Postdoctoral Fellowship : Cleveland, OH, United States

Molecular Mechanisms and Translational Investigations of Advanced Prostate Cancer

 

A postdoctoral fellowship position supported by the National Institutes of Health and the Prostate Cancer Foundation are available in the laboratory of Dr. Nima Sharifi at the Cleveland Clinic Lerner Research Institute in the Department of Cancer Biology. 

Our laboratory is focused on metabolic and molecular mechanisms of androgen synthesis and androgen receptor (AR) gain-of-function that lead to resistance to hormonal therapy. Specific areas include:

1) Metabolic and genetic changes required for androgen synthesis

2) Clinical validation in patients and clinical trials utilizing innovative approaches

3) Animal models of advanced prostate cancer for translational and therapeutic studies

4) Identifying targets for the development of new pharmacologic 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(5):1074-1084) and that we have shown in a predictive biomarker of poor outcomes after hormonal therapy (Hearn, et al. Lancet Oncol. 2016 17(10):1435-44). We are current evaluating this biomarker in a clinical trial and are pursuing similar mechanisms and developing new treatment modalities based on these discoveries.

 

We recently also discovered that abiraterone works by conversion to a more active steroidal metabolite (Li, et al. Nature. 2015 523(7560):347-51), that metabolism is pharmacologically modifiable to optimize therapy (Li, et al. Nature. 2016 533(7604):547-51), and that this is a class effect of steroidal androgen synthesis inhibitors (Alyamani, et al. Cell Chemical Biology. 2017 24, 1-8, July 20). We are currently working toward defining the relationship between metabolite generation and treatment response in patients and identifying new chemical entities that are determinants of treatment response.

 

Previously, we discovered that prostate cancer becomes resistant to hormonal therapy by the synthesis of dihydrotestosterone through a pathway that circumvents testosterone, instead requiring 5α-androstanedione, a previously underappreciated intermediate metabolite. This metabolic pathway occurs in patient tumors (Chang, et al. Proc Natl Acad Sci USA. 2011 Aug 16;108(33):13728-33).