Therapies Targeted to Androgen Receptor SignalingAxis in Prostate Cancer: Progress, Challenges,and Hope - published December 2019

[JLS1]

I was doing some research on ARL702H, which the Guardiant360 revealed for my husband. I think ARL702H is brought on from being on Zytiga + prednisone. - and this may be why switching from predisone to dexamethasone can help the Zytiga to continue working:

Role of Androgen Receptor in Prostate Cancer: A Review

World J Mens Health Published online Sep 10, 2018

wjmh.org/Synapse/Data/PDFDa...

1. Point mutations in androgen receptorPoint mutations in the AR gene were found in 15% to 30% of CRPC patients [15,16], most frequently in the LBD, followed by the NTD [3]. These point mutations can activate AR by losing the specificity of the ago-nist. For example, the point mutation of T878A results in the loss of specif icity for the agonist. Progesterone, estrogen, f lutamide, bicalutamide, and enzalutamide can activate AR with the T878A point mutation [17-19]. T878A was the f irst identif ied point mutation of AR driven by flutamide, but T878A also exerts resis-tance to second-generation AR agonists [20]. The F876L point mutation changes the LBD domain and confers resistance to enzalutamide [21,22]. T878A or L702H mutations were found in the plasma of 13% of CRPC patients with abiraterone resistance [23]. These muta-tions can be detected in plasma DNA and may help physicians in choosing the appropriate drugs for CRPC patients [24]. AR L701H and AR L701H/T877A are somewhat less sensitive to androgens but are highly responsive to the glucocorticoids cortisol and cortisone

Anyway, digging deeper I came across this article which I thought may hold some interesting, and hopefully valuable, information. It's Chinese to me, so I thought I'd post a link for someone else here who may be interested, and who may be able to decipher it:

researchgate.net/publicatio...

Therapies Targeted to Androgen Receptor SignalingAxis in Prostate Cancer: Progress, Challenges,and Hope

This is interesting:

"Cancers 2020,12, 51 10 of 26

Table 3.

List of compounds that interferes with the interaction of AR with co-regulators/co-factors, and their mechanisms of action (* compounds that are/were in

clinical practice, ** compounds that show promise in preclinical studies, but have not yet been evaluated in clinical trials or have yet brought to clinical practice),

*** compounds that showed promise in preclinical studies, but failed in clinical trial,

Targeting the Binding of AR and Co-Regulators

Compound Mechanism of Action Ref

MCB-613 ** The inhibitor of NTD that interacts with AF-1 region and inhibits AR activation and

AR-mediated signaling pathway. [112]

EPI-001 *** Selectively binds AF-1 domain of the androgen receptor and thus represses the

transcriptional activity of AR. [113]

Ralaniten (EPI-506)** The derivative of EPI-001, which acts as an inhibitor of NTD that interact with AF-1

region leading to the inhibition of AR activation and AR-mediated signaling pathway. [114]

EPI-002 ** The stereoisomer of EPI-001, which has the potency to disrupt the NTD of AR and

inhibits the transcriptional activity of AR. [115]

Targeting AR Co-Factor(s)

17-AAG *** Inhibits HSP90 and the ligand-independent nuclear localization of AR [116]

Methoxychalcones ** Stabilizes AR-Heat shock protein complex and thus prevents AR dimerization. [117]

Onalespib * Inhibits HSP90 leading to the degradation of client proteins including AR. [118]

Table 4.

List of natural compounds that target AR signaling and their underlying mechanisms of action. All of these compounds have shown promise in preclinical

studies, but have not yet been evaluated in clinical trials or have yet brought to clinical practice.

Compound Mechanism of Action Ref

Green tea extract (EGCG)

The polyphenol in green tea extract inhibits 5

α

-reductase activity thus impedes the androgen synthesis.

[119]

Mushroom extract The triterpenoid compound in the mushroom extract inhibits 5α-reductase activity and thus impedes

the androgen synthesis. [120]

Glycyrrhetinic acid Targets 17,20-lyase enzyme and thus decreases the testosterone level. [121]

Curcumin Curcumin analogs function as androgen antagonists, inhibit testosterone-, DHT-induced AR activity. [122]

Niphatenones The glycerol ethers from the sponge Niphates digitalis, which covalently binds to the AF1 region of the

NTD. [123]

Sintokamides The derivative of the marine sponge Dysidea sp that binds to N-terminal domain of AR and thus,

suppressed the AR activity. [124]

Selenium Regulates AR gene expression. [125]

Quercetin The flavonol pigment in onion and apple acts as the HSP70 inhibitor and induces the AR degradation. [126]

Berberine The plant phytochemical, which acts as the HSP70 inhibitor and thus induces the AR degradation. [127]

Hydroxytyrosol Inhibits AR expression. "

[Hidden]

So much info... how to digest so much ? Great job researching ! Thanks

[GP24]

This review was published on the 23rd of December, so probably only very few people have read it yet!

The tables you cited are discussed in the sections 5.3 and 5.4. I think you have to know the translocation of the androgen receptor in detail to understand what the authors are writing.

This article provides some additional information but it is still difficult to understand:

ncbi.nlm.nih.gov/pmc/articl...

Anyway the authors mention: "All of these compounds have shown promise in preclinical studies, but have not yet been evaluated in clinical trials or have yet brought to clinical practice." With other words they have only been tested with mice yet.

[bwochf in reply to GP24]

To me the question would be, did one of our "fellow travelers", who are for a long time on ADT (or ADT + Zytiga w Prednisone, etc.), "accidentally" regularly add Berberine or Curcumin or Green Tea or Red Reishi or Licorice, etc, to the "ADT". Could this then be the reason why for these "fellow travelers" the PSA increase was significantly smaller, or no increase at all?

[GP24 in reply to bwochf]

I did try several alternative meds but I could not tell if my PSA value would have developed differently if I would not have used this stuff. There was no control group. All I can say is that the PSADT did not change after I took it. Therefore I lost my motivation to use these meds.