September 19, 2008
NIH Podcast Episode #0067
Balintfy: Welcome to episode 67 of NIH Research Radio with news about the ongoing medical research at the National Institutes of Health—the nation's medical research agency. I'm your host Joe Balintfy. Coming up in this episode how a drug for herpes is showing promise for treating AIDS; and finding out about the genetic makeup of brain tumors. But first, new insight in treating asthma. That's next on NIH Research Radio.
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Monitoring Exhaled Nitric Oxide Does Not Help Manage Asthma
Balintfy: Thanks for tuning in. Some background on this first report: Researchers are often looking for what they call biomarkers: a biomarker is something that can be measured and show what a patient's medical needs are and what or how much treatment to give. For example, high blood pressure is a biomarker for heart disease. With asthma, which affects about 9-percent of children under 17, scientists were looking for a biomarker. They thought they had one in exhaled nitric oxide.
Balintfy: A new study shows that monitoring levels of exhaled nitric oxide in adolescents with asthma, and adjusting treatment accordingly, does not help manage their disease. Dr. William Busse is a principal investigator from the University of Wisconsin.
Busse: We thought that if we were more directed towards reducing airway inflammation by measuring the exhaled nitric oxide, asthma control would be better.
Balintfy: Asthma is a disease which is characterized by a number of key symptoms, usually coughing, wheezing and shortness of breath. These symptoms occur when the tissues of the lungs become inflamed and the muscles in the airways contract, making it difficult to breathe. Dr. Busse explains the scope of the study.
Busse: One group had sort of modification of their treatment based upon what we called guideline care. Guideline care is looking at patient's symptoms and lung functions and adjusting the medications according to these parameters. The other group—and this was all done in a blinded fashion—not only had assessments of these clinical parameters of their disease, but also had an assessment of their exhaled nitric oxide.
Balintfy: In the end, the study found that the group whose treatment was guided by exhaled nitric oxide did not end up with fewer or less severe asthma symptoms or fewer asthma attacks compared with the group that received treatment only based on the guidelines.
Busse: I think what one can conclude from the study is if you follow the recommendations for treatment of asthma as put forward by guidelines, which were just updated most recently, and this is through the NIH, one can very effectively manage patients with asthma. You don't necessarily need special equipment.
Balintfy: Approximately 550 adolescents in 10 cities across the United States participated in the study. It was conducted by the Inner City Asthma Network, which is funded by the National Institute of Allergy and Infectious Diseases. For more on the finding, published in the September 20th issue of The Lancet, visit www.niaid.nih.gov.
Herpes Virus Changes Anti-Herpes Drug to Form that Hinders AIDS Virus
Balintfy: A big part of medical research is what is called "basic science." That can be experiments on tissues, cells, genes - even molecules— to learn how the many complexities of the human body, all its parts, and diseases, work. Through some cutting edge research, a new potential use has been discovered for an established medication.
Balintfy: Researchers have found that an old drug shows new promise for treating AIDS. Dr. Leonid Margolis from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, notes that the drug, acyclovir, has a long history.
Margolis: It's a well known drug which was developed almost thirty years ago and can treat against herpes virus.
Balintfy: Dr. Margolis explains that in a recent series of experiments, the drug suppressed herpes the way it was supposed to, but also suppressed HIV.
Margolis: And that was a kind of miracle because it should not be suppressed.
Balintfy: He points out that acyclovir is one of the most specific drugs in medicine.
Margolis: It should only work against herpes virus and not against HIV and that was tested many times.
Balintfy: Dr. Margolis's initial experiments, however, were conducted in tissue samples. His research team then took additional steps to avoid mixing HIV with any herpes viruses by testing cells.
Margolis: We confirmed what people had done before us that acyclovir doesn't suppress HIV in cell lines, but in tissues it does suppress, so that was the question: how. So we decided since it was again proven that acyclovir is so specific about herpes that somehow herpes is involved in this process.
Balintfy: According to Dr. Margolis, the study findings show that when acyclovir is taken up by a cell infected with herpes viruses, the virus chemically alters the drug, adding a chemical compound called a phosphate group. Then the altered acyclovir interferes with the AIDS virus' ability to reproduce. For more on this study, visit www.nichd.nih.gov.
Balintfy: Coming up when we come back, an in-depth discussion on the most common form of brain tumors. Stay tuned.
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The Cancer Genome Atlas Reports First Results Of Comprehensive Study of Brain Tumors
Balintfy: Earlier this month, the Cancer Genome Atlas Research Network reported the first results of its large-scale study. This comprehensive study looked at the most common form of brain cancer, or glioblastoma. To discuss the study, we talked to Dr. Anna Barker, Deputy Director of the National Cancer Institute. The first question, what exactly is the Cancer Genome Atlas Research Network?
Dr. Barker: The Cancer Genome Atlas Research Network is a collaborative pilot program that's being conducted by the National Cancer Institute and the National Human Genome Research Institute. The goal of this pilot is to see if it's feasible, basically, to identify all of the genomic alterations in a specific cancer. And we've started the pilot program about a year and a half ago. We're about half way through it. Our goal is to examine three cancers and the first one is glioblastoma, which is the most common form of adult brain tumors.
Balintfy: What are some statistics on glioblastomas?
Dr. Barker: Well, it's the most common of the adult brain tumors. Glioblastoma is particularly of interest to us because basically it is a tumor where we've had very little impact on mortality. GBM when it's diagnosed actually is generally fatal in about 14 months. It's one for which we do have some therapies, but it's a particularly difficult tumor once diagnosed to treat. So beyond surgery, radiation and some limited chemotherapy, we really don't have much in the way of therapy for this tumor, nor do we have any early diagnostic techniques. So it's a particularly important tumor to us because it does afflict people most often in their most productive years.
Balintfy: Dr. Barker, let's turn to the study results published in Nature magazine. What were the findings?
Dr. Barker: We examined a little over 200 brain tumors and controls so we had normal DNA from these patients as well as their tumor. What we found was, one, we found three mutations that apparently—and these are changes in the DNA—that are apparently associated with a large percentage of glioblastomas. One of these genes has not been previously associated with glioblastoma in any specific way. We think it's going to be an important gene. It's called NF1, potentially as a therapeutic tool. Maybe of even more importance though, the Cancer Genome Atlas Network is an unprecedented team. There's about 135 people on this team from ten institutions working together on this project. And what they've been able to do with the data is to actually analyze the data in ways that we've never done before. So we've got data on how every aspect of the genome has changed all the way from changes in what we call copy number, expression or the protein expression of a change in the DNA, methylation which is the way the DNA is altered basically in the cell itself, and then the sequence of the DNA changes. And so, when you put all of that together into pathways, what we found was that three very specific pathways are altered in nearly all glioblastoma which may set the stage, it's early, but it may set the stage for some new approaches to developing new drugs. So pathway biology looks like the way that we're going to be going in the future. It's very exciting, and I think very, very encouraging.
Balintfy: So Dr. Barker, these newly identified pathways could they lead to treatments for brain tumors?
Dr. Barker: Yeah, we think so, and what this data is showing us is that in nearly all of these patients this multi-dimensional dataset is allowing us to see which pathways are activated, which pathways are de-activated. And so that's going to allow us to actually classify these patients into sub-groups and when you can do that, then you can actually ensure that patients are getting the right treatment, and they're not being over-treated or they're not being treated with the wrong agents, which is part of the issue with chemotherapy as you know. Yeah, I think it's pretty encouraging in terms of us being able to really get a handle on what's really not functioning in these patients in terms of these pathways which is, I think, the path toward personalized medicine which we talk a lot about.
Balintfy: Is it to early to predict when these discoveries might lead to new brain tumor treatments?
Dr. Barker: Too early. I think it's too early, but it may be a guide for how to use the therapies we already have. Again, it's a little early, but if you know that certain pathways are turned off or other pathways are turned on, then you may be able to combine drugs that we already have in different ways. That's not something that we've actually done very well so far because we just haven't had the data to say that combination is the right combination. So it could produce some short term gains for patients in terms of, you know, how do you combine drugs you already have. In terms of the future, though, I think it's going to actually lead us in some new directions for therapy.
Balintfy: When do you expect results from other studies by the Cancer Genome Atlas Research Network?
Dr. Barker: They're already underway so ovarian cancer, which is another of those cancers that's very, very hard to diagnose, we're just started on the characterization of that tumor and squamous cell lung cancer which is the lung cancer that is most commonly found in smokers is, again, already underway. Those samples are being characterized as we speak. We think over the next year we're going to have quite a bit of data on these three tumors, glioblastoma, ovarian cancer and squamous cell lung cancer, and we'll be able to, I think, to say more definitively how these multi-dimensional datasets, this very deep characterization of these tumors, is going to work out, you know, across a body of tumors, not just one tumor. So it's important we get some additional data, we look at another tumor or two. But we're encouraged enough to think that this project was an extremely, I think in some ways controversial project, but it's turned out to be very rewarding. And I think it's the wave of the future in terms of the way science is going to go. This team is, I think, is unprecedented in its depth and breadth as is the data. So that means that the analysis can be much more thorough and will, I think, in a lot of new directions for both diagnostics and therapeutics from this kind of study.
Balintfy: Dr. Barker, do you think the advancements made in this study are analogous to advances made in, say medical imaging - physicians being able get better pictures of tumors?
Dr. Barker: Yeah, I think probably that's a good analogy because this project is doing two things. One, it's bringing this large team together, you know, of these multi-talented, almost a dream team if you would, of genomicists and cancer biologists. But it's also producing a public dataset that can be mined by almost any investigator and then if you go through the right approval process, which we've got in place for the data to protect patients, then you can look at all the data. So it's doing two things. It's allowing this large team to look at the data but it's also allowing the entire cancer research community, and anyone else actually who wants to look at the data. So we're already seeing a lot of papers that are going to be published just from the public data and so I think it's going to create a whole new wave of discoveries. So in that sense, we're going to be looking at this tumor much, as you say, physicians were able to do with imaging to see certain characteristics of tumor. We're going to be able now to see all these molecular characteristics of the tumor, which we've never been able to do before.
Balintfy: Thank you very much Dr. Barker. Is there anything that we may have missed or you would like to reemphasize?
Dr. Barker: No. I think the Cancer Genome Atlas is the first application to a disease of the Human Genome Project. So having the normal sequence of the genome was necessary before we could do this project. I think bring all these pieces together with high quality bio-specimens with the best of the best in terms of bioinformatics and a team that actually represents sort of, as I say, a dream team of genomicists and cancer biologists has allowed us to really look at cancer in ways that, you know, we dreamed about for a long time. So I think it is the wave of the future, and it's very encouraging. It says that we're on the right track, and I'm happy to report that. I think that the right track here will take us to some new diagnostics and therapeutics for cancer.
Balintfy: One last question Dr. Barker, these upcoming studies on ovarian and lung cancers, where do things stand in terms of getting samples?
Dr. Barker: Well, that's an interesting story in itself. Maybe we can do that story another time, but one of the things we learned in this pilot—it's a pilot program—so we learned a lot of things in terms of how to do this kind of research. The one thing we've learned is that most of our repositories of human tissues in the country are really not adequate for molecular studies. So we've had to go through several thousand tumors to get the 206 glioblastomas that we're reporting on. So we're hopeful, for ovarian and lung cancer, that there will be more of those samples that actually qualify in terms of being high quality, but we're also prospectively collecting samples for ovarian and for lung cancer and also for GBM. So in the future, we're going to have to get ahead of this curve and prospectively collect these samples for these kinds of studies. They have to be very carefully collected and stored and curated plus we have to have all the data on the patients and you have to bring all that together. It's been a learning curve for the project and, I think, for science in general. But as a consequence, we've created a whole new series of guidelines for how you do this sort of thing, so this project is producing a great deal more than the results on the specific tumors. It's kind of showing us the way for personalized medicine, which is something we didn't plan on when we stated the project but, you know, it's a job that somebody had to do and so the Cancer Genome Atlas ended up sort of working out all these issues.
Balintfy: Thanks to NCI Deputy Director, Dr. Anna Barker. For more on the Cancer Genome Atlas, visit the website cancergenome.nih.gov. And for information from the National Cancer Institute, visit www.cancer.gov.
Balintfy: That's it for this episode of NIH Research Radio. Please join us again on Friday, October 3rd when our next edition will be available for download. I'm your host, Joe Balintfy. Thanks for listening. NIH Research Radio is a presentation of the NIH Radio News Service, part of the News Media Branch, Office of Communications and Public Liaison in the Office of the Director at the National Institutes of Health in Bethesda, Maryland, an agency of the US Department of Health and Human Services.