New study below [1]
By now, most will know that BAT = bipolar androgen therapy
New to me, SAT = supraphysiological androgen therapy
SARMS = selective androgen receptor modulators
***
Some will remember past discussions about the role of estrogen in PCa. My take on estrogen has always been that the estrogen:testosterone ratio [E2:T] is significant in PCa. This can be reduced to: T is biphasic - growth-permissive at low levels; regulates growth at high levels.
From the new paper: "AR signaling is dichotomous, inducing growth at lower activity levels, while suppressing growth at higher levels"
{Might men on active surveilance benefit from high-normal T?}
The authors wondered whether the regulatory aspects of AR could best be induced by a SARM - rather than testosterone, with its "poor drug-like properties as well as rapid and variable metabolism".
{Well, we know that drugs are always better than natural agents ... LOL}
from the Discussion section:
"AR signaling is critical for the growth and survival of most PCs throughout the entire course of the disease. However, successive treatments with drugs designed to inhibit AR signaling yield diminishing benefits and extensive cross-resistance (49). SAT may counter adaptive cellular mechanisms that contribute to a castration-resistant phenotype. Notably, the dynamic nature of bipolar T administration further exploits a requirement for adaptive responses to maintain optimal ratios of ligand and receptor that regulate cell survival and proliferation (14). Additionally, mechanisms that enhance AR function in low androgen environments, like AR amplification, may become liabilities when high concentrations of T activate the growth-suppressive functions of the AR. Unfortunately, the use of T as a therapeutic is accompanied by pharmacological limitations that preclude the optimal evaluation of AR agonism as a treatment strategy. For example, if cycling high and low AR agonism is an important facet of clinical benefit, it is challenging to rapidly adjust plasma androgen concentrations using the current methods of depot i.m. injections. Given these considerations, discovering a substitute for T with improved safety, delivery, and control would represent a significant advance in the use of continuous or bipolar AR agonist therapies in the clinic.
"In model systems, SARMs have been shown to be potent AR agonists, for example, restoring body and muscle mass of castrated rats (22). The pharmacokinetics of several SARMs have been extensively characterized (19, 22, 23, 50). In terms of AR agonist activity, SARM-2F and GTX-024 have superimposable transcriptional dose responses toward AR-driven reporters: saturating activity was achieved for both SARMs at 10–8 M (19). Similar dose-dependent transcriptional responses were observed in primary human skeletal muscle and prostate epithelial cells (22). While SARM abuse has been reported, and toxicities have been associated with adulterated or misrepresented products obtained via internet vendors (51), clinical studies using pure clinical-grade SARM compounds have demonstrated excellent safety profiles. For example, a phase II clinical study of GTX-024 (enobosarm) for cancer-induced muscle wasting did not report significant adverse events (33).
"Although the drug-like properties of SARMs are well supported by the literature, it was unknown whether SARMs, being partial agonists, would activate the AR potently enough to engage a growth-suppressive and differentiating transcriptional program in PC. In this study, we tested the hypothesis that nonsteroidal SARMs match the efficacy of steroidal AR agonists in suppressing the growth of castration-resistant PC. To this end, we evaluated SARMs in vitro and in vivo to establish their growth-suppressive activities in PC models. Like steroidal androgens, we found that SARMs induced the expression of luminal differentiation genes, blocked entry into the S phase, and repressed MYC and FOXM1 levels. Finally, by comparing transcriptomes, AR cistromes, and AR cofactor profiles, we demonstrated that SARMs recapitulated the global molecular effects of steroidal AR agonists.
"The most unexpected result from this study was the lack of meaningful differences between certain SARMs and steroidal agonists in PC cells. Previous studies have suggested that SARMs and steroidal androgens differentially recruit cofactors (21, 43). However, there does not appear to be a consistent set of cofactors responsible for the “androgenic” versus the “anabolic” effects. Part of this confusion may be due to the vast diversity of SARMs in both molecular scaffolds and the potency of their agonism. In our study, we found that the SARMs LGD-4033 and RAD140 were unable to suppress the growth of PC cells. Interestingly, GTX-024 and GTX-027 activated the AR sufficiently to suppress the growth of LNCaP and VCAP cells, but not 22PC-EP cells. These data suggest that the effect of a SARM depends on the cell-intrinsic context of AR signaling, like AR mutation or amplification status, as well as on the properties of the SARM itself.
"Currently, it is difficult to predict whether a particular SARM can activate the AR sufficiently to suppress the PC growth (45, 46). Given that certain SARMs behave as partial agonists in vitro and in benign tissues, and yet fully recapitulate AR activity in PC models, the switch from partial agonist to full agonist may reflect genomic and epigenomic alterations in prostate carcinomas, where cistrome reprogramming influences the development of castration resistance. These mechanisms should be further studied in the context of SARM sensitivity to predict likely responders.
"The effects of bipolar AR activation were not evaluated in this study. Preventing adaptation to a static, low or high androgen environment may be crucial, for long-term suppression of tumor growth. Understanding changes in gene expression, physiology, and the epigenetics of cells exposed to a changing androgen environment may help improve therapy by identifying feedback mechanisms that can be further exploited. Additionally, the current 28-day treatment cycle of BAT may not be the most effective. Given the control afforded by the drug-like properties of SARMs, shorter or longer treatment intervals could be evaluated to optimize the bipolar AR for the greatest effect.
"Future studies into the use of nonsteroidal agonists to suppress the growth of PC should explore strategies that augment the activation of the AR. One avenue could be to evaluate nonsteroidal, full AR agonists. Safety concerns notwithstanding, full agonists may be more effective replacements for steroidal agonists by potently inducing AR signaling, regardless of the cellular context, and so could induce the same systemic effects as those seen with T. Other possibilities include cotherapeutic approaches to directly activate the N-terminal domain of the AR or stabilize AR levels (52–54).
"Our findings strongly support further exploration of SARMs for the treatment of CRPC. The nonsteroidal compounds SARM-2F, T8039, GTX-024, and Cpd26 potently induced AR activity, repressed MYC signaling, and suppressed the growth of PC cells. SARMs compared favorably to steroidal androgens by regulating a largely overlapping set of genes and recruiting the same set of AR cofactors to chromatin. Since SARMs have already been tested in a variety of clinical settings for other health conditions, the path to implementing them in the clinic as a CRPC therapy could be accelerated. Given their convenient mode of delivery, favorable safety profile, and potential to improve general health, SARMs present an attractive therapeutic option."
-Patrick
Full text: jci.org/articles/view/146777
A Bit of Support for BAT or SupraT
BAT (Bipolar Androgen Therapy) 
question about iADT or BAT
