Biomarkers by definition indicate some state or process that generally occurs at a spatial or temporal distance from the marker itself, and it would not be an exaggeration to say that biomedicine has become infatuated with them: Where to find them, when they may appear, what form they may take, and how they can be used to diagnose a condition or predict whether a therapy may be successful.
Biomarkers are on the agenda of many if not most industry gatherings, and in cases such as Oxford Global’s recent “Biomarker Congress” and the GTC “Biomarker Summit”, they hold the naming rights. There, some basic principles were built upon, amended, and sometimes challenged.
In oncology, for example, biomarker discovery is often predicated on the premise that proteins shed from a tumor will traverse to and persist in, and be detectable in, the circulation. By quantifying these proteins—singularly or as part of a larger “signature”—the hope is to garner information about the molecular characteristics of the cancer that will help with cancer detection and personalization of the treatment strategy.
Yet this approach has not yet turned into the panacea that was hoped for. Bottlenecks exist in affinity reagent development, platform reproducibility, and sensitivity. There is also a dearth of understanding of some of the fundamental principles of biomarker biology that we need to know the answers to, said Parag Mallick, Ph.D., whose lab at Stanford University is “working on trying to understand where biomarkers come from.” And sometimes, too, accepted wisdom just isn’t so.
For example, there are dogmas saying that circulating biomarkers come solely from secreted proteins. But Dr. Mallick’s studies indicate that fully 50% of circulating proteins may come from intracellular sources or proteins that are annotated as such. “Right now we don’t understand the processes governing which tumor-derived proteins end up in the blood.”
Other seemingly obvious questions include “how does the size of a tumor affect how much of a given protein will be in the blood?”—perhaps the tumor is necrotic at the center, or it’s hypervascular or hypovascular. “The problem is that these are highly nonlinear processes at work, and there is a large number of factors that might affect the answer to that very simple question,” he pointed out.
Their research focuses on using mass spectrometry and computational analysis to characterize the biophysical properties of the circulating proteome, and relate these to measurements made of the tumor itself.
“We’ve observed that the proteins that are likely to first show up and persist in the circulation, on average, are more stable than proteins that don’t,” Dr. Mallick said. “This is something that people qualitatively suspected, but now we can quantify how significant the effect is.”
The goal is ultimately to be able to build rigorous, formal mathematical models that will allow something measured in the blood to be tied back to the molecular biology taking place in the tumor. And conversely, to use those models to predict from a tumor forward to what will be found in the circulation. “Ultimately, the models will allow you to connect the dots between what you measure in the blood and the biology of the tumor.”