There have been so many excellent articles on COVID-19. If you haven't read too many already, you can get a 1-minute overview from this video. 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 are an avid follower of prostate cancer biology, you can see a very familiar protein in the membrane where the virus binds to the exterior of the cell, TMPRSS2, a serine protease. 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. In the case of prostate cancer the androgen receptor, AR, binds to testosterone (or DHT) and then 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. Approximately 50% of prostate cancers express the TMPRSS2:ERG fusion gene, leading to a complex series of oncogenic events.
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. It is also possible 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.
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 Science figure), 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 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 figure with or without ADT could determine whether short-term use of ADT could enhance the treatment. I submitted this idea to NEJM on March 27 as a letter to the editor (it was rejected…) and then I came across a preprint of a beautiful article looking at exactly the hypotheses I laid out above. It was published on March 24, so others have had similar ideas! Using sophisticated in silico techniques to look for drugs that interact with TMPRSS2, 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."
I hope that clinical researchers will be able to take advantage of these insights and utilize them in our ongoing fight against COVID-19.
This post originally appeared on prost8blog, a blog to help patients and their families understand various aspects of prostate cancer, and is adapted and republished with permission from Dr. Glodé.
ASCO has developed and compiled resources to support oncology professionals during the COVID-19 pandemic. Resources include evidence-based answers to Frequently Asked Questions (FAQs) about clinical care of patients with cancer, a centralized collection of links to credible sources, the latest decisions about impacted ASCO meetings and programs, and oncologist-vetted information for patients. This page will be updated regularly as the COVID-19 public health situation evolves.
Dec, 12 2022 4:36 PM
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