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Move Beyond Setbacks and Just Do It, Researchers Tell AACC Attendees

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SEATTLE – Is proteomics ready to stop beating itself up and proceed to the next phase?
 
At last week’s American Association for Clinical Chemistry’s conference on translating proteomics from discoveries into diagnostics, presenters focused less on beating up on themselves for past setbacks and more on figuring out how to move past their shortcomings to create a genuine clinical pipeline.
 
To be sure, throughout much of the two-day conference, organized by AACC’s proteomics division, there was some hand-wringing over the quality of much of the current proteomics research, the paucity of protein biomarkers approved by the US Food and Drug Administration, and the fact that much still needs to be done before proteomics can be seen as little more than an exoticism in the molecular diagnostics field.
 
But unlike the last time the conference was held in the fall of 2006 — when the tone was of disappointment and frustration, and the advice being spread was to ratchet down expectations [See PM 10/19/06] — the message at this year’s meeting was for proteomics researchers to put their collective noses to the grindstone.
 
In his keynote speech opening the conference, Lee Hartwell, president and director of the Fred Hutchinson Cancer Research Center and co-recipient of the 2001 Nobel Prize in Physiology or Medicine, said that in the fight against disease, proteomics is not alone in falling short on results.
 
“The truth is we’ve had very little success in most diseases, and that’s disappointing,” he said, pointing to the declining rate of new drugs approved by the FDA.
 
Against that backdrop, molecular diagnostics — both protein- and gene-based — are seen as the key that will unlock the personalized medicine revolution. According to a report published last month by market research firm Global Industry Analysts, the global market for molecular diagnostics is expected to reach $3.67 billion by 2010.
 
Molecular diagnostics can lead to early disease detection, evaluate individual risk for disease, match disease to therapy, measure therapeutic efficacy, and monitor for disease relapse, Hartwell said. But for any of that to happen, “we need biomarkers,” he said.
 
The days of “molecular diagnostics … are upon us, and I think we see it most in cancer,” he said.  While DNA research has been the prime driver, proteins have greater potential as the basis for diagnostics because they are more diverse and dynamic than genes, and are more related to the physiology of a disease, he said. Changes in protein expressions and modifications are considered to be a more accurate reflection of disease states.
 
To be sure, there has been progress in protein biomarker research, Hartwell said. Instruments are improving and are leading to better research results; there are new, sensitive assays with multiplexing capabilities and mass specs with greater sensitivity; and while high-abundance proteins are still a major bottleneck, new tools are improving depletion of such proteins, bringing researchers closer to the low-abundance proteins that are believed to be the true fingerprints of diseases.
 

“I’m sure that if we had a good idea about the complexity of [our work], we’d quit.”

And proteomics technology development remains a hotbed of activity. During the conference, several presenters described work recently completed or still being conducted to improve the discovery and validation of protein biomarkers.
 
For instance, Eric Fung, CSO at Vermillion, described his company’s continuing work to develop a blood-based test for peripheral arterial disease, while Peter Kraus, a field applications scientist at Invitrogen, described protein microarrays as a high-throughput and multiplexed technology for antibody detection. And Larry Gold, founder and chairman of SomaLogic, presented his company’s work on aptamer arrays, which could be used with high affinity and specificity to identify disease-causing proteins.
 
Meanwhile, Henry Rodriguez, director of the US National Cancer Institute’s Clinical Proteomic Technologies for Cancer program, outlined the agency’s work developing proteomics technology. Among them is its Clinical Proteomic Technology Assessment for Cancer program, created to evaluate mainly mass spectrometry and affinity-based technologies [See PM 09/28/06], and its recent initiative to develop high-quality, highly characterized monoclonal antibodies [See PM 11/29/07 and 04/10/08].
 
But according to Hartwell, what’s missing is a large-scale and coordinated effort to bring proteomics from research labs to clinical settings. To figure out how to better “translate biomarkers to clinical practice,” Hartwell proposed a new model that would include all stakeholders, including clinicians, government regulatory agencies, and private and public payors.
 
According to Daniel Chan, director of the Center for Biomarker Discovery at the Johns Hopkins University, such a model may already be gestating. A working group comprising the AACC, the American Society of Clinical Oncology, the FDA, and the NCI’s Early Detection Research Network, has been created to explore strategies to develop cancer biomarkers for clinical practice. Members from each of these organizations held their first meeting last month to evaluate the current state of cancer biomarker research and identify challenges that need to be overcome.
 
For all the research being conducted, there is still a paucity of cancer biomarkers with clinical utility, he and others said during the conference. Hartwell referenced a 2006 study by Leigh Anderson and Malu Polinsky that found that of 1,261 candidate protein biomarkers for cancer described in the scientific literature, only nine have been approved by the FDA as “tumor-associated antigens.”
 
Most that have been approved are for monitoring therapy, Chan said. A few protein markers have been approved for predicting therapy or prognosis, and only one, PSA, is approved for early detection. No marker has ever been approved for cancer screening, he said. It can be argued that the HercepTest used to assess the appropriateness of Herceptin as a treatment for patients with a certain type of breast cancer also functions as a screen for overexpression of the HER2 protein, but the point was made: more biomarkers are needed.
 
Among the challenges that have been identified by the working group are poor study designs; biological variability among individuals; site variability in sample collection; and reagent and instrument variability.
 
These findings have led the group to determine that goals to develop biomarkers for clinical utility should include high analytical accuracy, long-term consistent results, and interchangeable results between different assays in order to avoid clinical confusion.
 
Federico Goodsaid, senior staff scientist in the genomics group at FDA’s Office of Clinical Pharmacology, added that it is important to distinguish the three different types of biomarkers: mechanistic, diagnostic, and predictive. All three, he added, play important roles in the molecular diagnostic development pipeline.
 
“We have to figure out how to encourage the development of all three biomarkers,” he said.
 

Finally, while each presenter cast an optimistic light on the field, they also said that much heavy lifting remains to be done in proteomics. Asked how many protein variants there are, Hartwell said the number is “big” and quipped that he’s “sure that if we had a good idea about the complexity of [our work], we’d quit.”

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