in the ULTRAPLACAD project are the Italian National Institute of Biostructures and Biosystems; University of Catania; Austrian Institute of Technology; Institute of Photonics and Electronics in the Czech Republic; Regina Elena Italian National Cancer Institute; University of Twente in the Netherlands; University of Siegen in Germany; University of Ferrara in Italy; VTT Technical Research Centre in Finland; Scriba Nanotecnologie in Italy; Ginolis Oy in Finland: Future Diagnostics Solutions in the Netherlands; Horriba Scientific in France; and Amires.

Subsequent to development of the industrial prototype and clinical testing, the team plans to make the test commercially available and apply for CE marking and other regulatory clearances. The commercial process will be managed by Horiba Scientific, Turco said.