Androgen Metabolism and Response in Prostate Cancer Anti-Androgen Therapy Resistance, Int J Mol Sci. 2022 Nov; 23(21): 13521

[cujoe]

This is by far the best overview paper I have seen on the topic of AR metabolism and the nature of treatment resistance for mainstream SOC drugs currently in use. Recommended reading for those wanting to more fully understand their disease. Here is the Abstract:

Abstract

All aspects of prostate cancer evolution are closely related to androgen levels and the status of the androgen receptor (AR). Almost all treatments target androgen metabolism pathways and AR, from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC). Alterations in androgen metabolism and its response are one of the main reasons for prostate cancer drug resistance. In this review, we will introduce androgen metabolism, including how the androgen was synthesized, consumed, and responded to in healthy people and prostate cancer patients, and discuss how these alterations in androgen metabolism contribute to the resistance to anti-androgen therapy.

Access to the full paper is here:

Androgen Metabolism and Response in Prostate Cancer Anti-Androgen Therapy Resistance, International Journal of Molecular Science, 2022 Nov; 23(21): 13521. Published online 2022 Nov 4.

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

As always, Stay S&W,

Ciao - K9

[MateoBeach]

As far as susceptibility to mutations that cause resistance (failure), Darolutamide is the superior choice. Hope it finds more extensive range of approved uses soon. Paul/ MB

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

Emergent AR mutations in men with advanced PCa treated with ARPI promote CRPC progression. The incidence of AR mutations was estimated to be around 15% for CRPC patients [4] and the availability of circulating tumour DNA assays now provide a sensitive method to serially detect (and treat) the emergence of resistant AR mutants. This current work expanded the list of experimentally evaluated AR mutants with 44 additional examples (bringing the total to 68) and quantified their response to four major endogenous steroids and three clinically used AR antagonists, including darolutomide. Among these, only darolutamide demonstrated complete inhibition of 67 out of the 68 studied AR mutant variants, with no significant signs of partial of full activation at even higher concentrations.

[cujoe in reply to MateoBeach]

Pablo - I recently reread the paper you so kindly gave me when we met in AZ last year. I see a new paper by one of the same authors that advances the work done back in 2020. While we are talking PCa metabolics, I'll try to get that up in post that also includes your insightful paper over the next day or so.

Hope all is well with you and your traveling companions. Will contact you direct soon about fall trip planning. In the meantime, Stay S&W,

Ciao - K9

[MateoBeach in reply to cujoe]

Looking forward to it amigo. All is well in the Oregon Summer. Pablo

[edfriedman]

Unfortunately, this paper ignores the importance of membrane androgen receptors (mAR). Higher levels of mAR correlate to higher Gleason scores. (See: ncbi.nlm.nih.gov/pmc/articl.... Also, a very effective method of killing prostate cancer cells is by targeting mAR while blocking intracellular androgen receptors, such as with high T plus flutamide. (See: academic.oup.com/jcem/artic...

By ignoring mAR, doctors are in effect fighting prostate cancer with one hand tied behind their backs.

[NPfisherman]

K9 Terror,

Thanks for posting this information. As we have discussed here several times, repeated exposure to drugs like ARPIs is on the same level as giving the same antibiotics repeatedly for an infection which leads to drug resistance.

Adaption theory/ gaming theory points to using the drugs at lower dose and stopping at a specific PSA goal, and restarting at a specific PSA can prolong the utility of these drugs and prevent resistance. My IADT n=1 experiment continues and is in evolution.

Hope all is well with you and yours...

DD

[cujoe in reply to NPfisherman]

Agreed! And darn fine to hear from one Don Pescado, NP. I trust you are not on a long ladder with a long paint brush at a Victorian Haunted House working in 90+ heat and humidity. Talk about ways to make yourself some unneeded heat shock proteins?

I'm fully on-board with an adaptive approach for the rest of this year. When I test hormones again, I will reduce dosage or set a cycle target numbers and stop for doubling to occur. Do to the various surprise developments since early 2021, I've actually been doing random treatment cycling over the last two years anyway. I hope to get a more finite plan in place now that things have settled down.

Hope all continues to be well with you, Lady M, and family extended. I especially hope your brother is doing better than expected and your son back on an even keel. And while it almost goes without saying after so many years . . .

Y'all continue to Stay Safe & Well. Ciao - K9 terror

[NPfisherman in reply to cujoe]

K9 Enemy of the State,

Have taken a break from Victorian project to get the Lady M through 2 separate assignments with Locum tenens and her mom through a knee replacement at 85... ate up almost 2 months...

As I always say....it is your voyage, so drive your own ship.... with you it is figurative and literal... lol.. I take it you are looking at BAT as a possible plan... You are knowledgeable, and I am sure in contact with Pablo as well.. You will figure it out...

My brother's PSA has stayed at .09 after 7 months...I do wonder if they left some residual prostate tissue behind that is causing this reading... My son is doing great again, and my youngest son may be moving my way... Lady M has not had as much time with her garden and plants, but doing well... We will go home this weekend... A trip to Spain and Portugal is in our near future...

Looking to get with Cardiologist and work on getting my LDL down to 40 or below as part of my dealing with the 4 horsemen ... Had issues with the painter on the house, but that seems straightened around, and hopefully he will get finished soon..

We haven't chatted in a while, so I will give you a call with my own treatment updates. at some point in the next few days.... When I get back to my desktop, I will get back to posting... long overdue...

Take care, amigo...

DD

[cujoe in reply to NPfisherman]

Look forward to the chat and welcome back!

[KocoPr]

Awesome article on how these androgens work

[cujoe]

KocoPr - As I mentioned in my earlier reply to MB, I working on a related post that expands this area of research. (Much more complex research papers.) I am also looking into Ed Friedman's comment and the slim research related to membrane AR (mAR). It does have a Wiki reference as a place to start:

en.wikipedia.org/wiki/Membr...

He may well have ID'd a critical feature of the AR that is not being seen by most researchers - and maybe zero MDs. Anything I find on that topic I will also post and look for Friedman to comment. Keep it S&W, Ciao - K9