Our 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.
Transcription of “Interview with Blossom Damania”
00;00;01;08 – 00;00;27;14
Ernie Hood
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 at Chapel Hill School of Medicine and member of the USC Lineberger Comprehensive Cancer Center.
00;00;28;07 – 00;00;57;28
Ernie Hood
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 herpes virus or K.S. HIV. She is also a Leukemia and Lymphoma Society research scholar and has received major support from the VIH Foundation, the American Herpes Foundation.
00;00;58;09 – 00;01;05;20
Ernie Hood
The American Association for Cancer Research and the American Heart Association. Blossom, welcome to Focus In Sound.
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Blossom Damania
Thank you, Ernie.
00;01;07;18 – 00;01;27;14
Ernie Hood
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?
00;01;27;18 – 00;01;54;05
Blossom Damania
Mm hmm. Yes, I think it’s been pretty underappreciated by the general public on the role of viruses in cancer. Usually, viruses are associated with things like flu or Ebola, and they 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.
00;01;54;15 – 00;02;13;15
Blossom Damania
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.
00;02;13;26 – 00;02;42;20
Ernie Hood
I see. Well, in your research, of course, you’re seeking to elucidate the underlying mechanisms at work. In the specific case of the association between the HIV virus and Kaposi 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.
00;02;42;26 – 00;03;17;11
Blossom Damania
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 of 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.
00;03;17;14 – 00;03;52;15
Blossom Damania
And what the virus does is that it modulates or changes or manipulates those pathways so that the virus is able to either stick latent and hidden from the host immune system or replicate itself and disseminate throughout the host’s body, or, in fact, 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.
00;03;52;22 – 00;04;20;07
Blossom Damania
The proteins they use to modulate these pathways are different, but the pathway modulation is the same. For example, if we can find a signaling pathway that’s modulated by Casey V, 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 or prevent the virus from doing that.
00;04;20;16 – 00;04;48;11
Ernie Hood
I see your work actually lies at the intersection between two scientific puzzles the virus cancer connection, and the mysterious tendency of some viruses, such as herpes viruses, to lie dormant in an infected person system, sometimes for many years. The case HIV virus is well known to be associated with Kaposi’s sarcoma, but you’ve made significant progress in uncovering what react evades the virus from its dormancy.
00;04;48;17 – 00;04;50;01
Ernie Hood
Tell us about your findings on that.
00;04;50;03 – 00;05;10;16
Blossom Damania
You’re right. Herpes viruses 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 is no cure for herpes viruses. There are drugs out there that will stop their replication, but they do not eject the virus out of the body.
00;05;10;16 – 00;05;46;14
Blossom Damania
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 ask the question, how does secondary infection with these other pathogens affect dormancy of the herpes virus that’s lying latent in a cell in order to do that?
00;05;46;15 – 00;06;14;03
Blossom Damania
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 a secondary pathogen infections.
00;06;14;08 – 00;06;40;29
Blossom Damania
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 herpes viruses are very successful in escaping that initial TLR or toll like receptor response. They somehow managed to escape that initial primary response to the incoming pathogen and establish themselves latently or dominantly in the cell.
00;06;41;12 – 00;06;43;16
Ernie Hood
And they escaped the immune system as a whole.
00;06;43;16 – 00;07;09;29
Blossom Damania
At that point, right? Yes. Yes. They’re very successful at doing that. But other pathogens may not be so. 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 of weeks you feel normal again. We wanted to know when you have secondary pathogen infection with things like influenza, what happens to herpes virus that’s lying inside the cell.
00;07;09;29 – 00;07;49;00
Blossom Damania
And so we actually screened all the two like receptors, which are the sensors of secondary pathogen infection, and found that when you activated two specific toll like receptors, TLR seven and TLR eight, you could actually get the herpes virus to reactivate itself and replicate and it actually then replicates and spreads in the body. So this is a mechanism that the herpes virus 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 naive cells that have not been infected.
00;07;49;12 – 00;07;55;10
Blossom Damania
This is sort of a survival response of the pathogen of the herpes virus to incoming secondary infections.
00;07;55;16 – 00;08;06;10
Ernie Hood
I see. So how does that reactivation in replication through the body apparently tie into the development of cancer? I understand that K.S. HIV encodes certain genes, for example.
00;08;06;12 – 00;08;34;28
Blossom Damania
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 lifecycle with the latent or dormant aspects of its lifecycle.
00;08;35;06 – 00;08;59;18
Blossom Damania
And it’s generally thought that the latent or dormant aspects of the lifecycle are associated with the cancer process. Oh. Transformation process. But that the replication part of the lifecycle 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.
00;08;59;19 – 00;09;14;15
Blossom Damania
So these two different aspects of the viral lifecycle contribute towards oncogenes, 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.
00;09;14;25 – 00;09;18;06
Ernie Hood
So it’s almost a perfect storm that develops, right?
00;09;18;07 – 00;09;19;02
Blossom Damania
Yes. Yeah.
00;09;19;02 – 00;09;20;27
Ernie Hood
In that signaling event, right?
00;09;21;03 – 00;09;21;16
Blossom Damania
Yes.
00;09;21;26 – 00;09;41;02
Ernie Hood
Blossom, I know that Kaposi sarcoma is known mainly as an often deadly complication of HIV aids. Is that the result of the combination of a compromise sized immune system and that secondary viral infection that you were referring to, which activates this cascade associated with the toll like receptors?
00;09;41;03 – 00;09;53;01
Blossom Damania
Yes, I do believe that immunosuppression with HIV is a key factor in the development of Kaposi sarcoma, which is the leading cancer that HIV patients manifest and often die off.
00;09;53;07 – 00;09;54;09
Ernie Hood
And it’s a skin cancer.
00;09;54;11 – 00;10;15;25
Blossom Damania
And it’s a skin cancer, but it’s not just on the external extremities. It can be internal to the lining of your lung or gastrointestinal or cavity or colon. Those places can all develop. Kaposi sarcoma is just you can’t see it. And a lot of times patients die of those internal lesions because they go undiagnosed oftentimes until it’s too late or untreated.
00;10;16;01 – 00;10;45;24
Blossom Damania
And yes, yes, we think that immunosuppression with HIV is really a very important factor for development of Kaposi sarcoma. I mean, people who are normal or seemingly healthy and don’t have any sort of immunosuppressive disease still develop. K.S. But it’s much more infrequently than an HIV infected individual. And just to give you an appreciation for the different if you’re HIV positive, you’re 20,000 times more likely to get Kaposi sarcoma than if you’re HIV negative.
00;10;46;09 – 00;11;10;15
Blossom Damania
And then comparing immunosuppression with HIV to just immunosuppressive therapy, the transplant patients normally take for transplantation, you’re about 600 times more likely to get Kaposi 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.
00;11;10;29 – 00;11;19;17
Ernie Hood
So, Blossom, what are the potential clinical implications of your findings? Does this new knowledge give any potential new targets or strategies for therapies?
00;11;19;28 – 00;11;52;25
Blossom Damania
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.
00;11;53;04 – 00;12;08;09
Blossom Damania
And we’ve had some good success using that. We’re currently trying to put together a clinical trial to test this out at UMC and other places and test whether these drugs will be efficacious in curing cancers associated with this virus.
00;12;08;15 – 00;12;12;23
Ernie Hood
So are you working with some of the translational departments here at USC?
00;12;12;24 – 00;12;25;18
Blossom Damania
Yes, I’m working with several physician scientists and clinicians at USC hospitals and hematology oncology group, and we’re trying to get a clinical trial going to test these drugs.
00;12;25;21 – 00;12;30;11
Ernie Hood
Well, that’s terrific. We’ll certainly be keeping an eye on that, hoping for a great success.
00;12;30;12 – 00;12;30;20
Blossom Damania
Yeah.
00;12;31;08 – 00;12;37;22
Ernie Hood
Blossom, tell us a little bit about your background and what led you to pursue this particular line of research.
00;12;38;01 – 00;13;04;02
Blossom Damania
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.
00;13;04;16 – 00;13;27;28
Blossom Damania
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 looking at how viruses can transform cells, how they can activate pathways that are required for the virus to survive, but as a consequence, also resulted in the cell being transformed and becoming carcinogenic.
00;13;28;09 – 00;13;49;28
Blossom Damania
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 whole cell. And so they manipulate those pathways because they need those pathways to survive. But as a result of that, you get the cell being also transformed. I don’t think the viruses intention was to cause the cancer.
00;13;50;03 – 00;14;13;07
Blossom Damania
Its intention was to just 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 postdoctoral fellowship case, HIV, Kaposi sarcoma associated herpes virus had just been discovered in 1994, and there was a lot of things that were unknown about it.
00;14;13;08 – 00;14;42;05
Blossom Damania
There were a lot of things to do that people who discovered it, you and 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. And so I decided to do a postdoctoral fellowship at Harvard Medical School in the lab of Ron DeRosa, understanding how HIV and associated herpes viruses were involved in the transformation process.
00;14;42;10 – 00;15;13;03
Blossom Damania
I started off being a very basic researcher, but the more I learned and I read about the diseases associated with CAS HIV, and it’s not just Kaposi sarcoma. There are two other lymphoid proliferative diseases which are cancers of blood cells. In this specific instance, B lymphocytes called a primary fusion lymphoma or PEL for short and multi-sensory Castleman disease and importantly with PEL, which is primary fusion lymphoma, the prognosis for people who have this disease is very, very bad.
00;15;13;11 – 00;15;26;29
Blossom Damania
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.
00;15;27;22 – 00;15;33;26
Ernie Hood
I see. Well, it sounds like viruses and K.S. HIV in particular are just endlessly fascinating.
00;15;33;27 – 00;15;34;07
Blossom Damania
Yes.
00;15;35;05 – 00;15;37;14
Ernie Hood
Where is your research headed from here, Blossom?
00;15;37;22 – 00;15;58;14
Blossom Damania
I think we continue to try and understand the things that govern cancer, HPV, 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.
00;15;59;02 – 00;16;21;14
Blossom Damania
Additionally, we are also looking at 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’re also looking at drugs that can inhibit the virus cancers once they’re formed. So three different aspects.
00;16;21;14 – 00;16;46;04
Blossom Damania
First is finding targets that would alert the host immune system to the virus infection. So that’s at the very beginning. And 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 ablated so at three different levels, we’re trying to identify mechanisms and target viral proteins.
00;16;46;13 – 00;16;54;28
Ernie Hood
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.
00;16;55;09 – 00;16;55;25
Blossom Damania
Thank you.
00;16;55;26 – 00;16;58;17
Ernie Hood
And we appreciate you joining us on Focus In Sound.
00;16;59;01 – 00;17;00;14
Blossom Damania
I love being here. Thank you.
00;17;01;24 – 00;17;22;29
Ernie Hood
We hope you’ve enjoyed this edition of the Focus In Sound podcast. Until next time. This is Ernie Hood. Thanks for listening.
