March 20, 2009
NIH Podcast Episode #0080
Balintfy: Welcome to the 80th episode 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, a lot about cancer: We’ll hear how the combination of exercise and rest can reduce cancer risk, also how genes play an important role in breast cancer progression. This episode also kicks off a series on proteomics – the study of proteins – and how proteomics holds promise for the early detection and treatment of cancer. But first news about an antibody that inhibits HIV infection. That's next on NIH Research Radio.
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Researchers Identify a Novel Antibody that Inhibits HIV Infection
Balintfy: Antibodies are large proteins naturally produced by the immune system to help fight disease-causing foreign invaders, such as viruses and bacteria. Researchers at the National Cancer Institute have identified a novel type of antibody that potently inhibits HIV infection. Wally Akinso brings us this report.
Akinso: Previous research has shown that reducing antibodies to the smallest independent functional fragment, known as a variable domain, can make them more useful as therapeutic agents. In this study, a small antibody fragment, known as a domain antibody, was shown to be highly effective in neutralizing HIV by preventing the virus from entering cells. Dr. Dimiter Dimitrov is with the NCI’s Center for Cancer Research.
Dimitrov: We found a new domain antibody, which was the very first human domain antibody found against HIV. And it shows an exceptionally high potency and activity against this virus.
Akinso: Dr. Dimitrov explains how this finding may impact public health.
Dimitrov: It targets a new structure of the HIV, which has never been targeted before. And therefore it has a promise to be use in combination with other drugs to fight drug resistance. In terms of the significance to the public this antibody can add another weapon in our armory against HIV.Akinso: Dr. Dimitrov adds that the study could lead to a potential therapeutic drug against HIV down the road. This is Wally Akinso at the National Institutes of Health, Bethesda, Maryland.
Exercise and Rest Reduce Cancer Risk
Balintfy: In our last few episodes, we heard a lot about the importance of physical activity, even for cancer prevention and cancer survivors. In this report, we learn how results from research also point to a sleep-exercise link when it comes to cancer prevention in women. A recent study presented at an American Association for Cancer Research conference suggests that regular physical activity can lower a woman’s overall risk of cancer—but only if she gets a good night’s sleep. Dr. James McClain at the National Cancer Institute explains that a lack of sleep can undermine exercise’s cancer prevention benefits.
McClain: The major findings of this study, although preliminary, are that among younger and more active women, a short duration of sleep appears to be associated with increased cancer risk.
Balintfy: Even though the exact mechanism of how exercise reduces cancer risk isn’t known, researchers believe that physical activity’s effects on factors including hormone levels, immune function, and body weight may play an important role.
McClain: We know quite a bit about the association between, the relationship between physical activity and cancer. We know that the more active you are, the more you reduce your risk of developing cancer. There have been a few studies that have looked at the relationship between sleep duration and cancer. Some of those have found that shorter duration sleep can increase your risk for cancer, but there’s been some mixed results on that. We were interested in the relationship between physical activity, sleep, and cancer just because we know there’s a lot of effects, beneficial effects of physical activity that seemed to be counterbalanced by the effects of short duration of sleep, so we wondered if maybe the relationship would change.
Balintfy: The study examins the link between exercise and cancer risk, paying special attention to whether or not getting adequate sleep further affects a women’s cancer risk. But Dr. McClain points out that the association of physical activity and sleep does not necessarily prevent cancer.
McClain: Sleep in our study did not prevent you from getting cancer, so you can’t just go and sleep more and reduce your risk of getting cancer. What we did find is that among the most active women in our study—these younger, more active women—that if they slept more than seven hours, they were protected relative to those who slept less than seven hours. So the women who were younger and more active, sleeping less than seven hours experienced more cancer, about one and a half times as much.Balintfy: Dr. McClain adds that the study was a cohort of about 6,000 women. Their physical activity and sleep was measured at the beginning. Then they were followed over a period of 10 years to see what kind of outcomes they experienced. For more on this study and other cancer research, visit www.cancer.gov.
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Inherited Factors Play an Important Role in Breast Cancer Progression According to Mice Study
Balintfy: From exercise and cancer risk, to genetics and breast cancer. Here’s another report from Wally Akinso featuring another expert from the National Cancer Institute.
Akinso: A new study in mice confirms that gene factors play an important role in breast cancer progression. In the study, conducted by the National Cancer Institute, scientists found that genes for factors contributing to susceptibility for breast cancer metastasis can be inherited. Dr. Kent Hunter, from the NCI, is the author of the study.
Hunter: We know that tumor susceptibility can run in families. So if you have patients whose parents had the same types of cancer that spread, those patients are more likely to have tumors that spread than patients who had parents with tumors that didn’t spread. So in addition to whatever random chance events that occur your family history also plays an important role in whether or not tumors will spread or not.
Akinso: The study results also show that gene activities in tumor cells and immune cells that invade tumors can contribute to the development of expression profiles called gene signatures which can predict cancer progression. Expression profiling is the measurement of the activity of thousands of genes at once to create a global picture of cellular function. To determine whether mouse gene expression profiles could be used to predict outcomes in human breast cancer, the investigators identified a gene expression signature that allowed them to distinguish between the tumors of mice that have a high or low inherited susceptibility of tumor metastasis. Dr. Hunter explains the progression of the study.
Hunter: We started with an animal model, in this case a mouse model, to do the genetics and find the information about the inheritance and the inherited traits. After that we’ve then gone into human samples and human populations to confirm the results that what we’ve seen in the mouse models is applicable to humans and it seems to be just as applicable in humans as in our mouse models.
Akinso: Dr. Hunter says the study provides additional evidence of the role of inherited genes in human breast cancer. He added that down the road they hope to develop more effective and therapeutic strategies. This is Wally Akinso at the National Institutes of Health Bethesda, Maryland.Balintfy: Keeping with the cancer theme, our feature interview deals with how the study of proteins may lead to early detection and treatment of cancer. Right after this break.
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Proteomics – Part 1 of 3 – The Promise of Proteomics for Personalized Medicine
Balintfy: This year, nearly one-point-five million Americans will receive the devastating news: they’ve been diagnosed with cancer. Also this year, more than half a million Americans will die of cancer. But today we know that early detection, diagnosis and treatment are the best hope for long-term survival. Specifically, chances of surviving cancer are greater if it’s diagnosed when still confined to the organ of origin – what’s called stage 1. So researchers today are looking at proteomics, the study of proteins, as an early detection tool.
In part one of our three part series, we talk to Dr. Henry Rodriguez, the director of the Clinical Proteomic Technologies for Cancer programs at the NCI. We start with some background. What is it that proteins do?
Dr. Rodriguez: What happens is, is that every cell happens to have, which is what people are very familiar with, is the DNA, but ultimately that DNA needs to form some functional unit that’s going to have the different capabilities to carry signals throughout the cell and throughout the body. Those workhorses is what people refer to as the proteins. So it can be the DNA itself as this beautiful blueprint, but ultimately that blueprint has to form a product, and the vast majority of those products downstream is going to be the protein.
Balintfy: What’s the importance of studying proteomics?
Dr. Rodriguez: Proteomics is very important to early cancer detection, both diagnosis also helps the treatment of cancer and that in turn relates to personalized medicine. Because the belief there is that cancerous cells ultimately will shed proteins and other molecules into their surrounding environment, and if these proteins are shown to have clinical utility — this is what we refer to as biomarkers — the result of this is that the real greatest promise for early detection in the treatment of cancer lies in our ability to find biomarkers and if feasible, in bodily fluids that are going to be very easily accessible, such as blood and urine, which is also one that people go after.
Balintfy: We’ve actually talked about biomarkers before on the podcast. But you mentioned clinical utility and how proteins are biomarkers. Can you explain that a little bit more?
Dr. Rodriguez: Sure. So if you look at it today, right now there happens to be two main dominant protein biomarkers that people are quite familiar with that you could test in blood. There’s actually more than two, but the main ones that people are quite familiar with happens to be both prostate-specific antigen, or PSA, and the other one has to be cancer antigen 125, commonly referred to as CA-125. Now, these are ones that actually have been FDA approved tumor associated antigens.
Unfortunately, both tests may result in false negatives, which is failing to detect cancer in those who have it, which is poor sensitivity, or false positive, which is testing positive for the presence of cancer in people who are actually cancer free, which is poor specificity. But today we do know that tumor-associated proteins do exist in blood, and those are two good examples. While not the best, it does exist.
So what you have now is that the National Cancer Institute is actually working on ways to try to improve the current methodologies that we have, and hopefully in our ability to detect better protein biomarkers that could lead to early detection of cancer.
Balintfy: So if we can see the proteins, and we can see how they’re biomarkers, then it leads to better tests for cancer. Is that an oversimplification?
Dr. Rodriguez: No, in fact that’s a perfect way of saying it. I mean, today, we absolutely do know that the earlier you’re able to detect cancer, the far better your survival rate’s going to be. So proteomics is one of those fields that people recognize. Here are two examples, and are there other ones in this vast amount, this huge ocean they call proteomics, which is all the potential proteins that a cell in the body happens to have.
Balintfy: There are a lot of proteins in the body. I heard that anywhere from a quarter of a million to a million distinct proteins —
Dr. Rodriguez: That’s right, so the best guesstimates could be as low as a quarter of a million or a million, but now if you throw into the factors that at the DNA level you have all these variations that could occur, that’s going to lead to modifying base-up [proteins downstream. More importantly, when a protein’s produced, the same protein itself can undergo multiple modifications, but that’s the beauty of the whole proteomics, is that as these different proteins are modified, they carry out their unique functions. So it’s not this easy to say there’s only “x” amount. There’s a huge ocean that’s out there. That’s great because that means there’s a big target area to go after, but at the same time, it lends to tremendous complexity for us to be able to mine that huge amount of diversity that exists.
Balintfy: How do you study proteins? How are you able to see and look at something so small? Is there technology out there that allows you to study the little proteins?
Dr. Rodriguez: Yeah, so in the field of proteomics, there’s two predominant platforms or technologies that happens to exist. One of them has to be mass spectrometry, and this is sort of this evolving, powerful, analytical technology that’s out there. It actually allows scientists now to detect and identify ever smaller amounts of these proteins. The method’s very precise, and it’s absolutely sensitive, and it has the ability to distinguish proteins at different composition by single-hydrogen atoms.
Now, the other platform uses nature’s own ways of capturing proteins, and those are the ones referred to as protein microrays. In the common press, people might refer to them as protein chips or biochips.
Now, what makes these unique is that they’re able to measure a multitude of different proteins, but the way they do it is by developing capturing reagents, actually fish out the protein from a complex mixture. There’s different ways of doing it, but the most common way of developing this affinity capture reagent is a monoclonal antibody, which is natural to every cell that’s out there, or to biology.
Balintfy: It’s an antibody, so that’s something — it’s another sort of biometric thing or — what exactly is an antibody?
Dr. Rodriguez: The easy way of looking at it is when you develop a disease, or let’s say you get influenza, the body has to defend itself, so it develops these proteins that will actually capture that. So antibodies is actually that component itself, and what they do there is, as opposed to mass spectrometry, which is just engineering base component behind it, it measures the mass. When it comes to protein chips, they’re actually using nature’s own antibodies to capture very specifically what it was intended to go after all along.
Balintfy: Great. I think we’re doing a good job of covering the broad topic of proteomics. Are there other things in this sort of introductory episode that you think are important to cover? Are there programs NCI is launching that deserve mention at this early stage?
Dr. Rodriguez: Yeah, so one of the things that I alluded to is that while I truly believe that proteomics is this very promising field, and it’s going to have a huge impact, especially in the area of early diagnosis, I also alluded to that there are good examples that you can now detect proteins that can be used for the early diagnosis of specific cancers, but yet, they’re not the best ones on top there. You know, so what NCI now has done, I think they’ve taken a very proactive and very bold move by launching in 2006, late 2006, this bold initiative that they refer to as Clinical Proteomic Technologies for Cancer Initiative.
People now refer to it as the CPTC, and what we’re doing here is, simply, we’re working very hard to improve the discovery and development of protein biomarkers and the way we’re doing that is by trying to optimize the current technologies that are out there. At the same time, developing new technologies and systems to significantly advance the field of cancer proteomics research, and of course, the way we’re going to do this is by establishing standards, rigorous quality control measures where that’s going to be applicable.
Balintfy: And I think that’s what we’re going to get to more in the next episode, is that right?
Dr. Rodriguez: Absolutely, we’ll go into more in depth, and I’ll tell you the more great promises that the field has to offer.
Balintfy: Great, thank you very much.
Dr. Rodriguez: OK
Balintfy: Thanks again to Dr. Henry Rodriguez at NCI. For more information about the NCI Clinical Proteomic Technologies for Cancer Initiative, visit the website proteomics.cancer.gov. And be sure to tune in, in two weeks.A quick personal note before we go, I’d like to give a big thanks to my coworker Jeff Dehoff here at the News Media Branch. He’s been a great help behind the scenes with the podcast and the NIH vodcast, “I on NIH.” And now he’s leaving NIH. Jeff, thanks for all your help. You’ll be missed.
Balintfy: That’s it for this edition this episode of NIH Research Radio. Please join us again on April 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.