NEW YORK (GenomeWeb) – The University of Manchester is collaborating with UK-based diagnostics firm Abcodia to identify protein biomarkers for risk stratification and early detection of lung cancer.
The effort is one of a series of biomarker development projects the university will run out of the Stoller Biomarker Discovery Centre that it plans to open next year supported by £17 million ($27 million) in funding largely from the UK's Medical Research Council.
The collaboration will use serum samples from a cohort of non-small cell lung cancer cases drawn from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) biobank, which Abcodia has licensed the rights to. Using these samples, Manchester researchers led by Tony Whetton, director of the Stoller Centre, aim to validate three candidate protein biomarkers for early detection of lung cancer and identify other potential markers using a combination of techniques including multiple-reaction monitoring and Swath-MS.
Rights to markers and other intellectual property emerging from the collaboration will be shared by the university and Abcodia, Whetton told GenomeWeb.
"Late clinical presentation of lung cancer is a major contributor to [patients'] poor prognosis, so there is a strong clinical imperative to find markers of early-stage lung cancer," Whetton said, laying out the rationale for the project.
And while a number of proteomics efforts — including the development of Integrated Diagnostics' Xpresys Lung test — have focused on identifying markers that can be used in concert with imaging techniques like CT scans, the Manchester researchers hope to develop markers that can be used for early detection and risk stratification independent of imaging data, he said.
The Abcodia collaboration builds on previous discovery work by Whetton and his colleague Phil Crosbie, who put together a collection of clinical plasma samples the researchers used for their initial work in the disease. That project, Whetton said, identified three candidate markers, which they now hope to validate in the UKCTOCS samples using MRM mass spec.
They will also look for new candidate markers in the UKCTOCS samples using Swath, he said, noting that "it just makes good sense to use the samples for as many approaches as possible."
Whetton and his colleagues used conventional shotgun mass spec combined with isobaric tagging for the initial lung cancer discovery work, but, he said, they have since moved to Swath as their primary discovery tool.
"Isobaric tagging has served us extremely well," he said, noting that in repeated validation experiments his team had found the data provided by the technique to be of high quality. However, he said, the relative speed and ease of DIA methods like Swath make it better suited to large-scale biomarker work.
"Isobaric tagging is a very great deal slower, so if you want to crank through a great many samples then it is extremely difficult," he said. "The Swath MS technique is going to give you just as good a penetration at probably 10 percent of the machine time. I think also the informatics [in isobaric tagging] is a bit more challenging."
Additionally, because Swath-style data-independent acquisition (DIA) mass spec methods collect MS/MS spectra on all ions in a sample, the technique avoids the issue of stochastic sampling that exists with traditional shotgun approaches. This means that while DIA methods don't typically identify as many peptides in a given sample as shotgun methods, they provide more reproducible quantitative information on the peptides they do identify, which makes the approach well-suited to quantitation of large sets of proteins across large numbers of samples — as is required in biomarker discovery and validation.
"So it's time for us to move on. Swath-MS is our chosen platform for biomarker discovery in the future," he said.
Several mass spec platforms, including instruments from Thermo Fisher Scientific, are capable of running Swath-style experiments, but Whetton and the Stoller Centre will be using instruments from AB Sciex, which released the first commercial Swath-style method in 2012.
The Stoller Centre will feature on the order of a dozen or so new mass spectrometers from AB Sciex including several triple-quadrupole instruments and a number of TripleTOF 6600 machines, Whetton said.
Additionally, the center will feature antibody-based platforms onto which markers and assays can be ported if necessary.
"The ethos is to have an automated workflow going from a discovery proteomics lab into a triple quad lab based around good clinical laboratory practice standards, and within that same area to have antibody-based protein detection and quantification techniques," Whetton said. "So it's kind of an automated workflow from samples coming in the door through to triple quad or antibody-based assays."
He added that while the new center will be focused on proteomic-based discovery, it also will be integrated with a number of other resources essential to effective biomarker development. For instance, the center will be linked to the new Manchester Molecular Pathology Innovation Centre, which is being built with £2.9 million in funds from the MRC.
"It's fine to develop these assays and have them come off the mass spectrometer and do validation, but then one needs to turn them into something which is of value to a pathology lab," Whetton said. "So, here the pathologists will be cheek by jowl with the mass spectrometrists and informaticians, and thereby you develop the kind of synergies and understandings of each others' activities that will help us carry forward the development of biomarkers for a variety of different diseases."
Additionally, the center's researchers will collaborate with health informatics researchers on developing what Whetton called "a safe haven to analyze patient data, proteomic data, and genomic data within the kind of strictures that the National Health Service requires for patient confidentiality," and they will also work with the Manchester Center for Genomic Medicine to incorporate genomic data into their work.
In addition to the lung cancer work, the Stoller Centre will also undertake ovarian cancer biomarker research using the UKCTOCS samples. Former University of Manchester researcher Ian Jacobs, now at the University of New South Wales, is one of the founders of the UKCTOCS trial, through which he and Massachusetts General Hospital researcher Steven Skates developed the ROCA ovarian cancer test, which uses longitudinal measurements of the ovarian cancer protein marker CA125 combined with transvaginal ultrasound to enable early detection of the disease.
Abcodia has licensed that test and launched it in theUK. It is planning a US launch in Q4 of this year. Jacobs is a non-executive director at Abcodia.
In addition to cancer work, Stoller researchers are also planning to do biomarker discovery for conditions like lupus, rheumatoid arthritis, and psoriasis with a focus on identifying markers of response to therapy, Whetton said.