NEW YORK – Cancer diagnostics firm Exact Sciences has moved into plasma proteomics with its recent $15 million purchase of Planegg, Germany-based OmicEra Diagnostics.
According to Exact CSO Jorge Garces, the Madison, Wisconsin-based company plans to use OmicEra's mass spectrometry-based proteomics technologies for cancer biomarker discovery. He added that Exact's decision to acquire the firm was informed by recent technological developments in mass spec-based proteomics.
"We have been involved in proteomics, but at the level of immunoassays in plasma and immunohistochemistry in tissue," Garces said. "The advances over the last three to five years in mass spec have allowed us to feel more comfortable using this technology for biomarker discovery."
As an example of these advances, he cited improvements in sample prep techniques to either deplete high abundance proteins or enrich lower abundance ones, improving depth of coverage; improvements in mass spec instruments themselves; and improvements in the data analysis and bioinformatic pipelines for proteomics.
OmicEra was launched in 2019 by researchers from the lab of Matthias Mann, head of the department of proteomics and signal transduction at Germany's Max Planck Institute of Biochemistry. The company specializes in mass spec-based proteomics and plasma proteomics in particular, an area where Philipp Geyer, cofounder and CSO of the firm, did extensive work while he was a Ph.D. student and postdoc in Mann's lab.
Garces said that while Exact does some protein biomarker discovery work in tissue, its primary focus with regard to proteins is in developing plasma-based markers.
Plasma has obvious advantages in terms of ease of sampling, and Exact, like many of its competitors in the multi-cancer early detection space, is developing blood-based clinical assays. Plasma has proved a challenging sample type for proteomics work, however, due to factors like its large dynamic range, which makes it difficult for mass spec-based experiments to achieve significant depth of coverage. While mass spec workflows can routinely characterize 5,000 or more proteins in tissue samples, they typically top out at around 500 proteins in plasma. Researchers have pushed that number to 3,000 or more using extensive depletion and fractionation, but such workflows are not compatible with the high levels of throughput needed for biomarker discovery and validation.
Even so, 500 proteins in plasma represents a significant improvement over the previous state-of-the-art, and ongoing developments in mass spec and sample preparation technologies could further boost the coverage of such experiments.
Garces highlighted the development of Bruker's timsTOF line of mass spec instruments as one specific advance that he sees driving plasma proteomics forward.
The timsTOF instruments use trapped ion mobility spectrometry (TIMS) technology to collect and separate ions based on their collisional cross sections. This collisional cross section data provides an additional layer of information that researchers can use to make protein identifications, improving the quality of the mass spec data. Additionally, researchers have used the design of the TIMS ion trap to develop new mass spec workflows that improve assay sensitivity.
At the American Society for Mass Spectrometry annual meeting last week, Bruker launched the latest version of the timsTOF, the timsTOF HT, which the company said offers increased dynamic range compared to previous editions, a feature that could aid in plasma analysis, where dynamic range is a major challenge.
Bruker's development of the timsTOF system was done in collaboration with the Mann lab, which has also led much of the assay development for the platform. In addition to Geyer, OmicEra's three other cofounders — CEO Ole Vorm, CTO Sebastian Virreira Winter, and CBO Sophia Doll — were all at some point researchers in Mann's lab.
The company "brings an enormous amount of expertise," Garces said. "They were beta site testers for a lot of these platforms. They have tremendous data analysis capabilities, and then they have expertise in preparing the sample prior to mass spec analysis."
Exact is especially interested in protein modifications, phosphorylation in particular, Garces said, analogizing these modifications to DNA methylation, which has been key to nucleic acid-based cancer early detection.
"We feel that modifications like phosphorylation and others will serve as an important signal in the identification of cancer," he said. "The beauty of these new mass spec platforms is that we can really begin to differentiate these types of changes that just couldn't be resolved before. In addition to quantitating the levels of protein, we can also detect the modifications and particular protein changes that result from disease."
Garces said Exact is using a variety of non-mass spec protein analyses tools in its work, as well. He declined to say what other companies it is working with, but highlighted SomaLogic, Olink, Seer, Nautilus Biotechnology, and Quantum-Si as firms with interesting technologies. He said Exact is also interested in high-plex spatial proteomic methods.
In the 2018 Science study detailing the original version of the test, the Johns Hopkins University team that developed the assay used Luminex immunoassays run on Bio-Rad's Bio-Plex 200 platform to look for plasma protein markers that could help distinguish cancer patients from healthy controls, identifying eight potentially useful proteins. In the DETECT-A study the researchers published in 2020 detailing the CancerSEEK test's performance in a cohort of roughly 10,000 women, they measured levels of nine plasma protein markers to help detect potential cancers.
As Qing Wang, formerly a faculty member in the lab of JHU researcher Bert Vogelstein, one of the developers of the CancerSEEK test, explained in a 2017 interview with GenomeWeb detailing the lab's plasma protein work, the hope is that plasma protein markers will be more sensitive than ctDNA, which is often not present at measurable levels in early-stage cancer. Proteins are often not very specific for cancer, however, a challenge that the JHU researchers aimed to address by raising the threshold for a positive result to levels well above those typically considered normal and by evaluating the protein measurements in the context of the ctDNA data, which is much more specific for cancer.
Wang has since left Vogelstein's lab and launched a company, Complete Omics, focused on mass spec-based plasma proteomics.
Discussing the utility of combining protein and nucleic acid data for cancer detection, Garces noted that Exact measures both protein and nucleic acids in its lead product, Cologuard, which detects the protein hemoglobin along with DNA mutations and methylation markers.
"We are looking to deploy this approach in our multi-cancer early detection [test] as we continue to enhance and evolve the CancerSEEK technology," he said. "I think more and more this will become a common trend."
Garces said the company plans to use the OmicEra mass spec technology for discovery of plasma proteins useful in CancerSEEK and other assays, but that it would, in the near term at least, move those markers to an immunoassay format for clinical use.
By and large, plasma proteomics still has yet to show it can live up to its promise. And cancer early detection is a particularly challenging application. This month, Max Planck's Mann and his colleagues published a paper in Nature Medicine presenting a set of plasma protein panels for diagnosing alcohol-related liver disease (ALD).
Mann noted that the study was one of the first to demonstrate that a plasma protein-based test could offer performance equivalent or better than existing clinical tools. However, he added that liver disease was a relatively easy target for plasma proteomics given the size of the organ and its exposure to the circulatory system.
"Compared to early detection of cancer, we are doing the low-hanging fruit," he said, noting that, as with ctDNA, some cancers may not release enough proteins into the blood to be detected via plasma proteomics.
He said, though, that he believed Exact's acquisition of OmicEra made sense as a move to expand its research toolkit. (Mann is not involved in OmicEra, though it was founded by alums of his lab.)
"If I were Exact I would also invest in mass spec, because in many cases it is a very good complementary technology," he said. "I think it will be very useful."