THE AMERICAN ASSOCIATION for Cancer Research (AACR) has recognized Nima Sharifi, MD, with the 2021 AACR–Waun Ki Hong Award for Outstanding Achievement in Translational and Clinical Cancer Research.
Dr. Sharifi is Director of the Center for Genitourinary Malignancies Research at Lerner Research Institute and the Kendrick Family Endowed Chair for Prostate Cancer Research at the Cleveland Clinic, and Professor in the Department of Molecular Medicine at Case Comprehensive Cancer Center at Case Western Reserve University. He was honored for his pivotal contributions to the understanding of how steroid metabolism contributes to prostate cancer progression, defining the first example of a gain-of-function steroidogenic enzyme missense mutation that permits dihydrotestosterone (DHT) synthesis from adrenal precursors. In a series of clinical studies, he illustrated that this missense mutation represents an effective predictive biomarker in castration- resistant prostate cancer.
Nima Sharifi, MD
Early in his career, Dr. Sharifi challenged the generally accepted dogma that testosterone is an obligate intermediate metabolite that undergoes a 5α-reduction to form DHT from adrenal precursor steroids in castration-resistant prostate cancer. He demonstrated that a different steroid, androstenedione, is also capable of undergoing a 5α-reduction to form 5α-androstanedione and eventually DHT, thus driving tumor progression. Although it was already known that DHT in castration-resistant prostate cancer is capable of driving androgen receptor function, no specific mutation had been identified until Dr. Sharifi described the first gain-of-function mutation in 3β-hydroxysteroid dehydrogenase-1 encoded by HSD3B1, which leads to greater enzyme levels and increases the metabolic flux from steroid precursors to DHT, in turn contributing to the development of castration-resistant prostate cancer. Tumors that harbor HSDB1 mutations are generally dependent on these genetic lesions and are often responsive to pharmacologic inhibition. Dr. Sharifi has shown that in patients with prostate cancer treated with androgen-deprivation therapy, those who inherit such enzyme variants develop resistance much more rapidly than those without such enzyme variants.