Nima Sharifi, M.D., is a medical oncologist who began his independent career as an Assistant Professor at UT Southwestern in 2008. In 2013, he was recruited to Cleveland Clinic, where he is the Kendrick Family Chair for Prostate Cancer Research and Director of the Genitourinary Malignancies Research Center. His research program is focused on human steroid metabolism phenotypes and how these processes regulate normal physiology and disease.

The first line of therapy for metastatic prostate cancer includes androgen deprivation therapy (ADT), which blocks the release of gonadal testosterone and suppresses intratumoral concentrations of the most potent androgen, dihydrotestosterone (DHT). Metastatic disease eventually becomes resistant to ADT, is termed castration-resistant prostate cancer and is frequently driven by tumors making their own DHT from extragonadal (mainly adrenal) precursor steroids. Dr. Sharifi’s group identified a common missense-encoding germline variant in the first and rate-limiting enzyme that regulates intratumoral androgen synthesis. The adrenal-permissive HSD3B1 allele enables, whereas the adrenal-restrictive HSD3B1 allele limits, conversion from adrenal precursor steroids to downstream potent androgens, which in turn dictates clinical outcomes in prostate cancer – findings that have been independently validated worldwide. In addition to prostate cancer outcomes, HSD3B1 inheritance also regulates other phenotypes dictated by extragonadal sex steroid synthesis.

Another series of discoveries identifies a major role for aberrations in glucocorticoid metabolism in prostate cancer resistance to next-generation androgen receptor (AR) antagonists and systemic effects that occur with these agents that mechanistically explain certain adverse effects. AR antagonists induce loss of 11βHSD2, the enzyme that normally inactivates cortisol, resulting in elevated tumor glucocorticoids that enable drug resistance. A similar mechanism occurs systemically in treated patients, biochemically phenocopying the syndrome of apparent mineralocorticoid excess, resulting in drug-induced hypertension and leading to increased systemic exposure to biologically active glucocorticoids. Finally, tumor manipulation of NADPH generation by hexose-6-phosphate dehydrogenase blockade, normalizes glucocorticoid metabolism and reinstates tumor responsiveness to potent AR antagonists. The essential mechanisms elucidated by Dr. Sharifi’s group have broad relevance to multiple pathophysiologic processes.