Testicular androgens regulate the prostate gland throughout life. Androgens trigger morphogenesis during foetal development, maturation in puberty, and differentiation in adulthood. The onset of prostate cancer causes a switch in androgen receptor (AR) signalling that stimulates proliferation of prostate epithelium. Thus, since the 1940s, the standard-of-care for advanced prostate cancer has been to block AR activity. This temporarily controls tumour growth, but there are drawbacks. Tumours eventually develop diverse mechanisms of resistance, and patients endure mounting side-effects, including decreased sexual function. This underscores the need for new treatments.
A new strategy may reverse the decades-old paradigm of ongoing blockade of AR signalling. With Bipolar Androgen Therapy (BAT), patients oscillate between low (castrate) and high (supraphysiologic) testosterone levels. This involves simple, monthly injections of an FDA-approved dose of testosterone, and it may relieve patients of the side-effects of androgen suppression. Using high doses of testosterone to treat prostate cancer may seem counterintuitive; however, clinical trials show promising results.
Some tumours respond to BAT, while others do not. Therefore, our team is using patient-derived models of prostate cancer to investigate which tumours are most responsive to BAT. Our contemporary cohort spans diverse forms of aggressive prostate cancer from patients who progressed on current treatments, including potent AR signalling inhibitors, chemotherapy and radioligand therapy. Our data shows that BAT-sensitive patient-derived models have high levels of AR, but low levels of ligand-independent AR variants. Moreover, we have demonstrated that aggressive pathologies of prostate are sensitive to BAT. Collectively, these studies are refining the subgroups of prostate cancer that are most likely to benefit from BAT and informing the design of combination therapies to increase response rates to BAT.