TMPRSS2 and COVID-19: Serendipity or Opportunity for Intervention? Lorelei Mucci & Philip Kantoff
May 4, 2020
Joining Alicia Morgans is Lorelei Mucci and Philip Kantoff discussing a recently published article that addresses some of the potential overlaps between TMPRSS2 and COVID-19.
Philip Kantoff, MD., is the Chair, Department of Medicine; The George J. Bosl Chair Memorial Sloan Kettering Cancer Center. He is a board-certified medical oncologist and researcher specializing in the treatment of genitourinary cancers. His lab focuses on understanding the genetics and genetic epidemiology of prostate cancer, and the discovery of novel treatments for genitourinary cancers. As Chair of the Department of Medicine at Memorial Sloan Kettering, he oversees a department that is leading the development and testing of better cancer therapies.
Lorelei Mucci, MPH, ScD, Associate Professor, Epidemiology, Harvard T.H. Chan School of Public Health (HSPH), Boston, MA
Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.
Alicia Morgans: Hi, this is Alicia Morgans, Associate Professor of Medicine and GU medical oncologist at Northwestern University. I am so excited to have here with me today Professor of Epidemiology, Dr. Lorelei Mucci, who is at the Harvard School of Public Health, the Harvard T.H. Chan School of Public Health, and Dr. Phil Kantoff who is a Professor as well, medical oncologist and the Chair of the Department of Medicine at Memorial Sloan Kettering Cancer Center. Thank you both for being here with me today.
Philip Kantoff: Thanks, Alicia.
Lorelei Mucci: Thank you, Alicia.
Alicia Morgans: Of course. I wanted to chat with the two of you about a recently published review article that you wrote with some co-authors really helping us think through some of the overlaps between TMPRSS2 and COVID-19, TMPRSS2, of course, being really important for prostate cancer progression, something that you've studied for many years, TMPRSS2-ERG, Phil. Can you tell us a little bit about why wanted to talk about this and where you see that overlap?
Philip Kantoff: Right, so just by review, TMPRSS2-ERG, which is a fusion abnormality that happens in about 50% of prostate cancers, is probably the most common abnormalities seen in prostate cancer. It brings together the TMPRSS2 regulatory region with the ERG transcription factor and allows for overexpression of ERG in early prostate cancer. And it turns out that TMPRSS2 is androgen-regulated, at least in human prostates. And we were wondering, the authors of this review article, as well as many others, whether there was any relationship between TMPRSS2 and the male to female discrepancy in COVID because it turns out that COVID-19 requires TMPRSS2 to enter into the lung cell. And we were wondering that perhaps there's more TMPRSS2 in the male lung as a result of androgen versus the female lung.
Lorelei Mucci: So one of the other interesting pieces of the TMPRSS2-ERG fusion, which will be very interesting to try to understand in the context of COVID-19 is the fact that about 50% of men of European ancestry, that their tumors contain TMPRSS2-ERG fusion. Actually, men of African descent, as well as men of Asian descent, actually have a lower prevalence of the TMPRSS2-ERG fusion. I think that's very interesting also when you think about the fact that the COVID-19 pandemic seems to be really hitting hard individuals of African ancestry. So I think thinking through this very complicated relationship and what we know in the context of cancer and how it might translate to learning more about COVID-19 I think will be a very interesting area.
Alicia Morgans: So, along those lines, thinking about which populations may be hardest hit, in general, we've seen from the reports that we have so far that men seem to be contracting COVID-19 more commonly than women, and that's really... Of course prostate cancers only in men. That really overlaps with your TMPRSS2 interest. But at this point, are there known differences between TMPRSS2 expression in the lungs of men and women? And does that necessarily mean anything, the expression levels? Are there different ways for us to think about how TMPRSS2 may be measured differently in different ways that may be affecting these populations?
Philip Kantoff: There isn't that much data available, but there is one study that looks at TMPRSS2 expression in lung, in males versus females at the RNA level, and there did not appear to be any difference in TMPRSS2 RNA expression between males and females.
Lorelei Mucci: Yeah. It's also very interesting that TMPRSS2 is actually expressed in a number of different cells, including not only prostate but lung and then many aspects of the gastrointestinal system. And I don't know that we know very much about differences in expression of TMPRSS2 in normal tissues between men and women. And then I think one of the things that we'll need to understand as well is what does the expression of TMPRSS2 look like, for example, in lung, in the setting of being exposed to an infection. And I'm not sure we know that yet in humans.
Philip Kantoff: Right. So there's a recent paper, Alicia, that was published by Nima Sharifi. I don't even know if it's out yet, but I've seen it, and it's a mouse study looking at a TMPRSS2 expression and at the RNA and I believe at the protein level as well, and in mice, there does not appear to be a difference in expression as well. Now in that paper, he does not look at the prostate, TMPRSS2 expression in the prostate. He does demonstrate that when enzalutamide is given to mice, that the expression of TMPRSS2 in the lung does not decrease. It's suggesting that it is not androgen-regulated in the mouse lung tissue, but he didn't show in that paper that TMPRSS2 was regulated by androgen in the prostate. So it does throw a little water on the concept that maybe the male-female differences are related to TMPRSS2 expression.
Alicia Morgans: And that may be true, but it also may still be involved in the process. As we know, it is certainly required for viral entry into cells, so even if it doesn't explain that sex difference, that doesn't necessarily negate its ability to potentially be a target in our fight against COVID.
Philip Kantoff: Absolutely, Alicia. We're not suggesting that it's not a target. It does raise the question that the male-female disparity, which can be multifactorial, but TMPRSS2 is potentially a target because it is involved in viral entry and there are proteases that are available that do interfere with TMPRSS2 activity. Some of them I believe are in clinical trials right now.
Alicia Morgans: Yeah and that's what I wanted to ask about next. It seems like there are several proteases that could be potentially identified and used and there's actually even one, it looks like a Phase I/II trial for camostat that is currently ongoing, started just earlier this month in April to determine whether this may be something that could help. I don't know that trial certainly well, it's not open at our center, but it would be wonderful to think that we could use a protease that could be tolerable to people as well as prevent them from having an infection.
Philip Kantoff: My knowledge about this is about this extensive as yours, but there were several protease inhibitors rather, camostat, the nafamostat, and aprotinin that do attenuate TMPRSS2 protease activity, and the camostat is in a Phase I/II trial right now.
Lorelei Mucci: I think there was potentially some concern given the fact that TMPRSS2 is expressed so broadly in different cell types, whether or not we're going to see potential toxicities. That's going to remain to be seen, so the clinical trial that's currently open is a Phase I/II clinical trial.
Alicia Morgans: Absolutely. We always need to ensure that we understand safety first, and it doesn't look like this is a study that's actually open in the United States. Just kind of reviewing, it looks like these are folks who have had a recent infection, but they are trying to catch them early on to see if they can prevent some later complications. But of course as a Phase I, really dose-finding for tolerability and toxicity. So more to come there for sure. And as you look forward and think about this potential relationship, are there studies that you'd like to see done besides certainly those working on the protease inhibitors? Are there epidemiologic investigations that could look further and more deeply into this relationship?
Lorelei Mucci: One of the interesting... And again I think even in prostate cancer we're early on in this, but one of the interesting observations is there seem to be unique inherited genetic factors that predispose men either to develop TMPRSS2 or positive prostate cancer or tumors that are lacking this common gene fusion. So I think you can expand on that to think about whether inherited genetic susceptibility might influence the role of TMPRSS2 more broadly in making a man or any individual more susceptible to infection or more susceptible to disease severity. So I think that's going to be an area of a lot of interest to look at the inherited aspects of genetic susceptibility to COVID-19 and what we might learn from prostate cancer, for example.
Alicia Morgans: I completely agree. I think there's so much to learn in the COVID-19 pandemic, so much that we still don't understand and questions for us to ask. And I really just love the thought from our GU oncology community that we could use some of the knowledge that we've already gained through some of the work that certainly Phil and his group have done over the years on TMPRSS2, TMPRSS2-ERG, really to catalyze our understanding and perhaps our counter attack on COVID-19. I sincerely appreciate both of you lending your insights and your expertise and I wish you safety and health as you move forward. And thank you so much for sharing this with us today.
Philip Kantoff: Thank you so much, Alicia. Have a good day.
Lorelei Mucci: Wonderful to talk to you. Alicia.