Q. Many laboratories have been using mass spec as the means to discover new biomarkers, and the success of these efforts relies on effective collaboration between clinicians and mass spectrometrists. What has been your experience in fostering these collaborations?
Very good. The clinicians come to us early. They know that we, as mass spectrometrists, are going to save them huge amounts of money if we can be successful at identifying a biomarker for their clinical trials and identifying which patients the trials should enroll.
So the clinicians are interested, but they do come to us before we are ready with the appropriate tools to deal with their data. Also, from what I’ve seen, the FDA is looking for biomarker information. So, again, the clinicians are coming to us, saying, “We have this new drug on the market and the FDA would like some biomarker information about it. What can you provide for us?”
Again, the issue is do we have the right tools to do the job and, in addition, can we do it in a cost-effective and timely manner?
Timeliness has been a big issue for us. We have identified putative biomarkers but then we have not had the antibodies available to validate them. In the meantime, the next-phase of a client’s clinical trial has started, so what have we really accomplished?
We have to pose the question: “Is this something we can accomplish in a reasonable time?” and, once we get results, “Is anyone going to be able to do something with these data again, in a reasonable time?”
I have had good success in fostering collaborations with clinicians at BMS. We have performed some experimental pharmacogenomic clinical trials where we used proteomics as one of the techniques to identify novel marker candidates. Some of our will work will soon be published.
I think proteomics is a relative newcomer when compared to RNA-expression profiling in a clinical setting. Furthermore, proteomics continues to rapidly evolve into a stable profiling platform. This sometimes leads to issues with timeliness and delivery of data/results and can create early disappointments. Clinical trials can run from a few weeks to several months. Typically, clinicians expect results within a few weeks of the close of a clinical trial to meet several key deliverables. So, we need to be careful about setting expectations when we discuss protein-profiling projects with clinicians, pick appropriate projects, and be expeditious with protein-profiling results and deliverables.
I agree with Gary that new tools are being developed. I like to use the analogy that we are trying to build a race car and working on improving it while racing it on the race track.
I think mass spec is going to be the future of how biomarkers (proteomic and metabonomic) will be discovered. But we need to be cautious as well as savvy about how we go about picking appropriate experiments and projects in areas of unmet need. We can not just perform “quick and dirty” experiments with low-resolution mass spec data and claim success of having identified biomarkers. Rigorous replication and independent validation of results in subsequent study is necessary to gain further confidence of candidate markers.
Sometimes clinical trials take years. In a experimental pharmacogenomic clinical trial in which I’ve been involved, it has taken over four years just to procure samples. Then it requires about six weeks to get LC/MS profiling data. The data acquisition is typically followed by several exploratory statistical data analyses, a lot of which is data-dredging, and this can take upward of a few months before you actually have a list of candidates that you want to go after and identify. Finally, biological context is typically required to establish further credibility of candidate biomarkers.
Then, we investigate availability of assays for these candidates. If one doesn’t exist, how long is it going to take to put an assay together? A targeted SRM/MRM-based mass spec assay, is typically the quickest way. That said, at times these markers may be present at low abundance, as a result, it may not be that straightforward and easy to establish a quick targeted mass spec assay. Combination of biochemical approaches with targeted mass spec detection may be required. This assay development approach depends on availability of biochemical reagents and may add a significant amount of time to assay development/delivery.
Discussing all these issues with clinical colleagues is necessary to build alignment, concensus, and thereby develop a successful collaboration.