Research Projects
A short circuit from gonadal circulation to the prostate and sneaky testosterone
We have recently discovered that a subset of men with prostate cancer have very high periprostatic concentrations of testosterone (Alyamani, et al. J Clin Invest. 2023). This periprostatic venous testosterone probably comes from the enriched testosterone that is made in the testes. This prostatic testosterone exposure is not detectable by the usual measurements in blood. Men who have what we term sneaky testosterone physiology appear to have worse clinical outcomes after surgery. We are currently working on the implications of this variation in local testosterone physiology as well as how this alternative physiology is detectable through non-invasive means.
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).