A Rogel Cancer Center researcher is exploring how a protein involved in prostate cancer might also play a role in COVID-19, and if prostate cancer treatments could work against the virus.
What is the connection between COVID-19 and cancer? Arul Chinnaiyan, M.D., Ph.D., has focused his entire career on cancer, identifying a protein that plays a key role in the development of prostate cancer in 2005. It turns out that same protein may also factor into how coronaviruses replicate.
Chinnaiyan, director of the Michigan Center for Translational Pathology at Michigan Medicine, received a $390,000 grant from the National Cancer Institute to explore the possible role of TMPRSS2 in SARS-CoV-2 and whether a treatment commonly used in prostate cancer could potentially fight COVID-19.
Here, Chinnaiyan shares more about his research project with the Michigan Health Lab blog.
How did you connect the dots between your prostate cancer research and COVID-19?
Chinnaiyan: We weren't exploring this area but we knew that coronaviruses use two key host proteins to gain entry and replicate within cells. One of those proteins is TMPRSS2. This was appealing because we had discovered TMPRSS2-ETS gene fusions in prostate cancer and knew that TMPRSS2 was regulated by the androgen receptor. It made a lot of sense to explore this in the context of SARS-CoV-2.
The idea behind this proposal was to see if TMPRSS2, which we know is exquisitely regulated by the androgen receptor in the prostate, also is regulated that way in the lungs. That was what was intriguing about this. When you knock out TMPRSS2 in mice, the mice become relatively resistant to SARS-CoV-2, which suggests this protein is quite important for the virus to regulate and replicate. That's what the interest was here.
There are FDA approved drugs that can block TMPRSS2 expression in the prostate. If TMPRSS2 is indeed androgen-regulated in the lungs, one could then speculate that drugs directed at the androgen receptor could block TMPRSS2 in the lungs of COVID-19 patients. This proposal allows us to explore in preclinical models if this happens in the lungs. And if promising, to establish a clinical trial using drugs such as enzalutamide, which are already approved for prostate cancer, in the context of COVID-19.
Your whole career has been focused on cancer research. How does it feel to tackle something completely different like COVID-19?
Chinnaiyan: Changing gears was interesting. Since we've been inundated by COVID-19 in both the lay press and the scientific literature, I was already immersed in that space.
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In the spring when we had to ramp down in the labs, we had to halt most of our cancer research-related studies. This was an opportunity to pursue a gene that is involved in prostate cancer progression, that we have studied at great length already.
If we do find that TMPRSS2 is regulated by the androgen receptor in the lungs, the ability to apply this to COVID-19 is appealing because anti-androgen treatments are already FDA approved. We can move rapidly forward with drugs that are already safe and approved in one indication. If a drug hasn't already been tested in clinical trials already, it's more challenging.
What is appealing about this approach to treating COVID-19?
Chinnaiyan: It's a homerun hypothesis to pursue. We have most of the samples we need for this study already banked in our lab. We just never really looked at the lung because there was no reason to at the time. So now we are going back and looking very carefully at lung tissues for TMPRSS2 expression and whether it's androgen receptor-regulated. A relatively rare amount of cells in the lungs express TMPRSS2, so we have to do a lot of pathology analysis looking at tissue or single cell analysis where you can hone in on rare cell populations to study the presence of TMPRSS2 and androgen receptor in lung and bronchial epithelial cells, which are most affected by COVID-19.
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Then if TMPRSS2 is regulated by the androgen receptor in the lungs, we can look at using drugs designed to inhibit TMPRSS2 expression by blocking the androgen receptor, such as enzalutamide. If it's not androgen-regulated in the lungs, we can explore other agents that suppress TMPRSS2.
The other factor that makes this exciting is that it might explain the observations that COVID-19 seems to affect males more than females: males have much more androgen signaling than females.
What is your timeline for exploring the relationship between anti-androgen treatment and COVID-19?
Chinnaiyan: We have been actively working on this since the spring, with provisional approval of the funding. We have some early data in this space but it's not definitive yet. This grant is a nice collaboration between our lab and Jonathan Sexton, Ph.D., who has a BSL-3 lab (which allows laboratory work on certain types of contagious viruses, including SARS-CoV-2). He's able to study the live SARS-CoV-2 isolate, so we are testing this general hypothesis in collaboration with him.
In parallel, based on some of the early data, we are trying to establish a clinical trial. Two of our medical oncologists, Ulka Vaishampayan, MBBS, and Zachery Reichert, M.D., Ph.D., are looking to establish a clinical trial using an anti-androgen in COVID-19 patients. They have had success studying these drugs in prostate cancer patients and would partner with our investigators in infectious disease and internal medicine.
With most samples for our preclinical work already banked in our lab, and since agents like enzalutamide are FDA-approved, we can accelerate the timeline and, if it proves effective, have immediate impact on COVID-19 patients.
This article is from the Health Lab digital publication.
Department of Communication at Michigan Medicine
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