Author: Sam Rollin
Rollin, Sam, 2025 Resolving the Androgen Receptor Enigma of Prostate Cancer, Flinders University, College of Medicine and Public Health
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Prostate cancer is a leading cause of male cancer mortality and the most frequently diagnosed cancer in Australia. This malignancy is driven by the androgen receptor (AR), a hormone-activated transcription factor that regulates genes associated with growth and survival. Accordingly, the mainstay treatment for advanced and metastatic prostate tumours is to inhibit AR signalling, either by reducing levels of circulating androgens or by blocking AR binding to androgens. Unfortunately, these therapies are not curative and disease progression to an incurable and lethal state referred to as castration-resistant prostate cancer is inevitable. New therapies for castration-resistant prostate cancer are urgently required.
Intriguingly, it is known that “hyperactivating” the androgen receptor with very high (supraphysiologic) doses of androgen can inhibit prostate tumour growth. This paradoxical phenomenon - where therapies that result in very low and very high androgen levels are beneficial for patients - is of increasing interest for modern prostate cancer therapy. However, the mechanism(s) by which supraphysiologic androgen treatment has anti-cancer activity remain largely unknown. This study aimed to develop understanding of these mechanisms, with a focus on investigating how supraphysiological androgen therapy (referred to as SPA throughout this thesis) influences tumour immune activity and cancer cell phenotype.
We found that supraphysiologic androgen therapy induced immune pathways associated with anti-cancer activity, including interferon signalling, antigen processing and presentation, and immune cell chemotaxis. Indeed, supraphysiologic androgen therapy promoted recruitment of macrophages to prostate cancer cells, which resulted in enhanced cancer cell death. These findings were further validated by examining transcriptomic data from patient tumours collected during a recent clinical trial, which demonstrated that supraphysiologic androgen therapy activated many of the same anti-cancer immune mechanisms that were observed in our pre-clinical studies.
In addition to its effects on the tumour immune microenvironment, supraphysiologic androgen therapy also reinforced differentiation of prostate cancer cells, enhancing features of normal prostate luminal epithelial cells. This effect was likely to be directly mediated by AR, since transcriptomic and cistromic approaches revealed activation of canonical AR target genes characteristic of a luminal epithelial lineage state, and downregulation of genes associated with cancer cell plasticity. A key factor downregulated by supraphysiologic androgen therapy was EZH2, an oncogene that drives cell plasticity and progression of prostate cancer. Combining supraphysiologic androgen therapy with an EZH2 inhibitor promoted cell differentiation and more effectively reduced cancer proliferation.
In summary, our study found that supraphysiological androgen therapy modulates the tumour immune environment to favour anti-cancer immune activity and could act also as a “differentiation” therapy to promote a more well-differentiated and less aggressive cancer cell phenotype. This research will be important for future efforts to improve the efficacy of supraphysiologic androgen therapy for patients.
Keywords: Androgen Receptor; Bipolar Androgen Therapy; Prostate Cancer; Testosterone; Tumour Immune Landscape; Plasticity
Subject: Medical Science thesis
Thesis type: Doctor of Philosophy
Completed: 2025
School: College of Medicine and Public Health
Supervisor: Luke Selth