Prostate Cancer Research
Prostate cancer patients are typically treated with an antihormone therapy such as enzalutamide, which is an antagonist or blocker of the androgen receptor. When these patients fail, it is often because the tumors start making more of a related receptor, the glucocorticoid receptor, which is activated by the stress hormone cortisol. We have made antagonists, or blockers, of the glucocorticoid receptor.
In addition, a majority of men with treatment-resistant prostate cancer are prescribed steroid hormones. While these medications have been shown to improve survival, long-term use carries side-effects including high blood pressure, bone loss and muscle wasting. Our research has demonstrated how compounds can be engineered to retain the desired effects while blocking certain side-effects.
Thank you to the BallenIsles Men’s Golf Association for supporting our lab’s work on prostate cancer.
Breast Cancer Research
Hormone therapies for breast cancer have been one of the greatest success stories of molecularly targeted medicines. But a significant fraction of patients don’t respond to these therapies. Drugs like tamoxifen, fulvestrant or anastrozole are frequently prescribed for estrogen-sensitive breast cancers. But over time, some cancers develop resistance, through inflammatory processes identified by our group and others in 2017, and through expression of resistance genes including EGFR. Our lab is developing compounds that interfere with estrogen’s ability to activate its cellular receptor in the traditional way, as seen with the hormone therapy tamoxifen, but also by a second inhibitory mechanism, distorting the estrogen receptor binding pocket and binding with side chains. With a new mechanism of action, the compounds do what you could expect from combining two different drugs, but in one molecule. Thank you to the women of Frenchman’s Creek for supporting our breast cancer research through the years.
Glucocorticoid Research
Early in the Covid-19 pandemic, the glucocorticoid drug dexamethasone became the standard of care for COVID-19 treatment later in illness, as it helped quiet overaggressive immune attacks in delicate lung tissue and blood vessels. But glucocorticoids are also among the more problematic of medicines, as prolonged use or high doses can lead to adverse events including high blood pressure, muscle wasting, bone loss, vulnerability to infections, vision problems, anxiety, swelling, weight gain, high blood sugar, insulin resistance, diabetes, and more, while naturally occurring glucocorticoids in the body can contribute to prostate cancer progression.
Our group engineered more precise glucocorticoids able to act in tissue-specific or activity-specific way, while limiting specific adverse events. SR11466 and SR16024, demonstrate medically useful traits including inflammation control, plus muscle-sparing ability, or mitochondria-building potential. One compound boosts muscle and energy supply, and the other reduces risk of muscle-wasting and bone loss.