Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer

Abstract

Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits.

The Androgen Hormone-Induced Increase in Androgen Receptor Protein Expression Is Caused by the Autoinduction of the Androgen Receptor Translational Activity

“…Therefore, the influence of low and high levels of androgens on AR signalling have been investigated in this study. Multiple investigations have reported decreased cell proliferation of the hormone-sensitive LNCaP cell line when treated with concentrations above 1 nM R1881 [21,33]. In detail, optimal growth media supplemented with 10 nM R1881 induced cell growth inhibition, cell cycle arrest and apoptosis in LNCaP cells [21,33].…”

“…Literature has reported that the AR splice variant V7 as expressed in C4-2 cells is responsible for a constitutive AR activation and androgen-independent cell growth [36][37][38]. However, adaptions to high levels of R1881 have also been reported previously and explained by extensively passaging [21]. Several mechanisms have been introduced to be responsible for the biphasic effects of AR, including transcription of cell cycle-inhibitory genes like p16 and p21, downregulation of MYC, CDK1, and BCL2, and induction of oxidative stress [39][40][41][42][43].…”

“…The AR signalling has been reported to play an essential role in several diseases, including PCa [10,[14][15][16][17][18]. Furthermore, treatment with high levels of androgens has been discussed as a possible therapeutic option in PCa [21]. Therefore, the influence of low and high levels of androgens on AR signalling have been investigated in this study.…”

“…As proliferation and progression of PCa are highly dependent on androgens, androgen deprivation therapy (ADT) and treatment with antiandrogens are the gold standard for locally advanced or metastatic PCa [20]. Since 2006, it is also discussed that, next to the inhibition of the AR by ADT and antiandrogens, treatment with high testosterone levels also inhibits prostate cancer proliferation and may provide a new therapeutic option [21].…”

Administering Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer 1–6 Days Compared to More Than 14 Days after the Start of LHRH Agonist Is Associated with Better Clinical Outcomes Due to Androgen Flare

“…Testosterone at supraphysiologic doses in men with CRPC has been reported to produce promising results [ 43 , 44 ], with trials suggesting a clinical benefit in a subset of patients [ 45 ].…”