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INSIDE TRACK: Search for Markers in Prostate Cancer

AliAli TradonskiSharon MairSharon Mair, MD 

By Kurt Woock

When Ali Tradonsky recruited her mother, Sharon Mair, MD, FASCP, to assist with a high-school science project, it’s safe to say she did not have her sights set on making national news. But, Tradonsky, now a freshman at the University of Pennsylvania, wasn’t a typical student. Mair, a surgical pathologist at Sharp Grossmont Hospital, San Diego, wasn’t a typical team leader, and the project was no vinegar-and-baking-soda volcano. Instead, the pair, along with one of Tradonsky’s classmates, Tammy Rubin, and a small team of researchers, embarked on a nearly 3-year course to discover a biomarker that could predict a prostate cancer’s potential aggression in its early state. Success was far from guaranteed, but they eventually found it. Mirroring a test used in breast cancer research, the team tested 20 antibodies and found four that showed promise, though widespread testing is needed to confirm the results. Their results were published in the June 2012 issue of the American Journal of Clinical Pathology (AJCP). Clinical Lab Products spoke with both Tradonsky and Mair about the origins and the outcomes of their ambitious project.

CLP: Out of all the possible studies, why did you pursue prostate cancer?
     Tradonsky: There are so many cancers, such as leukemia and breast cancers, that we have learned so much about using genetic testing. We figured we should apply the same methods to prostate. It’s one of the most common cancers in men, and it’s definitely the most overtreated. The purpose was to find a molecular biogenetic marker that could differentiate the aggressive cases from the indolent ones.

CLP: Dr Mair, why did you sign on?
     Mair: This was a study I had really wanted to do for more than 10 years, ever since PSA was approved and came on the market as a screening test. Basically, what that led to was a whole lot of additional cases of prostate cancer being diagnosed at very early stages when they are largely clinically insignificant. But once you make the diagnosis, there’s no accurate, reliable method right now to determine which of those cases are going to behave in an aggressive, truly life-threatening fashion and that therefore need to be treated. And we know the vast majority of cases are going to be indolent. For the longest time, I had wanted to do a study to distinguish the two so we could spare this enormous number of men, who didn’t need treatment, from undergoing treatment. Also, if I was going to commit 2 years of my life to this project, it needed to be something worthwhile. I knew it would probably be the hardest thing any one of us has ever done, but it was going to be a shot at something really significant.

CLP: How were high-school students and research scientists able to work on the same level?
     Mair: I told Ali and Tammy, “Understand that before I even let you do anything that involves scientific testing, you’re going to need to know everything about the prostate. It’s really going to be a major deal.”
     Tradonsky: We needed to learn everything about the prostate: anatomy, physiology, histology. We learned all of that. We attended a male autopsy, where we examined the prostate.

CLP: How did the idea progress?
     Tradonsky: At first, we thought it might be useful to use DNA sequences as opposed to protein products. We later realized that it was very expensive and much harder to work with actual DNA sequences. There are many positives to working with protein products. We realized you could use archival tissue. Much of the tissue we worked with had been in storage for years. Also, using proteins, we could see under the microscope if the protein was on a cancer cell or a benign cell.
     Mair: Many years ago, a group of scientists were working at Stanford [University] to differentiate subcategories of breast cancer. They believed if different breast cancers behaved differently, there had to be some kind of molecular differences. They analyzed the gene sequences for 5,000 breast cancers. At the end of that, they found five different classes of breast cancer that could be differentiated by their gene sequences. And within those gene sequences there were some genes that were prognostically significant. They manufactured the protein products of these gene sequences to be able to test for them under the microscope. Those same scientists then started a company, called Advanced Genomics Institutes (AGI).
     We were going to originally work with gene sequences, but that’s very expensive and very labor-intensive. Whilst we were in the process, the lab we were working with connected with AGI, so we then had access to their proprietary proteins. We met with the head scientist at AGI. He said, “Rather than reinvent the wheel here, we have all the antibodies to these gene sequences. Let’s see if any of these are prognostically significant in prostate.” We started testing the antibodies in a test population of prostate cancer, just to see whether the antibodies would be reproducible and could be used on the prostate tissue.Out of the more than 80 we started with, there were only 20 that were reproducible and robust in prostate tissue.

CLP: How were you able to get enough funding? 
     Mair: We were doing most of the work ourselves. We applied to the Grossmont Hospital Foundation for a grant. When we applied for funding, they said, “We are going to support this because it’s a really neat idea. We think it’s amazing that it’s a mother-daughter team. But we’re telling you now, we don’t think this is going to materialize. It’s going to be so hard to pull off. But we’re going to support you anyway. We’ll give you the money because you deserve the chance.” I think they were absolutely right. It was craziness on our part.

CLP: Were the odds truly against you?
     Mair: Absolutely. It was completely unlikely we would succeed. When we started out, Ali and Tammy were so idealistic. I said, “You have to understand, this is like finding a needle in a haystack.” We just got very lucky because we found four antibodies that were meaningful.

CLP: How would an eventual test based on this research work?
     Mair: We have a four antibody model: Each patient tests positively or negatively for each marker. Based on how the patient tests on each of the four, you come up with an index. I think that the majority of people would have at least one of the good markers expressed. I think the most important thing would be to detect those who are strongly Hey2 positive. Those cancers in our study that were Hey2 positive had a poor prognosis. It’s going to be a very small number of patients, but those are the patients you want to identify and you want to try to treat immediately, locally, with everything you can. And maybe it’s not worth putting them through the misery of chemotherapy because we know they’re not going to respond. Using this algorithm of the four-antibody test, clinicians can decide whether they want to treat immediately if it’s an aggressive case or if they want to embark on what we call watchful waiting in more favorable cases. Hey2 might be to prostate cancer what HER2/neu is to breast cancer—an indicator of disease aggression. If so, then hopefully down the road someone can manufacture an antibody therapy. Ideally, there would be a monoclonal antibody, which would be a targeted therapy.

CLP: What does the future hold?
     Tradonsky: Ideally, we’ll be doing a large-scale validation study. We studied 240 cases; we’d need to study thousands of cases. Hopefully after that, we could develop a kit with these four antibodies.

CLP: What does this research mean for people in clinical backgrounds like you, Dr Mair?
     Mair: As practicing clinicians, we have a huge advantage, even an obligation, to define and determine what needs to be looked at in research because it’s clinically relevant and significant and needed. A lot of research that takes place and gets funding is so theoretical that it never translates into anything meaningful. I think pathologists look at things differently. Clinicians and pathologists need to look at situations where we fall short in diagnosis or therapy and say, “There is a problem here, an unanswered question—let’s do the research so we can give patients something better.” That is the direction I’d like to see more research take. Oftentimes, the research money doesn’t get channeled into the clinically relevant questions.

Kurt Woock is associate editor for CLP.

Click here to read the AJCP article.