Tag Archives: pandemic

COVID-19, ADT and Prostate Cancer


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Spoiler alert: As I start to write this, my intent is to delve into some basic science readers may find too detailed/complex and some speculation that has limited/no support and should NOT be taken as anything other than hypothesis generating. I fell in love with biology in about the 8th grade and with thinking about how to answer biology questions in medical school, so this is more self-indulgent writing rather than being written to inform.

Starting with the COVID-19 story, there have been so many excellent articles that if you haven’t read too many already, you can get a one minute overview from this video. Now for some more Screen Shot 2020-03-29 at 8.47.20 AMdetailed science. This figure from an excellent article in Science shows the real details of how the virus works and some of the drugs that might be useful in stopping or slowing it down at the cellular level. If you use your best “Where’s Waldo” approach, (and if you are an avid follower of prostate cancer biology) you may find a very familiar protein hiding in the membrane where the virus binds to the exterior of the cell, TMPRSS2. This protein is an enzyme in the family of serine proteases, proteins that can cut peptide bonds at the site of the amino acid serine. Trypsin is another example of this category of enzymes we use in the lab to release cells from petri dishes, and you use various enzymes every day in your dishwasher to digest proteins stuck to your dishes. As shown in the figure, TMPRSS2 plays a crucial role in the entry of the SARS-CoV-2 virus into the respiratory epithelial cells leading to COVID-19 disease.

I first heard of TMPRSS2 several years ago in a lecture at the PCF annual scientific meeting. Investigators at the University of Michigan found that in a large percentage of prostate cancer, the androgen response elements in DNA that control the expression of TMPRSS2 have become fused to an oncogene, ERG. Every gene in our DNA is controlled by “upstream” segments of DNA called promoters or enhancers that regulate the expression of the gene. In the case of prostate cancer the androgen receptor, AR, binds to testosterone (or DHT) and then the is translocated to the nucleus where it binds to DNA at the sites of androgen response elements, leading to transcription and expression of the “downstream” genes. A reasonable analogy is to think of testosterone flipping a light switch to “on” and the AR being the wire going to the light bulb, TMPRSS2, in our case. You are familiar with this if you know about drugs like Lupron, Zytiga, or Xtandi that block testosterone signaling in various ways. Although taking any of these drugs turns off many genes related to prostate cancer development and progression, one of these genes is clearly ERG (if you have the TMPRSS2:ERG fusion), and of course you probably turn down expression of TMPRSS2 in normal cells.

So what does this have to do with COVID-19? As you may have seen, men have approximately twice the mortality of women from infection with SARS-CoV-2. There are no doubt many possible reasons. Men smoke more. Men may not practice social distancing as much. Men have more heart disease. But what if one reason is that they express higher levels of TMPRSS2 in their respiratory epithelium? The exact mechanism of TMPRSS2 in the infection can be found in this article.  A cartoon from the article illustrates the several points in the viral infection cycle where TMPRSS2 (and other serine proteases) acts to facilitate the entry, replication and budding of the virion from a cell.

Screen Shot 2020-03-29 at 10.19.32 AM

The article discusses several drugs that are being investigated to inhibit TMPRSS2 that could hopefully be effective in fighting COVID-19. One of them, camostat (seen in the first figure in this post), is already scheduled to begin clinical trial at the end of this month.

However, there is already a very interesting global “clinical trial” underway if you have followed the above (and necessarily complex …sorry!) story about TMPRSS2. If ADT, familiar to all men with metastatic or high risk prostate cancer, turns down the expression not only of ERG and other oncogenic pathways, but also the expression of TMPRSS2, it might reduce the infection rate or morbidity/mortality from COVID-19. Looking at large global databases, it may be possible to see whether men with a diagnosis of both “prostate cancer” and “COVID-19”  can be extracted from the data, and then whether within this grouping, those men on ADT have a better outcome than those not on ADT. It would be complex, of course, since some of the men not on ADT might be on chemotherapy, or more sick in general, and thus more susceptible to dying from the infection. It might also be possible to see what the expression levels of TMPRSS2 in the pulmonary epithelium of men versus women are as a potential partial explanation of the differences in mortality. Finally, and this would be the most intriguing possibility of all, a clinical trial that combined some partially effective “drug X” from the list of drugs in the first figure with or without ADT could determine whether short term use of ADT could enhance the treatment. Proof that no one ever has a “unique” idea (and of the speed with which you can share ideas in today’s internet environment), in doing a minimal amount of literature research on this topic, I came across a preprint of a beautiful article looking at exactly the hypotheses I laid out above. It was submitted only 5 days ago! The authors have found very significant differences in the levels of expression of TMPRSS2 among adults using published databases and hypothesize that this could explain why some individuals may be more susceptible to bad outcomes. They also evaluate the potential of down regulation of the gene with ADT drugs like enzalutamide or estrogens and they conclude, “Together, these results identify existing drug compounds that can potentially be repurposed to transcriptionally inhibit TMPRSS2 expression, and suggest that the activation of estrogen pathways or inhibition of androgen pathways can be a promising modality for clinical intervention in SARS-CoV-2 infection.”

In summary, if you have prostate cancer and are on ADT, the well known side effects you put up with are unpleasant to say the least. But there is a “not-zero” possibility that your ADT is also protecting you. The best advice is still to practice social distancing, wash your hands, and be vigilant regarding your health, but maybe there is a silver lining in this story. I hope so, and there are already clinical and basic scientists exploring the hypotheses discussed above. Be well and my best wishes during these trying times!

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Filed under General Prostate Cancer Issues, Prostate cancer therapy

(Love) Advice in the time of (Cholera) Coronavirus


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I wanted the title to look like this, but the software wouldn’t let me: Love Advice in the time of Cholera Coronavirus. In any case, if you are a patient or in the patient age range of prostate cancer you are automatically at some increased risk. There isn’t much evidence that cancer patients in general who aren’t on chemotherapy or an immunosuppressive agent have much increased risk. In fact, patients on ADT may actually do a little better based on reactivation of thymic function. Here is a quote from this complex article by James Gulley and colleagues:

Analyses of these data suggest that AR expressed by thymic epithelium play an important role in thymocyte development, and could explain why androgens induce apoptosis of thymocytes in vivo but not in vitro (31). In subsequent studies, androgen withdrawal led to increased thymopoiesis and reversal of thymic atrophy in post-pubertal male mice (32) and even in aged mice (33, 34). Furthermore, thymopoiesis decreased with the administration of testosterone (35, 36). Castration also results in increased T- cell export in aged mice and increased naive splenic T cells compared to aged controls (34).

Although persistent thymic function is evident in older individuals, it is decreased, as demonstrated by lower TREC [T-cell receptor rearrangement excision circles] levels (37). However, studies show that ADT can induce thymic renewal in older individuals (38). In one study, elderly prostate cancer patients given GnRH-A experienced a notable increase in TRECs in 6 out of 10 cases, indicating renewed thymopoiesis (34). These studies suggest that the effects of androgen ablation are not limited to the young, as evidenced by restoration of thymic function and export of naïve T cells after surgical (orchiectomy) or medical (GnRH-A) castration.

 

The enhanced thymopoiesis associated with ADT has important clinical implications for the treatment of immunocompromised patients and for immunotherapy for prostate cancer (see Figure 3 for a summary of ADT’s effects on the T-cell compartment). Thymic renewal in these patients may increase the diversity of the T-cell repertoire, increasing the pool of antigens recognized by the immune system. In the setting of vaccine therapy, an increased naïve T-cell compartment may enhance the response to immunotherapy.

 A few patients have asked me about whether to postpone surgery. In general, for patients with “average” (Gleason 3+4) tumors, this would probably be OK. It is a harder decision for those with Gleason 4+3, or any component of Gleason 5. It will have to be an individual decision (as are all decisions of this sort) with your doctor. The same would apply to radiation therapy treatment which can have some immunosuppressive effects, but certainly has never been studied in this situation.

In general, I would also recommend that you put aside your political biases and listen to the scientific experts. I was disturbed by a poll presented this morning on Face the Nation that indicated a significant difference in the perceptions of risk between Republicans and Democrats. This virus does not know or care about your party or politics. Practice the social isolation being recommended by Fauci and the other experts: “We should be over-reacting to this…” It would be just fine to look back and say we did that.

If you want to delve further into the science of this (which also dispels a lot of misinformation about where the virus comes from and how it arose), you should certainly look at this presentation: http://www.croiconference.org/

And in case you haven’t been thoroughly inundated with advice or just came out from under a rock, here is the succinct list of expert recommendations:

  • Social Distancing to flatten the curve of the pandemic (reduce infectivity rate from >2 to <1):
    • Wash/sanitize hands frequently
    • If sick, do not go to work
    • Work from home if at all possible
    • Maintain your personal space when around others
    • Eliminate travel (don’t be fooled by cheap flights or hotels)
    • Reduce exposure to groups of people
    • COVID-19 can persist on hard surfaces for several days so wipe down frequent contact surfaces repeatedly
    • Recognize that social distancing will have some mental health implications so be especially compassionate

Stay home. Stay well. Here is a list of things to do:  Fun Free Time Activities_

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Filed under General Prostate Cancer Issues, Prostate cancer therapy