Postdoctoral Research Associate

The Nima Sharifi Laboratory is seeking to recruit outstanding postdoctoral associates with a primary interest in the fundamental mechanisms of human biology, biochemistry, metabolism, genetics, or medicinal and analytical chemistry. These positions present exceptional opportunities to partner with an outstanding clinical urology program in a new institute dedicated to rapidly translating basic discoveries to the clinic. The overarching goal of the institute’s research program is to define the underlying biochemical and clinical behavior of genitourinary cancers, in order to identify new strategies that will ultimately lead to durable clinical benefits. The Sharifi laboratory focuses on mechanistic discovery to understand the metabolic and molecular mechanisms of androgen synthesis and other areas of steroid metabolism that lead to resistance to hormonal therapy. Our work is revealing fundamental endocrine mechanisms in both normal physiology and disease, including stress, aging, and glucocorticoid resistance, with broad applications to oncology and cancer physiology. Specific research areas include: Metabolic and genetic changes required for hormone therapy resistance in prostate and breast cancers Discovery of entirely new mechanisms of endocrine physiology and regulation Clinical validation in patients and clinical trials using innovative approaches Identifying targets for the development of new pharmacologic therapies Drug discovery for novel therapeutic targets We discovered the first example of a gain-of-function in a steroid-synthesizing enzyme that enables prostate cancer resistance to hormonal therapy (Chang, et al. Cell. 2013;154:1074-84). We also discovered that abiraterone works by conversion to a more active steroidal metabolite (Li, et al. Nature. 2015;523:347-51), that metabolism is pharmacologically modifiable to optimize therapy (Li, et al. Nature. 2016;533:547-51) and that these events are a class effect of steroidal androgen synthesis inhibitors (Alyamani, et al. Cell Chem Biol. 2017;24:825-32) and genetic determination of metabolite generation (Alyamani, et al. J Clin Invest. 2018;128:3333-40). We reported that blockade of hexose-6-phosphate dehydrogenase normalizes glucocorticoid metabolism and reverses enzalutamide resistance, credentialing a new pharmacologic vulnerability (Li, et al. Sci Transl Med. 13; 2021). Most recently, we reported that the BMX kinase controls the same steroid-synthesizing enzyme that enables treatment resistance, thus indicating potential new treatment vulnerabilities for sex steroid-dependent cancers (Li, et al. J Clin Invest. 2023;133(2):e163498). This position is ideal for an individual with a strong interest in rapid translation of basic mechanistic discoveries to the bedside as this is a principal goal of the Sharifi Laboratory. For example, we have shown that our discovery of a gain-of-function in a steroid-synthesizing enzyme is a predictive biomarker of poor outcomes after hormonal therapy (Hearn, et al. Lancet Oncol. 2016;17:1435-44; JAMA Oncol. 2018;4:558-62; JAMA Oncol. 2020;6(4):e196496). We are currently evaluating this biomarker in an active clinical trial and are pursuing similar mechanisms and developing new treatment modalities based on these discoveries. #J-18808-Ljbffr