Thermo Fisher Scientific and researchers from George Mason University led by Lance Liotta and Emanuel Petricoin will try to develop a new workflow that could eventually validate protein biomarkers to where they can play in the clinical setting, the partners said this week.
Under the two-year agreement, Thermo Fisher’s Biomarker Research in Mass Spectrometry Center will cross-validate an undisclosed number of candidate protein and peptide biomarkers discovered by researchers at GMU’s Center for Applied Proteomics and Molecular Medicine. The disease states to which the biomarkers are linked include cancer, Alzheimer’s disease, and cardiovascular disease.
In addition, CAPMM researchers will use Thermo Fisher’s Quantum Ultra triple-quadrupole mass spectrometer to develop a workflow based on multiple-reaction monitoring, a method they hope will break the biomarker validation impasse.
“The endgame here is to develop and assess the utility of an MRM-based approach for biomarkers, especially peptidomics biomarkers that we have been identifying in various disease states,” Petricoin, chair of the department of molecular and microbiology at GMU, told ProteoMonitor this week.
Along with CAPMM co-director Liotta and Mark Ross, director of the center’s Mass Spectrometry Laboratory, Petricoin will lead the university’s work on the partnership.
To reach a point where protein biomarkers can be validated and turned into marketable tests, “you’re going to have to reach out to commercial entities,” Petricoin said. “They can’t just be done in an academic environment or a government lab.”
As part of this deal, any biomarkers that are found to have clinical value will become the property of GMU, Petricoin said, though Mary Lopez, director of Thermo Fisher’s Biomarker Research in Mass Spectrometry Center, said the company will have the option to commercialize assays resulting from the partnership.
Work by Thermo Fisher on the partnership will take place at BRIMS, located in Cambridge, Mass.
“Once we partner with our collaborators and if we do develop assays that have clinical applications, Thermo Fisher happens to be the eighth-largest diagnostic company in the world,” she said. “We have many different avenues to bring these types of assays to market, if we choose to do that.”
Both parties declined to discuss the financial terms of the agreement.
The announcement of the deal comes amid a groundswell of criticism from the proteomics community about the poverty of protein biomarkers with any clinical utility and gripes that protein biomarker research to date has been plagued by slipshod science.
By trying to develop an MRM-based workflow, Thermo Fisher and the CAPMM are seeking to create a sensitive and specific method with high throughput for biomarker validation.
And by having their candidate markers cross-validated, CAPMM researchers will address a major criticism about many biomarker studies: the lack of independently validated results.
“The proteomics world has moved from qualitative technologies to quantitative technologies, and quantitative technologies will allow more efficient validation of biomarkers that have been discovered.”
Typically, verifying and validating a candidate peptide or protein biomarker discovered by mass spectrometry requires the use of immunoassays such as ELISAs and developing antibodies against the discovered antigen.
“The problem with that is it takes a long time to get those good antibodies,” Liotta said. “You could be in a position where you’ve identified some fantastically good diagnostic markers by mass spec, but then no antibodies exist for those proteins, and it could take, in some cases, years to get good antibodies if they’re not commercially available.”
Because the Quantum Ultra instrument is able to pick up “unique fragments” of the analytes, researchers can at least in theory “validate the existence of the protein based on the exact size of the fragment of the protein … without requiring an antibody,” Liotta said.
In its effort to develop an MRM-based validation and verification workflow, CAPMM will harvest biomarkers using a nanoparticle technology developed in-house that captures biomarkers from blood samples and protects them from degradation after they have been extracted [See PM 01/10/08]. After assays of the proteins or peptides have been created, the Quantum Ultra will be used to validate them.
The first part of CAPMM’s work will be to look at known analytes such as PSA and CA 125, and try to develop an MRM-based assay for them. They will then assess the assays for their ability to detect the analytes in serum and the reproducibility of the method.
In the second stage of the work, CAPMM will develop MRM assays for biomarkers discovered by its scientists. Helping them develop the targeted assays will be Thermo Fisher’s Sieve software for label-free differential protein expression analysis, as well as software that the tool vendor is still beta-testing.
“Hopefully if we develop workflows that are consistent and reproducible, we would be able to then assess the clinical utility by large numbers of cases and controls,” Petricoin said.
The collaboration is the first of its kind that Thermo Fisher has publicly announced since its BRIMS Center changed its focus last year from protein identification to biomarker validation and assay development [See PM 04/12/07]. However, Lopez said that other similar but smaller collaborations are also underway. Additional collaborations are currently being negotiated, she added.
“We have a technology and workflow that we believe has value in a clinical environment,” Lopez told ProteoMonitor. “The proteomics world has moved from qualitative technologies to quantitative technologies, and quantitative technologies will allow more efficient validation of biomarkers that have been discovered.”
The problem has been that there has been no standard method for biomarker validation that was high-throughput and sensitive and specific, she said.
“The MRM workflow with the triple quad in combination with a high-throughput method for sample prep is exactly that technology,” Lopez said. “What we hope to do is to be able to take the list of markers that Drs. Petricoin and Liotta have discovered, and then put them through this workflow and efficiently determine which ones are going to be useful.”
The proteomics community, beset by validation problems for years, will be keeping its fingers crossed. At the Human Proteome Organization’s annual conference in October, several speakers took to task the state of clinical proteomics generally, and biomarker research in particular. Sam Hanash, a principal investigator at the Fred Hutchinson Cancer Research Center and the founding president of HUPO, described the state of biomarker research at the time as “chaotic” and compared it “the Wild West.” [See PM 10/11/07 and 10/18/07].
At US HUPO’s most recent annual meeting in March, keynote speaker Leigh Anderson, founder and CEO of the Plasma Proteome Institute, said that despite the excitement surrounding proteomics in its early days, the field has progressed at nowhere near the pace people had anticipated. Furthermore, he added that much dirty, difficult work still remains before proteomics-based diagnostics will have any clinical and market significance [See PM 03/20/08].
The issue hasn’t been a shortage of candidate biomarkers, but that very few of them have been able to move beyond the discovery stage to validation, regulatory approval, and commercialization.
This week, Petricoin said that the hope is for the Thermo Fisher collaboration to result in methods that will help overcome existing validation bottlenecks.
“If it’s a workflow that looks viable, we’re obviously going to be publishing and presenting this so that other people can kick the tires as well,” Petricoin said. While public-private collaborations like his group’s alliance with Thermo Fisher are nothing new, he said that such partnerships are even more necessary to bring proteomics to the clinical level.
“We’re going to have to see more of that because at the end of the day, these biomarkers for public benefit and for patient benefit have to be commercialized,” he said. “None of these biomarkers is used in the clinic or ordered by a doctor unless it’s commercialized … and [reimbursed] by insurers.”