Molecular Mechanisms and Translational Oncology
Do you have a background in molecular, biochemical or chemical mechanisms, cancer, medicinal or analytical chemistry? Are you interested in translational medicine and taking your mechanistic findings rapidly to the bedside in a vibrant clinical research program? If so, a postdoctoral fellowship position supported by the National Institutes of Health and the Prostate Cancer Foundation is available in the laboratory of Dr. Nima Sharifi at the Desai Sethi Urology Institute at the University Miami Miller School of Medicine.
Our laboratory focuses on mechanistic discovery to understand the metabolic and molecular mechanisms of androgen synthesis and androgen receptor gain-of-function 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, that will lead to broad applications to oncology and cancer physiology. Specific 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
- Animal models of advanced cancer for translational and therapeutic studies
- Identifying targets for the development of new pharmacologic therapies
- Drug discovery for new therapies
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 recently 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. https://doi.org/10.1172/JCI163498).
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.
The position will provide a unique and multidisciplinary exposure to tumor metabolism, molecular oncology, drug development, and clinical trials.
The ideal candidate has a Ph.D. degree in biochemistry, chemistry or molecular biology; has the appropriate expertise in discovery of molecular, biochemical or chemical mechanisms; and is highly driven. Outstanding verbal and communication skills are required. Interested candidates should send their CV and contact information for 3 references to:
Nima Sharifi, M.D.
Scientific Director, Desai Sethi Urology Institute
Email: DSUIscience@miami.edu