Bipolar androgen therapy: the rationale for rapid cycling of supraphysiologic androgen/ablation in men with castration resistant prostate cancer

Abstract

Androgen ablation is highly effective palliative therapy for metastatic prostate cancer but eventually all men relapse. New findings demonstrating that androgen receptor (AR) expression continues in androgen ablated patients has resulted in the classification "Castration Resistant Prostate Cancer" (CRPC) and has led to the development of new second-line "anti-ligand" hormonal agents. In this background is the paradoxical observation that the growth of some AR-expressing "androgen sensitive" human prostate cancer cells can be inhibited by supraphysiologic levels of androgens. This response may be due to effects of high-dose androgen on inhibiting re-licensing of DNA in cells expressing high levels of AR. It may also be due to recently described effects of androgen in inducing double strand DNA breaks. Based on available preclinical data described in this review demonstrating the effects of supraphysiologic levels of testosterone on inhibition of growth of CRPC xenografts, we initiated a clinical trial in men with CRPC testing the effect of monthly treatments with an intramuscular (IM) depot injection of testosterone. This IM formulation achieves supraphysiologic levels of testosterone that cannot be achieved with standard testosterone gel-based applications. The supraphysiologic testosterone level is followed by a rapid drop to castrate levels of testosterone with each cycle of therapy. This "bipolar androgen therapy" will not allow time for prostate cancer cells to adapt their AR expression in response to environmental conditions. The goal is to determine if a clinical response can be achieved through this non-adaptive rapid cycling approach in men with CRPC.

Fig. 1

Effect of R1881 and bicalutamide on the growth of indicated androgen receptor positive cell lines after 5 days exposure. PacMetUT1 was provided by Dr. De Graffenried (U. Texas Health Science Ctr.), Myc-Cap by Dr. Charles Sawyers (Memorial Sloan Kettering) and VCap by Dr. Ken Pienta (U. Michigan). These lines have been previously described [–41]. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Fig. 2

Effect of increasing concentrations of R1881 on the growth of wild type PC-3 or PC-3 cells infected lentivirus containing AR gene. Details of this lentiviral construct can be found in Ref. [17]. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com]

Fig. 3

Invivostudies with testosterone therapy in LNCaP human prostate cancer xenografts. A: Adapted cells (open squares) grow well in castrate animals but rapidly regress upon exposure to supraphysiologic testosterone (T, closed circles), even though tumors are large (~500 – 600 mm³). Adapted cells growing in castrate animals regress when treated with testosterone (closed squares) but begin to grow with sustained testosterone therapy after ~100 days. B: Protein levels of AR show baseline AR levels in non-adapted intact animals. Cells adapted to grow in low testosterone and castrate animals have increased levels of AR. Cells that have begun to re-grow in presence of T show AR levels that have returned to baseline (adapted from Chuu et al. [20]).

Fig. 4

Testosterone treatment and acid phosphatase response adapted from Pearson case report [24]. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]