At the apex of the Cold War, NATO deployed a net of high-powered radar stations along the frozen edge of North America, poised to alert commanders of approaching Soviet missiles. Designed to supply crucial minutes of warning, the sites sit ready but unusedwatchdogs with no intruder.
In contrast, cancer researchers know their quarry but lack the know-how to construct a parallel early-warning system. For example, imaging technologies like MRI detect small cancers, but may not find precancerous cells. These cells look normal on the outside under the microscope but inside ferry a deadly warhead of genetic mutations. If there were ways to detect such renegades before they turned malignant, lives might be saved.
Thats the dream that drives a cadre of respected researchers in the nascent Early Detection Research Network (EDRN), a $20 million collection of 30 National Cancer Institute-funded institutions committed to developing effective cancer "radar."
At a mid-April organizing meeting in Florida, these researchers talked of blood, urine, and saliva tests that could one day quickly and painlessly flag early cancers and precancerous conditions.
But first, scientists need to find signals that exclaim cancer is imminent, biological smoke plumes of abnormal proteins and genetic additions and deletions. Dozens of candidates for such biomarkers exist, but none have proven themselves in the clinic. The EDRN wants to change that, and soon.
Division of Labor
Much of the meeting focused on building the networks infrastructure to speed the science. Like an assembly line where each worker perfects a specific task, the EDRN splits the work load to build on the strengths of its grantees.
As the front line, the 18 biomarker development laboratories, funded last fall, are searching blood, tissue, and other samples for biomarker candidates. Each lab focuses on one or a few cancer sites. When any particular marker shows enough promise, it will movewith the blessing of the networks steering committeeto one of three validation laboratories.
These labs will subject potential biomarkers to batteries of practicality tests to determine if the biomarker will work in a clinical setting without the luxury of million-dollar equipment budgets. "The results of our validation tests are going to be yes or no," said William Grizzle, M.D., Ph.D., principal investigator at the University of Alabama at Birminghams validation laboratory. "If yes, then we will look at our ability to upscale the assay for use in human studies, perhaps in cooperative group clinical trials. If we cant take an assay and make it work in all of the hospitals, its not going to be very useful."
After a biomarker is validated, the networks clinical and epidemiological centers will take over. Using their experience recruiting patients for cancer monitoring studies, nine centers will accrue the volunteers needed for initial clinical testing.
"For biomarkers to be useful, you have to have a high degree of quality assurance. Large, statistically normal populations have to be studied," said the meetings featured speaker, Bernard Levin, M.D., from the University of Texas M. D. Anderson Cancer Center in Houston. Levin added that "interesting but underpowered" studies plague biomarker research. "Thats why were all here. Sharing is clearly the most important issue."
Share, Share Alike
In a cowboy state like Colorado, spit shouldnt be in short supply. But for researchers seeking early signs of lung cancer, there can never be enough. Wilbur Franklin, M.D., from the University of Colorado Health Sciences Center, Denver, said he and his colleagues have spent upwards of a decade and $3 million dollars collecting sputum from smokers at high risk of lung cancer. They need more.
The addition of sputum and blood collections from network collaborators Margaret Spitz, M.D., M. D. Anderson, and William Rom, M.D., New York University School of Medicine, will augment Franklins pool, allowing him to test many more tantalizing biomarkers.
Similar arrangements will take advantage of large collections of blood and prostate tumor specimens at Johns Hopkins Medical Institutions, Baltimore, and the University of Texas Health Sciences Center, San Antonio; colon polyp samples at the University of Michigan, Ann Arbor; ovarian tissue samples from Brigham and Womens Hospital, Boston; and precancerous cervix specimens from the Centers for Disease Control and Prevention, Atlanta. A Hopkins collection of nearly 100,000 blood samples from Washington County, Md., and a cancer registry of 1,300 families housed at Creighton University, Omaha, Neb., round out the biological resources from the clinical centers. In addition, each of the 18 biomarkers development laboratories maintains collections, many of them holding 1000 or more samples.
"Its very important to pull together the samples with the science in the biomarkers labs. It gives us a huge advantage," said Franklin.
Complexity Abounds
Many network researchers said that they expect the best tests for early cancer will not be single biomarkers like prostate specific antigen, but rather patterns of markers. Dealing with the ocean of information generated by searching for and analyzing such patterns will require new statistical approaches, a task for the networks data management center at Fred Hutchinson Cancer Research Center in Seattle. But the biomarker revolution will have another consequence.
"Were going to find things floating in the blood and other places, and theres not going to be any way to know what to do about them," said Bruce Trock, Ph.D., part of the biomarker development laboratory at Georgetown University, Washington, D.C.
Already, when physicians identify a precancerous condition, such as precancer of the cervix, they often balk at the next step. Prophylactic surgery is an option, but unnecessary in many cases.
Generating new biomarkers that identify precancerous conditions will mean that more and more people will be told that they mayor may nothave cancer. The reason for the confusion is that on the road between healthy tissue and metastatic cancer multiple genetic mutations appear. Most of these precancerous lesions pose no threat. The trick is deciding which is whichsomething even the best pathologists struggle with.
The concern over the anticipated increase in "precancer" as a diagnosis led to a proposal that the EDRN move beyond identification of single biomarkers to the development a molecular taxonomy of all precancerous conditions. The suggestion by Donald E. Henson, M.D., program director at NCI, sparked vigorous discussionincluding complaints about the lack of precancerous condition data in cancer registries such as the NCIs Surveillance, Epidemiology, and End Results programand a resolution to hold a molecular taxonomy workshop in early 2001. "Sooner or later, the cancer community is going to have to deal with precancerous lesions and what to do with them," said Henson.
The work of Bogdan Czerniak, M.D., Ph.D., and colleagues at M. D. Anderson is one approach to such a taxonomy. The M. D. Anderson team is cataloging all genetic mutations found in precancerous bladder lesions. Their ultimate goal is a chip that will light up patterns of gene expression that signal a menacing lesion.
Several other EDRN researchers are jumping into proteomics, a new technology that reads cellular patterns of protein expression. If a cells genome is its blueprint, then its proteins are the hammers, nails, and wood that build the cell and keep it running. Analyzing proteins, then, brings science one step closer to finding out whats really gone wrong in the cellular machinery.
One proteomic technology, SELDI (surface-enhanced laser desorption and ionization) spectrometry produces a molecular weight "map" of protein expression for each sample that looks like a bar code. Comparing bar codes from normal, precancerous, and cancerous tissue may identify patterns of protein expression associated with early cancerous changes.
Trock and his collaborators at the FDA, NCI, and Georgetown have found "preliminary evidence of reproducibly different" protein expression patterns in normal and malignant breast tissue, and other teams are applying the technology to ovarian, colon, and prostate cancers.
Whether gene chips or proteomics will ever arrive as clinical tools for detecting cancer early remains to be seen. But for now, with the EDRN structure in place, the reality of advanced tests for early cancer seems much closer.
Sudhir Srivastava, M.D., Ph.D., chief of the biomarkers research group at NCI, voiced his confidence this way: "If this group cant do it, I dont know who can."
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