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Stoller Centre Develops Protein Panel for Early Detection of Lung Cancer

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NEW YORK – A team led by researchers from the University of Manchester has developed a protein panel for the early detection of lung cancer.

Described in a paper published last month in the Journal of Proteome Research, the panel was able to identify patients up to a year before their diagnosis with an accuracy of 89 percent. The researchers now hope to test the panel in additional, larger patient cohorts, said Anthony Whetton, senior author on the study and director of the University of Manchester's Stoller Biomarker Discovery Centre.

Established in 2016 with £17 million ($21 million) in funding largely from the UK's Medical Research Council, the Stoller Centre is focused on identifying and developing protein biomarkers for a variety of conditions, ranging from cancers to arthritis to kidney and metabolic diseases. A key part of the center's mission has been to establish "industrialized" workflows for proteomics, which it has largely done using Sciex's data-independent acquisition Swath mass spec approach.

By "industrialized," Whetton and Sciex mean discovery proteomics workflows that are routine and streamlined and capable of running large numbers of samples. Sciex began four to five years ago promoting its Swath technology as ideal for such work and helped outfit both the Stoller Centre and the Australian Cancer Research Foundation International Centre for the Proteome of Cancer (ProCan) in Sydney with collections of Swath-capable instruments with the aim of demonstrating the feasibility of the industrial proteomics idea.

Since then, the field has to a significant extent shifted in this direction with many prominent researchers and vendors emphasizing the number of samples systems are able to reproducibly analyze more than the depth of proteomic coverage a particular workflow enables.

The lung cancer work did not use an especially large cohort (25 cases and 25 controls), but Whetton said his lab's experience with the Swath workflow has borne out his initial hopes of streamlining proteomic discovery.

"We've been very pleased with it because of the ability to get through a great deal more samples in a good deal less time," he said, adding that he would answer "yes," to the question of whether the center had in fact managed to "industrialize" mass spec-based protein biomarker discovery.

He said he didn't have an exact number for how many samples the center had processed since opening but said it was "thousands and thousands."

"The throughput is extremely high compared to most other centers in the world," he said. He cited a recent study he and his colleagues ran looking for biomarkers of kidney disease in which they analyzed around 600 plasma samples over the course of a few weeks.

In the lung cancer study, the researchers used Swath on a Sciex TripleTOF 6600 mass spec to analyze 50 serum samples from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) biobank — 25 from healthy controls and 25 from patients who were diagnosed with lung cancer within 50 months of the blood draw. Running the samples using a two-hour LC gradient, they identified 65 proteins that were differentially expressed between the two groups. Using hierarchical clustering and principal component analysis, they identified a panel of 11 proteins that distinguished between cases and controls one year prior to diagnosis with sensitivity of 88 percent and specificity of 89 percent. A 12-protein panel that included a marker identified by earlier research was able to distinguish between cases and controls at three years to diagnosis with sensitivity of 79 percent and specificity of 78 percent.

Whetton said that further research in additional cohorts was required to establish what the clinical utility of the panel might be, but broadly speaking he said he believed a blood-based protein test would likely prove most useful for risk-stratification of patients to determine who should receive imaging-based lung cancer screening.

Screening with low-dose computed tomography (LDCT) has proven effective at reducing lung cancer mortality in high-risk populations, but there is still considerable uncertainty and debate about how to best define these populations. Currently, this is primarily done based on age and smoking history, but protein and other biomarkers could play a role, as well.

"I think the ideal is that we have a blood-borne biomarker test for risk and stratification, so that one can look at the results of this test and determine whether further follow-up is required," Whetton said. "I think that's the space that is awfully important with respect to lung cancer."

With regard to the ongoing effort to industrialize proteomic research, Whetton said he and his colleagues are currently in the process of further shortening their mass spec runtimes to increase throughput as well as making changes to their protocols that will keep their instrument columns cleaner.

He said that they are also assessing whether Sciex's new scanning Swath workflow could benefit their research.

The company introduced the technique at the American Society for Mass Spectrometry annual meeting in June. The methods used a sliding quadrupole window as opposed to stepped isolation windows, which boosts performance by improving ion accumulation and providing additional information for matching of precursor and fragment ions.

In early work with the method, Sciex researchers have achieved a 30 percent boost in peptide identifications compared to conventional SWATH approaches.

"I think scanning Swath shows a great deal of promise, but it's not part of our pipeline as of yet," he said.

While the bulk of the Stoller Centre's proteomic work is done on Sciex instruments using Swath, it also has a Thermo Fisher Scientific Orbitrap Lumos that Whetton said the lab uses "for deep-dive studies into specific samples."

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