Roles
Professor
Scientific Director, Desai Sethi Urology Institute
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Biography
I am a prostate cancer medical oncologist and physician-scientist and the overall focus of my laboratory is to identify how steroid metabolism governs prostate cancer resistance to hormonal therapies, including development of castration-resistant prostate cancer (CRPC). Advanced prostate cancer responds initially to gonadal testosterone deprivation therapy but tumors eventually become resistant and progress because they acquire the metabolic capability of regenerating intratumoral androgens. My work in this field has uncovered the dominant pathway to DHT synthesis (Chang, et al. PNAS. 2011), identified the first example of a gain-of-function missense in the rate-limiting steroidogenic enzyme that increases DHT synthesis (Chang, et al. Cell. 2013), promotes the development of CRPC in patients (Hearn, et al. Lancet Oncology. 2016; Hearn, et al. JAMA Oncology. 2018; Hearn, et al. JAMA Oncology. 2020).
My group has identified novel abiraterone metabolites that are found in patients, may redefine the mechanism of abiraterone action and are pharmacologically manipulable (Li, et al. Nature. 2015, Li, et al. Nature. 2016 and Alyamani J Clin Invest. 2018). We also discovered an aberration in glucocorticoid metabolism that is critical for drug resistance (Li, et al. eLife 2017) and is pharmacologically reversible by targeting H6PD (Li, et al. Science Translational Medicine 2021). Most recently, we identified the first post-translational modification of 3ßHSD1 that is required for its cellular activity and synthesis of DHT, suggesting a strategy to counter the aggressive disease and poor outcomes conferred by the gain-of-function missense (Li, et al. J Clin Invest 2023). As Scientific Director of the Desai Sethi Urology Institute at the University of Miami Miller School of Medicine, I also direct program development efforts. -
Education & Training
Education
Post Graduate Training
Licensures and Certifications
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Honors & Awards
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Research Interests
Genetic mutations and variations in androgen synthesis machinery
We investigate how genetic anomalies enable cancer cells to evade ADT and produce their own hormones for fuel. Our team discovered that a variation in the HSD3B1 gene—called HSD3B1(1245C)—encodes an enzyme that is effectively hyperactive and plays an important role in this process (Chang, et al. Cell 2013). We have also shown that this variant alters response to treatment and could be used as a predictive biomarker when designing treatment regimens (Hearn, et al. Lancet Oncol 2016; Hearn, et al. JAMA Oncol 2018; Almassi, et al. JAMA Oncol 2018; Hearn, et al. JAMA Oncol 2020). Our laboratory is working to transition this discovery into the clinic by developing a blood test to detect the variant, and also collaborating on clinical trials to test alternative treatments for prostate cancer patients who have the inherited variant.
How genetics affect treatment response.
Our team is interested in optimizing treatment regimens for all patient populations. Our team found that patients with the HSD3B1(1245C) variant metabolize abiraterone (a commonly prescribed prostate cancer drug) differently than men without the variant. They produce higher levels of a metabolite that shares a similar molecular structure with androgens, thereby “tricking” androgen receptors into turning on pro-cancer pathways. Our lab is working to confirm these results and identify an effective alternative drug for these patients (Li, et al. Nature 2015; Li, et al. Nature 2016; Alyamani, et al. J Clin Invest 2018).
Aberrations in glucocorticoid metabolism.
We have found that prostate cancer develops aberrations in glucocorticoid metabolism that enables the development of resistance to potent AR antagonist, including enzalutamide. For example, the normal metabolic pathway that inactivates cortisol is lost, generating elevated tumor concentrations of cortisol that are required for drug resistance (Li, et al. eLife 2017). We recently identified hexose-6-phosphate dehydrogenase blockade as a strategy that can reverse aberrant metabolism and reverse drug resistance (Li, et al. Science Translational Medicine 2021). Unexpectedly, AR antagonists also perturb glucocorticoid inactivation systemically. This leads to a systemic increase and exposure to bioactive glucocorticoids in patients treated with enzalutamide and apalutamide and may be the basis for certain adverse effects that occur with these drugs (Alyamani, et al. Annals Oncol 2020).
Interface between glucocorticoids and androgens.
Glucocorticoids have had a long-standing role in the treatment of inflammatory disease processes, including severe asthma. However, patients often have disease that is resistant to the anti-inflammatory effects of glucocorticoids. An underappreciated observation of treatment with systemic glucocorticoids is that adrenal androgens are suppressed. We have recently found that HSD3B1 genetics is associated with clinical response to glucocorticoids in severe asthma. This is probably due to suppression of adrenal androgens which are metabolized by the enzyme encoded by HSD3B1 to more powerful androgens and are processed in individual patients according to their HSD3B1 genotype (Zein, et al. PNAS 2020). -
Publications
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Professional Activities
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