Welcome to FOCUS In Sound, the podcast series from the FOCUS newsletter published by the Burroughs Wellcome Fund. I’m your host, science writer Ernie Hood.
My guest on this edition of FOCUS In Sound is Dr. Blossom Damania, associate professor of microbiology and immunology at the University of North Carolina-Chapel Hill School of Medicine and member of the UNC Lineberger Comprehensive Cancer Center. In 2006, Blossom was named a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease in support of her research into the role of signaling proteins in the pathogenesis of viral-associated cancers such as Kaposi’s sarcoma-associated herpesvirus, or KSHV. She is also a Leukemia and Lymphoma Society Research Scholar, and has received major support from the V Foundation, the American Herpes Foundation, the American Association for Cancer Research, and the American Heart Association.
Blossom, welcome to FOCUS In Sound…
Thank you, Ernie.
We don’t typically think of cancer as an infectious disease, or at least most people, I think, and I think many people may still have difficulty wrapping their heads around the concept that viruses can cause cancer, although it’s certainly become well established that that is the case. Could you give us a quick overview of that association?
Yes. I think it’s been pretty under-appreciated by the general public, the role of viruses in cancer. Usually viruses are associated with things like flu or Ebola, and there actually have been a number of human viruses that are associated with human malignancy, and these viruses usually establish lifelong latency in the human population, and normally don’t cause much of a problem, but under conditions of immunosuppression, such as people infected with HIV or people taking immunosuppressive therapies in order to get a transplant for example; it’s under those types of circumstances that these viruses can manifest themselves and have oncogenic potential.
In your research you’re seeking to elucidate the underlying mechanisms at work in the specific case of the association between the KSHV virus and Kaposi’s sarcoma, as well as some other cancers, and you’ve had good success in unraveling the elements of that association. But before we talk about those findings, I’m curious about whether you see that work as a model for describing the etiology of viral-associated cancers overall…
Yes. I think that many of these viruses, although they’re very different from each other, they use very similar mechanisms or pathways to actually induce the transformation process or the oncogenic process. So I think that understanding how one virus can induce transformation opens a window into how other oncogenic viruses in the human population also cause cancer.
So for example, there are several signal transduction pathways which are essentially pathways that our cell uses to proliferate, or stay quiescent, or not grow, and what the virus does is that it modulates or changes or manipulates those pathways so that the virus is able to either stay latent and hidden from the host’s immune system, or replicate itself and disseminate throughout the host’s body or infect a new individual. The virus has viral proteins that it comes with that can modulate these host signal transduction pathways. And the same signal transduction pathways that are modulated by one virus may also be modulated by other oncogenic viruses. The proteins they use to modulate these pathways are different, but the pathway modulation is the same. For example, we can find a signaling pathway that’s modulated by KSHV, but it’s also modulated by other oncogenic viruses like Epstein-Barr virus. Once we understand the pathways that the virus deems important enough to modulate, we can perhaps identify new drug therapeutics to block those pathways and prevent the virus from doing that.
Your work actually lies at the intersection between two scientific puzzles…the virus/cancer connection and the mysterious tendency of some viruses, such as herpesviruses, to lie dormant in an infected person’s system, sometimes for many years. The KSHV virus is well-known to be associated with Kaposi’s sarcoma, but you’ve made significant progress in uncovering what reactivates the virus from its dormancy. Tell us about your findings on that…
You’re right. Herpesviruses establish lifelong latency in the human host. We may be infected when we are five or ten years old, and once infected, we have the virus with us for life, because there’s no cure for herpesviruses. There are drugs out there that will stop their replication, but they do not eject the virus out of the body. So once infected, you’re infected for life. We’ve been trying to understand how this virus persists for so long and so successfully in an individual, and one of the hypotheses we wanted to test was: during your lifetime—say you live 70 years—you’re likely to be infected by a wide number of pathogens—viruses, bacteria, fungi. We asked the question, how does secondary infection with these other pathogens affect dormancy of the herpesvirus that’s lying latent in a cell?
In order to do that, we looked at proteins called toll-like receptor proteins, which are sort of the guardians of the cell in an infectious process. These proteins are the first proteins that actually recognize an incoming pathogen, whether it’s a virus, a bacteria, or a fungus. They sort of alert the cell to the fact that it’s being invaded by a foreign pathogen. And when they alert the cell, they activate several intrinsic mechanisms to fight that secondary pathogen infections. For example, it makes a lot of interferon, which sort of helps to kill the incoming pathogen, and also kill the cell as a result. It’s clear that herpesviruses are very successful in escaping that initial TLR, or toll-like receptor, response. They somehow manage to escape that initial primary response to the incoming pathogen, and establish themselves latently, or dormantly, in the cell.
And they escape the immune system as a whole at that point, right?
Yes. They’re very successful at doing that. But other pathogens may not be. For example, influenza virus doesn’t establish lifelong latency. So you get infected with the virus, your body reacts to it, gets rid of the virus, and in a couple weeks you feel normal again. We wanted to know, when you have secondary pathogen infection with things like influenza, what happens to herpesvirus that’s lying inside the cell? And so we actually screened all of the toll-like receptors, which are the sensors of secondary pathogen infection, and found that when you activated two specific toll-like receptors, TLR-7 and TLR-8, you could actually get the herpesvirus to reactivate itself and replicate. And it actually then replicates and spreads in the body. So this is a mechanism that the herpesvirus has used to subvert an immune pathway which is important for pathogen infection, but it takes advantage of that by actually using that signal to actually replicate itself and then spread to other, naïve cells that have not been infected. This is sort of a survival response of the pathogen, of the herpesvirus, to incoming secondary infections.
How does that reactivation and replication through the body apparently tie in to the development of cancer? I understand that KSHV encodes certain genes, for example…
Right. That’s an interesting point. I think the replication aspects of the virus and the oncogenic aspects of the virus have to go hand-in-hand, because without one or the other you wouldn’t have lifelong persistence, you wouldn’t have transmission through the human population, and you wouldn’t have the cancers arising in the context of infection. I think what’s happening is that the virus needs to balance the replication aspects of its life cycle with the latent or dormant aspects of its life cycle. And it’s generally thought that the latent or dormant aspects of the life cycle are associated with the cancer process, or transformation process, but that the replication part of the life cycle is required for not only dissemination and persistence through the human population, but also that several of the replicative proteins actually induce growth factors and cytokines, which are important for growth of the cancer. So these two different aspects of the viral life cycle contribute to its oncogenesis, but without the replication cycle or the latent cycle, you can’t have the cancer developing, or the virus persisting through the human population. So they sort of go hand in hand.
So it’s almost a perfect storm that develops, in that signaling event.
Blossom, I know that Kaposi’s sarcoma is known mainly as an often deadly complication of HIV/AIDS…is that the result of the combination of a compromised immune system and that secondary viral infection you were referring to, which activates this cascade associated with the toll-like receptors?
Yes. I do believe that immunosuppression with HIV is a key factor in the development of Kaposi’s sarcoma, which is the leading cancer that HIV patients manifest and often die of.
It’s a skin cancer, right?
It’s a skin cancer, but it’s not just on the external extremities. It can be internal, so the lining of your lung or gastro-intestinal cavity or colon, those places can all develop Kaposi’s sarcoma. It’s just that you can’t see it. And a lot of times patients die of those internal KS lesions because they go undiagnosed oftentimes until it’s too late.
Or untreated, I imagine…
Yes. We think that immunosuppression with HIV is really a very important factor for development of Kaposi’s sarcoma. People who are normal or seemingly healthy and don’t have any sort of immunosuppressive disease still develop KS, but it’s much more infrequently than an HIV-infected individual.
And just to give you an appreciation for the difference, if you’re HIV-positive, you’re 20,000 times more likely to get Kaposi’s sarcoma than if you’re HIV-negative. And then comparing immunosuppression with HIV to just immunosuppressive therapy that transplant patients normally take, for a transplant patient you’re about 600 times more likely to get Kaposi’s sarcoma than if you’re not taking immunosuppressive drugs, whereas with HIV infection it’s 20,000 times more. So something about HIV infection is really accelerating the pace at which a person can develop this cancer.
What are the potential clinical implications of your findings? Does this new knowledge give any potential new targets or strategies for therapies?
Yes. We’ve been examining pathways that are required for the virus to survive in the infected cell, and one of these pathways is very important to prevent cell death and enhance cell survival. We’ve been looking at several compounds that actually inhibit this pathway and therefore induce cell death of the infected cell, which is what you would want. We’ve been studying this at the bench as well as using animal model systems to study how these compounds would affect the cancer induced by the virus, and we’ve had some good success using that. We’re currently trying to put together a clinical trial to test this out at UNC and other places, and test whether these drugs will be efficacious in curing cancers associated with this virus.
Are you working with some of the translational departments here at UNC?
Yes. I’m working with several physician-scientists and clinicians at UNC Hospitals, in the hematology/oncology group, and we’re trying to get a clinical trial going to test these drugs.
Well, that’s terrific, we’ll certainly be keeping an eye on that and hoping for great success…Blossom, tell us a little bit about your background, and what led you to pursue this particular line of research.
I knew I wanted to do research when I was an undergraduate. So I was at Mount Holyoke College from ’89 to ’92, and I had an outstanding teacher, a professor in biochemistry, Dr. Su, and she really instilled a passion for research and science in me, and that made me realize that doing this as a career would be something that I would love to spend my time on. So I applied to graduate school, and I went to the University of Pennsylvania, and that’s where I started working on viruses. And that’s where it all started in terms of how viruses can transform cells, how they can activate pathways that are required for the virus to survive, but as a consequence also result in the cell being transformed and becoming carcinogenic. I think the end result of viruses is that they don’t want to induce cancer, but they need particular pathways in order to survive inside a host cell, and so they manipulate those pathways, because they need those pathways to survive. But as a result of that, you get the cell also being transformed. I don’t think the virus’s intention was to cause the cancer. Its intention was just to persist and survive.
That understanding, I think, first occurred to me in graduate school, and I realized that I wanted to pursue that further. At the time, when I was applying for a post-doctoral fellowship, KSHV, Kaposi’s sarcoma-associated herpesvirus, had just been discovered in 1994, and there was a lot of things that were unknown about it; there were a lot of things to do. The people who discovered it, Yuan Chang and Patrick Moore, had sequenced the viral genome. There were more than 84 genes to work on. And so it was a very exciting time; a lot of unknowns, a lot of things that we could research. So I decided to do a post-doctoral fellowship at Harvard Medical School, in the lab of Ron DuRocher, understanding how KSHV and associated herpesviruses were involved in the transformation process.
I started off being a very basic researcher, but the more I learned and I read about the diseases associated with KSHV, and it’s not just Kaposi’s sarcoma, there are two other lymphoproliferative diseases, which are cancers of blood cells—in this specific instance B lymphocytes—called primary effusion lymphoma, or PEL for short, and multicentric Castleman’s disease…and importantly, with PEL, which is primary effusion lymphoma, the prognosis for people who have this disease is very, very bad, so they have a survival time of less than six months once they’re diagnosed. That made me realize that this is not just an abstract disease that I’m studying at the bench, but something that maybe I can make a difference for.
Well, it sounds like viruses, and KSHV in particular, are just endlessly fascinating. Where is your research headed from here, Blossom?
I think we will continue to try and understand the things that govern KSHV biology—how it manages to remain dormant, and if there’s anything we can do to sort of make its presence known to the host immune system, that would be one way we could perhaps find some sort of therapy that would help the host immune system combat the virus infection. Additionally, we are also looking at the viral genes that are involved in the oncogenic process, and also trying to identify new drug targets that we could manipulate, or whose effects we could negate in order to prevent the cancer from forming. And then thirdly, we are also looking at drugs that can inhibit the virus cancers once they’ve formed.
So, three different aspects: first is finding targets that would alert the host immune system to the virus infection. So that’s at the very beginning. And then the middle of the road would be to identify drug targets that inhibit viral genes from doing their thing, which is promoting cancer progression. And then, if you already have the tumor, to find drugs that can actually ablate it. So at three different levels we’re trying to identify mechanisms and target viral proteins.
Well Blossom, it’s just been fascinating to learn about your work, and we certainly wish you the best of luck for continued success, it’s very important what you’re up to.
And we appreciate you joining us on FOCUS In Sound…
I loved being here! Thank you.
We hope you’ve enjoyed this edition of the FOCUS In Sound podcast. Until next time, this is Ernie Hood. Thanks for listening!