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Principal Investigator: Eric R. Fearon
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2020
Award: $390,000
Funding agency: National Cancer Institute
Coronaviruses employ two key host proteins to gain entry and replicate within cells, angiotensinconverting enzyme 2 (ACE2), an essential receptor of entry, and cell surface transmembrane protease serine 2 (TMPRSS2), a serine protease that cleaves coronavirus spike proteins following receptor binding to promote viral fusion and entry into cells. Chemical inhibitors and RNA interference of TMPRSS2 have been shown to markedly slow coronavirus entry and replication in human lung epithelial cell lines. In vivo studies with TMPRSS2 transgenic knockout mice have further shown that loss of TMPRSS2 can reduce coronavirus replication in lungs, elicit a weaker proinflammatory response, and result in milder lung pathology. Importantly, initial data stemming from studies on the novel coronavirus responsible for the COVID-19 pandemic, SARS-CoV-2, show that viral entry mechanisms appear similar to other coronavirus family members, as SARS-CoV-2 entry into cells is decreased upon TMPRSS2 inhibition. Altogether, these data strongly suggest that modulation of TMPRSS2 levels may be an effective treatment strategy for patients infected with SARS-CoV-2. The Chinnaiyan lab discovered TMPRSS2 as the androgen-regulated 5’ partner of the TMPRSS2- ERG and TMPRSS2-ETS family of prostate cancer gene fusions. TMPRSS2 expression is directly regulated by the androgen receptor (AR), which has been extensively studied and targeted through various therapeutic interventions for the treatment of prostate cancer. Preliminary data from our lab suggests that lung TMPRSS2 is also androgen-regulated. Notably, several FDA-approved agents targeting AR activity in prostate cancer, such as enzalutamide, can markedly inhibit TMPRSS2 expression through antagonism of AR. We, therefore, hypothesize that FDA-approved drugs that markedly inhibit TMPRSS2 expression, like enzalutamide, may be effective in inhibiting coronavirus replication and possibly infection. Recent data from Italy (and other countries) suggests that males, who implicitly have higher levels of androgen than females, die of coronavirus by a factor of two-to-one, providing orthogonal evidence that AR activity may indeed be a player in COVID-19 progression. Thus, we would like to quickly generate pre-clinical data to support the idea that agents that suppress AR/TMPRSS2 may be repurposed to treat or prevent coronavirus infection. Based on this pre-clinical data, we would quickly assemble a clinical team to initiate a clinical trial investigating FDAapproved AR antagonists in patients infected with SARS-CoV-2. Critically, most samples for these studies are already banked in our lab to support an accelerated timeline, and since agents like enzalutamide are FDA-approved, this project could have immediate clinical impact for COVID-19 patients.
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