COVID-19 and androgen-targeted therapy for prostate cancer patients

Abstract

The current pandemic (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health challenge with active development of antiviral drugs and vaccines seeking to reduce its significant disease burden. Early reports have confirmed that transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2) are critical targets of SARS-CoV-2 that facilitate viral entry into host cells. TMPRSS2 and ACE2 are expressed in multiple human tissues beyond the lung including the testes where predisposition to SARS-CoV-2 infection may exist. TMPRSS2 is an androgen-responsive gene and its fusion represents one of the most frequent alterations in prostate cancer. Androgen suppression by androgen deprivation therapy and androgen receptor signaling inhibitors form the foundation of prostate cancer treatment. In this review, we highlight the growing evidence in support of androgen regulation of TMPRSS2 and ACE2 and the potential clinical implications of using androgen suppression to downregulate TMPRSS2 to target SARS-CoV-2. We also discuss the future directions and controversies that need to be addressed in order to establish the viability of targeting TMPRSS2 and/or ACE2 through androgen signaling regulation for COVID-19 treatment, particularly its relevance in the context of prostate cancer management.

Keywords: ACE2; COVID-19; SARS-CoV-2; TMPRSS2; androgen signaling; prostate cancer.

Figure 1.. The hypothalamic-pituitary-gonadal axis in prostate cancer and androgen regulation of TMPRSS2 and ACE2.

Left, Pulsatile release of gonadotropin-releasing hormone (GnRH) or luteinizing hormone releasing hormone (LHRH) from the hypothalamus regulates production and release of gonadotropins (luteinizing hormone or LH and follicle-stimulating hormone) from the anterior pituitary gland. LH stimulates testosterone synthesis in the testes while increasing systemic concentrations of testosterone inhibits GnRH and LH signaling. Androgens, in particular, testosterone are fundamental to the pathogenesis and evolution of prostate cancer. Dehydroepiandrosterone (DHEA) is converted to testosterone and dihydrotestosterone (DHT) in the skin and hair follicles and is produced in the adrenal gland under the control of adrenocorticotropic hormone (ACTH) and in the gonads under the control of GnRH. Right, Continuous stimulation of pituitary GnRH receptors results in desensitization and downregulation of these receptors with eventual decrease in circulating sex steroids inclusive of androgens. This negative-feedback loop serves the basis of androgen deprivation therapy via LHRH agonists, while antagonizing the LHRH receptor represents another method of suppressing testosterone secretion through inhibition of downstream LH signaling. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral entry into host cells is dependent on transmembrane serine protease 2 (TMPRSS2) and angiotensin converting enzyme 2 (ACE2), which have been found to be expressed in human lungs and other tissues. TMPRSS2 and ACE2 appear to be androgen regulated genes where androgen receptors are expressed in human lungs. Androgen receptor (AR) signaling has been shown to increase TMPRSS2 expression while decreasing ACE2 expression. Thus, while SARS-CoV-2 could be putatively targeted through TMPRSS2 and androgen signaling suppression (a standard treatment paradigm in prostate cancer), ACE2 expression may be enhanced with androgen suppression. It is unknown whether this would result in a net increase in risk for severe infection, or a potential benefit from preserving the protective effects of ACE2 protein expression, while hindering a key step in conformational change and viral entry to nonimmune cells.