NEWS

$104 Million Proteomics Initiative Gets Green Light

Karyn Hede

The National Cancer Institute's Board of Scientific Advisors (BSA) in June approved a 5-year, $104 million Clinical Proteomic Technologies Initiative just 3 months after turning down an earlier version of the measure that some board members said lacked proof of concept. What's more, the board approved the measure despite the fact that its price tag increased by $15 million from its initial $89 million estimated cost.

"I can tell you that particularly in tight money times it didn't make anyone particularly happy that the price tag went up," said Robert Young, M.D., BSA chairman and president of Fox Chase Cancer Center in Philadelphia.



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Robert Young

 
Approval for the initiative followed presentations by NCI staff who tried to address issues that came up at its initial presentation at the board's March meeting, during which members voiced concerns about reproducibility and comparability of proteomic analyses, a lack of common reagents and public data sets, ineffective transfer of technologies to clinical applications, and an inability to manage the massive volume of data produced by proteomic techniques. After tabling the initiative, the board asked a subcommittee chaired by Joe Gray, Ph.D., director of life sciences at Lawrence Berkeley National Laboratory, to work with NCI staff to rework the proposal.

The program that emerged to address these issues is a three-pronged approach: $35.5 million to establish Clinical Proteomic Technology Assessment Consortia that will evaluate new technologies to ensure reproducibility and develop standardized protocols; a $56 million Technology Development Core that will support development of new computational methods, protein separation techniques, and support for animal model work through the investigator-initiated R01 mechanism; and a $12.5 million Proteomic Reagents Core that will award contracts and small-business awards to develop standard reagents and methods that will be distributed to investigators.

Expunged from the proposal was a $15.8 million clinical specimen and data collection effort that would have collected and annotated biospecimens specifically for proteomic analysis. Advisors had balked at its inclusion due to the current lack of understanding of how biospecimens destined for proteomic analysis should be handled and preserved. Instead, the NCI will invest in an intramural program to be headed by Carolyn Compton, M.D., the new director of the NCI's Laboratory for Human Specimen Banking Research, who will lead a team of investigators in looking at tissue handling issues and natural variability in samples.

"Our goal is to fund this next year," said Greg Downing, D.O., Ph.D., director of NCI's Office of Technology and Industrial Relations, adding that he expected the NCI to issue RFAs for the project in the first quarter of fiscal year 2006, with a review of applications around September 2006.

One Step Forward, Two Steps Back

There is still some controversy over the revised proposal that stems in part from uncertainties surrounding the utility of current serum-based proteomic technologies to accurately diagnose or aid in the treatment of cancer.

A public dispute over the reproducibility of a widely hailed proteomic-based test for ovarian cancer developed by former NCI scientists Lance Liotta, Ph.D., and Emanuel Petricoin, Ph.D., now at George Mason University in Fairfax, Va., has soured some researchers on the potential utility of proteomics.

"I'm a little bit concerned that to invest that amount of money in technology development in the absence of proof of concept that this is clinically useful is premature, in my opinion," Jane Weeks, M.D., BSA board member and associate professor of health policy at Dana-Farber Cancer Institute in Boston, said at the June BSA meeting.



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Jane Weeks

 
Proteomics is basically protein biochemistry on a large scale. Laboratories that used to painstakingly study one protein of interest can now quickly identify hundreds and soon perhaps thousands of proteins simultaneously using a combination of protein microarrays, separation techniques, and tandem mass spectrometry. For clinical purposes, the "holy grail" would be to find patterns of protein signatures that could identify the early changes associated with the development of cancer. That quest has excited the imagination of many investigators.

"If you take a look at the milieu of the cancer problem and say what change would dramatically alter outcomes in a relatively short period of time, I think almost everybody would agree that major new techniques for enhancing early diagnosis would make a huge impact," said Young.

But in that quest, argues clinical epidemiologist David Ransohoff, Ph.D., of the University of North Carolina at Chapel Hill, some investigators have let their search for telltale patterns get the best of them.

"Basically, if you let the computer run long enough, a computer can fit any set of predictors to any set of outcomes, but it may be idiosyncratic or overfit and just work with that [one set] of data," he said. "It doesn't reflect how the real world works and it isn't reproducible."

Ransohoff has been a critic of some of the early efforts by investigators to compare protein profiles of cancer versus noncancer patients' sera and come up with a reliable diagnostic assay for cancer. He has written extensively on the need for proteomic studies, which are often observational in nature, to take extreme caution to eliminate sources of bias. He pointed out that there is a huge opportunity for research in proteomics that is done correctly but that much of the published research has not taken enough care in eliminating results that could be due to chance or unintentional bias.

Ransohoff raised his concerns in a minisymposium organized by NCI before the March BSA meeting. At that meeting he suggested that instead of leaping into such a large project, the NCI start small to help figure out if proteomic technologies are going to be worth the investment. But, if anything, the initiative grew larger between March and June, with the addition of research on animal models and computational support.

"We need [to study] a group of specimens with and without cancer that have been collected and handled in uniform way and that is large enough to generate a pattern and then test it on a group that has not been involved in the derivation of the pattern," he added in an interview. "With the right kind of thought and attention this can be done."

Yet others aren't waiting for proof of principle to launch programs aimed squarely at the discovery of biomarkers for cancer diagnosis, prediction of therapeutic response to treatment, and probability of disease recurrence, among other applications.

One such NCI-funded effort already under way teams Lee Hartwell, Ph.D., director of the Fred Hutchinson Cancer Research Center in Seattle, an architect of the NCI's proteomic initiative, with six other institutions looking for breast cancer markers. Part of the team effort is devoted to technology development.

"There have been a lot of so-called biomarkers developed based on too few experiments," said Richard Smith, Ph.D., a Battelle Fellow at Pacific Northwest National Laboratory, Richland, Wash., and a member of Hartwell's breast cancer marker team. "How do you validate a biomarker? How do you understand natural variability? We just need a lot of measurements, but most of the approaches to proteomics have been really very low throughput, except for the methods that give you very shallow coverage of the proteome."



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Richard Smith

 
Smith is pioneering new high-throughput, high-resolution methods to analyze blood serum proteins using a combination of protein separation techniques and mass spectrometry that he says can dig much deeper into the proteome. He agrees that current technologies haven't reached the point where broad dissemination of the techniques is warranted.

"The problem has been in the quality of the data that has been produced," said Smith. "I'd say there has been a misuse of a lot of the tools. There aren't a good set of rules and people are largely left on their own. There's some good work being done and some not so good work being done, and if you take all this together it looks like there is a lot of variability in what's being seen."

Smith said the lack of standards and reproducibility argues for the NCI's initiative rather than against it.

"Standardization is absolutely essential if this [proteomic technology] is going to be credible and have a good chance at success," said Smith. "It's far beyond what any single lab can do. There are a lot of different skill sets needed to pull this whole thing off. This is really large science and if you try to cram it into an R01 you may get good science, but it is boutique science. I think it's an incredibly important step to really develop a foundation that the broad community can have faith in."

Gray, who helped reshape the proteomic initiative, concurs: "I think the reason we have had difficulty in validating some of the promising signatures that have been reported is because we haven't invested in the technology standardization as proposed in this concept, and, as a consequence, the data haven't been as reliable as we would like. I think it's necessary to do what's proposed here to even test the hypothesis that there are biomarkers out there."

Yet Ransohoff argues that, "The question on the table scientifically is whether any discovery-based serum proteomic study [has] shown a high level of discrimination without chance or bias to explain the results, because if the answer to that is ‘no,’ and if the investment that a funding agency is going to make is predicated on the belief that there's a high degree of discrimination and now let's work out the details ... then it may turn out that the initial premise that the technology works may be incorrect. It may turn out the technology doesn't work nearly as well as presumed, and that's what I'm worried about."

In the end, the promise of proteomics won out over the skepticism, and the board voted unanimously to approve the measure.

"I think most of the Board of Scientific Advisors have a healthy skepticism about whether or not its going to work, but the potential for this to make an impact is huge, and I think that's probably why most of us believed it is worth the investment," said Young.



             
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