Bipolar Androgen Therapy: When Excess Fuel Extinguishes the Fire

Abstract

Androgen deprivation therapy (ADT) remains the cornerstone of advanced prostate cancer treatment. However, the progression towards castration-resistant prostate cancer is inevitable, as the cancer cells reactivate androgen receptor signaling and adapt to the castrate state through autoregulation of the androgen receptor. Additionally, the upfront use of novel hormonal agents such as enzalutamide and abiraterone acetate may result in long-term toxicities and may trigger the selection of AR-independent cells through "Darwinian" treatment-induced pressure. Therefore, it is crucial to develop new strategies to overcome these challenges. Bipolar androgen therapy (BAT) is one such approach that has been devised based on studies demonstrating the paradoxical inhibitory effects of supraphysiologic testosterone on prostate cancer growth, achieved through a variety of mechanisms acting in concert. BAT involves rapidly alternating testosterone levels between supraphysiological and near-castrate levels over a period of a month, achieved through monthly intramuscular injections of testosterone plus concurrent ADT. BAT is effective and well-tolerated, improving quality of life and potentially re-sensitizing patients to previous hormonal therapies after progression. By exploring the mechanisms and clinical evidence for BAT, this review seeks to shed light on its potential as a promising new approach to prostate cancer treatment.

Keywords: bipolar androgen therapy (BAT); metastatic castration-resistant prostate cancer; novel hormonal agents (NHAs); positron emission tomography (PET); prostate cancer; prostate-specific membrane antigen; supraphysiologic testosterone.

Figure 1

The androgen receptor signaling pathway. The 5-a reductase enzyme converts testosterone into the highly active dihydrotestosterone (DHT). Unbounded AR is located in the cytoplasm, chaperoned by a complex of proteins such as HSP90. Upon the binding of DHT, AR separates from chaperone proteins, dimerizes, and relocates to the nucleus, binding to androgen response elements (AREs) found in AR target genes.

Figure 2

Oncogenic role of AR as a licensing factor and SPT-mediated disruption of DNA licensing. AR acts as a licensing factor for DNA replication in prostate cancer. During early G1, bounded AR joins the origin of replication sites (ORS), which are bound by the origin recognition complex (ORC). Then, cell division cycle 6 binds the ORC, which is necessary for loading MCM proteins and CDT1, forming the pre-replication complexes required for the G1-dependent DNA licensing. After the genome is replicated in the S-phase, replication complexes are removed from ORS during mitosis and degraded to ensure that ORS is available for subsequent relicensing. It has been hypothesized that upon SPT administration, ligand-dependent stabilization of AR during mitosis might prevent its degradation in the M phase, which disrupts the relicensing process, resulting in subsequent G1/S arrest.

Figure 3

Proposed mechanisms for growth-inhibitory effects of SPT. (A) SPT is hypothesized to disrupt the interactions between distal super enhancers and the c-Myc promoter, which results in c-Myc downregulation and its target gene S-phase kinase-associated protein 2 (SKP2). SKP2 suppression entails the loss of the ubiquitin-mediated degradation of cyclin-dependent kinase (CDK) inhibitors p27 and p21, causing G1 arrest. (B) By activating AR signaling, SPT may cause transcriptional repression at specific binding sites in the second intron of the AR gene (ARBS2) through recruiting lysin-specific histone demethylase 1 (LSD1) and the subsequent demethylation of activating histone marks such as H3K4 me1-2, which results in a reduced expression of full-length AR and its spliced variants. (C) SPT-mediated AR activation may induce senescence through multiple mechanisms: decreasing the expression of p63, a protein which opposes senescence; promoting the production of ROS, which leads to Rb hypophosphorylation and the subsequent suppression of E2F target genes; increasing the expression of p16, which promotes the formation of senescence-associated heterochromatic foci (SAHF) through the p16-Rb-E2F axis. (D) SPT may induce ds-DNA breaks by the recruitment of topoisomerase II beta (TOP2B) to AR target genes. Increased ROS production potentially plays a role in conversion of transient ds-DNA breaks into true ones. (E) Autophagosome-mediated nucleophagy of damaged DNA appears to activate cytosolic nucleic acid sensors, stimulating the innate immune system, which results in cytokine and chemokine release including CXCL10 and the eventual activation of immune cells. (F) Through increasing ferritin degradation, SPT has been suggested to increase the labile iron pool, leading to lipid peroxidase-mediated cell death or ferroptosis. (G) SPT administration seems to facilitate Bax protein’s translocation to mitochondria, thereby promoting apoptosis.

Figure 4

Serial PSMA PET/CT shows radiographic response despite overall PSA progression after three cycles of BAT. A 75-year-old patient with metastatic castration-resistant prostate cancer (mCRPC), who had been heavily pretreated with hormonal agents, was enrolled in the PSMA-BAT study (NCT04424654) and received 400 mg of intramuscular testosterone every 28 days for three cycles. The patient underwent PSMA-PET/CT imaging at baseline, at the six-week mark, and at the twelve-week mark. After three cycles of BAT, a clear radiographic response was observed despite an overall increase in PSA levels. Tumor volume, Total lesion, and SUVmax were reduced, while PSA levels more than doubled compared to baseline. (A) Timeline of testosterone injections, imaging acquisitions and images of the corresponding PSMA studies; Concurrent measurements are shown as (B) PSMA PET/CT total lesion chart; (C) PSMA PET/CT tumor volume chart; (D) SUVmax chart; (E) PSA chart.