Supraphysiological Androgens [SPA] Promote Tumor Suppressive Activity of the AR Through cMYC Repression and Recruitment of the DREAM Complex

[pca2004]

New study [1]. 

I have struggled to understand how Denmeade’s BAT (Bipolar Androgen Therapy) depends on supraphysiological levels of androgen (testosterone = ~2,000 ng/dL), considering that Morgentaler’s saturation model has it that androgen receptors [ARs] have all the testosterone they can use at fairly low physiological levels (<350 ng/dL). 

I am not aware of a BAT study comparing a testosterone target of 2,000 ng/dL with high-normal 1,000 ng/dL, say.  Denmeade claims that the higher level induces double-strand breaks in PCa cells (but not normal cells). 

In my own use of testosterone, supraphysiological androgen has not been necessary to maintain ADT sensitivity (for many years).  However, Denmeade's focus has been on CRPC cases.

“The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA) results in growth repression and improved outcomes in subsets of prostate cancer patients.  

“A better understanding of the mechanisms contributing to SPA response and resistance could help guide patient selection and combination therapies to improve efficacy.  

“To characterize SPA signaling, we … 

… etc, etc, etc … 

“Overexpression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression of E2F target genes. 

 “These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM complex. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.” 

From a 2021 paper [2]: 

“… findings demonstrate an intricate balance between AR and MYC, and indicate that increased MYC in response to androgen deprivation contributes to castration-resistant PCa, while decreased MYC may contribute to responses to supraphysiological androgen therapy.” 

“In support of the physiological significance of this MYC repression, we found DHT (dihydrotestosterone) treatment of CRPC xenografts could rapidly suppress MYC, a response that may contribute to the efficacy of supraphysiological androgen therapy in CRPC. Conversely, androgen deprivation in vitro and castration in vivo led to rapid and persistent increases in MYC. The expression of MYC and of MYC-regulated genes is also increased in CRPC, including in clinical samples without MYC gene amplification. This indicates that decreased AR activity in CRPC can be compensated by increased MYC, and that this may contribute to progression to CRPC after androgen deprivation therapy” 

From a 2022 (Denmeade) paper [3]” 

“Here, we show that growth inhibition of prostate cancer models by SPA required high androgen receptor (AR) activity and were driven in part by downregulation of MYC.” 

“While BAT was originally designed to cycle testosterone levels with the intention of minimizing adaptation to high or low levels of androgens, … data suggest that there may be clinical benefit to more extreme oscillation of AR activity by alternating the use of SPA with an AR inhibitor.” 

“Previous clinical studies have demonstrated that BAT can be an effective therapy for some patients with mCRPC. This study assessed the molecular mechanisms that drive the efficacy of BAT.  

“Our results indicate that high prostate cancer AR activity is required for tumor regression by BAT, which occurs in part through downregulation of MYC. High AR expression was required for downregulation of MYC and growth inhibition by SPA” 

“A subtlety of our findings is that tumor AR activity, but not AR abundance, predicted clinical outcomes for patients on BAT …  

“A better understanding of the regulation of AR activity may allow for the development of strategies to boost and sustain AR activity in order to enhance sensitivity to BAT.” 

“A key question to understanding BAT is: what are the molecular events that result in regression of tumors with high AR activity? Our results suggest that SPA/BAT can significantly downregulate MYC expression, and this occurs only in prostate cancer with high AR activity.” 

“Acquired resistance is a significant limitation to the use of BAT. We show that acquired resistance to SPA can be driven by downregulation of AR in vitro. BAT induced downregulation of AR mRNA and protein in most patients in our study … 

“… methods to prevent AR negative autoregulation have the potential to prevent acquired resistance to BAT. To our knowledge, no such methods currently exist, however, AR-axis inhibitors are widely known to induce adaptive upregulation of AR in patients with CRPC.  Thus, we tested sequential treatment of prostate cancer models with SPA followed by the AR inhibitor enzalutamide. Our results indicate that acquired resistance to SPA can be overcome by treatment with enzalutamide, which induced upregulation of AR and increased susceptibility to SPA.” 

-Patrick 

[1]  pubmed.ncbi.nlm.nih.gov/373... 

[2]  ncbi.nlm.nih.gov/pmc/articl... 

[3]  ncbi.nlm.nih.gov/pmc/articl... 

[Bhraen2]

Thank you for your continued contributions that are very beneficial to all of us.

[cujoe]

Patrick - this post inspired me to complete my TRT post started last week. As a postscript I have included the superb GRU interview with Morgenthaler from earlier this year. For those unfamiliar with his research & clinical practice using TRT - and which led to the development of his "Saturation Model", it will explain them all. Post link:

healthunlocked.com/fight-pr...

From your post:

"A subtlety of our findings is that tumor AR activity, but not AR abundance, predicted clinical outcomes for patients on BAT. . "

How would a patient determine which condition was in play? PSA doubling time? Response to AR inhibitors? Both?

Stay S&W,

Ciao - K9

[pca2004 in reply to cujoe]

Hi Cujoe,

Perhaps someone with CRPC considering BAT should start with a month on a 'lutamide'? Might Casodex [Bicalutamide] do the job?

After one month of BAT, another month of the lutamide - & so on.

Denmeade has patients on continuous ADT, but someone with CRPC isn't going to have much of a testosterone recovery imo. Denmeade describes day 28 of BAT as being one of "near-castration", rather than being within the usual target range for ADT castration. The important thing about BAT is the rapid modulation of testosterone from supraphysiological to low, imo.

Quitting ADT while alternating between lutamide & BAT might be quite bearable.

Frequent tracking of PSA would soon reveal efficacy or otherwise.

-Patrick

[cujoe in reply to pca2004]

Patrick,

While not yet doing a BAT routine, it is a possibility for down the road. (Along with consideration of a PSMA monoclonal combo) I've been on a quite erratic bical+ regime for the last year - after a short 2 mo lupron repeat of the 3 mos I did back in 2017 (which bought me a 4 +/- year treatment vacation). After last year's lupron repeat failed to be durable, I had intended to do a dosing experiment using bical initially and later adding dutasteride - with a dose reduction in both to shoot for a stable PSA at/below/near "undetectable". Advancing gynecomastia got in the way and I had to stop the bical (and dutasteride) in favor of daily tamoxifen leading to recent RT.

I'm now back on bical and am continuing a low-dose tamox @ 1/2 tab every other day. A LEF male hormone panel after 3 weeks of that combo showed expected results with 40% reduction in PSA and E2 back in the mid 20s (from upper 30s). Free T was also up above my normal production of around 1% of total T (which with the bical boost now ranges in the mid-to-upper 700s).

My next MO appt is in mid July and I expect to be back/near <0.1 "undetectable" PSA at that time. I will then consider adding dutasteride for 30 days while continuing with bical + low dose tamox (for a bit of E2 alpha control). I'll need to get my MO to stay on board with this non-SOC treatment program and extend the necessary scripts. So far he has, and I suspect it is due to the continued written support documentation I provide at every appointment.

Actually, while metastatic, I am obviously still HS and my actual reason for the question was to determine if I could gauge in advance the probability for BAT success based on measuring "tumor AR activity" and "AR abundance".

Also, having recently dug deep into Gatenby/Moffitt's theoretical framework for Adaptive/Evolutionary First Principles, their current technique would suggest cycling any treatment (as it seems you have successfully done repeatedly over your long disease history) is a better approach than trying to establish a reduced-dosage, stable-state condition.

It goes without saying (as I say it), that any thoughts you may have will be much appreciated.

Stay S&W,

Ciao, Kaptin cujoe

PS Your suggestion of ?lutamide (without ADT) for BAT is a protocol I have wondered about for some time, esp, for hsPCa; i.e. if the AR is blocked at a cellular level, why does testosterone need to be blocked at all during the off-part of the cycle?

[PCaWarrior in reply to pca2004]

FYI: I did this and it works (switch from high T to Xtandi for 3 weeks). PSA dropped to 0.04. My usual nadir is 0.2-0.5. I was on constant Lupron (an injection every 3 months). I monitored for a while and skipped my injections but the headache and wear and tear on my veins prompted me to resume Lupron shots.

I'm doing the ADT/ARTA again but with darolutamide. IMO it doesn't need to be separated from BAT. Semantics, but including an ARTA during low T of BAT is simply a drug addition.

[Ramp7 in reply to pca2004]

I'm using Propionate Testosterone for my BAT protocol, half life is very short. Results in a dramatic decline and shock to the cancer.

[Ramp7]

Very interesting points you bring up. Things that I have thought about myself. I was on Lupron / Zytiga for 18 months. Last year a trial study at Dana Farber. Zytiga was dropped, Lupron continued. Six months into BAT using Propionate with Lupron still in the background. Regarding the rapid modulation of Testosterone, Propionate achieves that most eloquently. As you mention and I discussed with Dr. Denmeade. (Is Lupron really necessary at this point in the journey?) After over three years on Hormone type intervention, my body is probably producing very little on it's own. Maybe just monitor in now. Hmmmm

[Ramp7]

Darolutamide can also achieve the same desired results as Enzalutamide with less side events.

[MateoBeach in reply to Ramp7]

Yes. I agree and am also using darolutide to sharply block any remaining AR activity when coming off my high T and going into castrate month. Using Orgovyx during that month but that might not be necessary as you point out.

The biggest question for me is: How long in AR blockade with low or castrate testosterone is needed to upregulate the ARs and down regulate MYC, a “reset” for the next cycle of SPA BAT? I am doing one month. STEP-UP trial is testing 2 months. Do you know the answer? Paul

[Ramp7 in reply to MateoBeach]

As we already know, each of us is a unique snowflake. The time question may end up being an individual discovery. I'm coming up on 3 weeks castrate with Propionate after my 4th cycle. Blood test tomorrow. My reaction to BAT after just 6 months does not appear as pronounced as after the 2nd cycle. Things to consider.

[MateoBeach in reply to Ramp7]

Unique indeed, Mark. Slowly we continue to unravel the threads to solve the puzzle, or parts of it anyway. I also have noticed less dramatic response to high T over time. May represent residual AR down regulation. So I will increase my time on darolutamide to 2 or 3 weeks at start of castrate cycle to attempt reversing it. Though I have a limited supply and may need to switch to enzalutamide. Too bad there is no assay or test for AR and MYC activity short of IHC. Paul

[Ramp7 in reply to MateoBeach]

I have yet to request any meds such as Xtandi or Darolutamide. Curious as to response from my MO.

[nuc1111]

Thanks Patrick--- An important treatment for some of us

[edfriedman]

Dr. Danmeade seems to ignore the fact that membrane androgen receptors exists and almost totally counteract intracellular androgen receptors. See: pubmed.ncbi.nlm.nih.gov/176...

It is possible to use this knowledge as well as knowledge about estrogen receptors (since increased testosterone will result in an increase in estrogen) in order to improve upon the current use of BAT. See: researchgate.net/publicatio...

[cujoe in reply to edfriedman]

Hi, Mr. Freidman,

Your comments are always a fine addition to the discourse here. And, BTW, I find the notes section of your book is filled with important insights that I completely missed in reading the text alone.

With solid benefits shown for the use of both SERMs and investigative SARMs agents, what is your view on their use for PCa - and why they have not yet been adopted for use as adjuncts to (or replacements of) current SOC. That would especially seem to be the case for SERMs, since tamoxifen has been shown to act mostly on ERa, while preserving the benefits of ERb, and has been in continuous common use for 40+ years, i.e.:

SERMs:

1. A Systematic Study of the Impact of Estrogens and Selective Estrogen Receptor Modulators on Prostate Cancer Cell Proliferation, 2020.

nature.com/articles/s41598-...

2. Selective estrogen receptor modulators contribute to prostate cancer treatment by regulating the tumor immune microenvironment, 2022

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

3. Toremifene, a selective estrogen receptor modulator, significantly improved biochemical recurrence in bone metastatic prostate cancer: a randomized controlled phase II a trial - 2015.

bmccancer.biomedcentral.com...

SARMs:

4. Selective androgen receptor modulators: the future of androgen therapy?, 2020

tau.amegroups.com/article/v...

5. Selective androgen receptor modulators activate the canonical prostate cancer androgen receptor program and repress cancer growth, 2021.

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

6. A Selective Androgen Receptor Modulator (OPK-88004) in Prostate Cancer Survivors: A Randomized Trial, 2021.

pubmed.ncbi.nlm.nih.gov/340...

Again, thanks for your continued contributions to the PCa knowledgebase in general and for your participation here at FPC and elsewhere. Any comments/insights you are able to provide will be both valued and appreciated.

Stay Safe & Well,

Ciao, Kaptin cujoe

[edfriedman in reply to cujoe]

Thank you for your compliments. The complicated science was intentionally put into the Notes section in order to make the reading of the book without referring to the Notes much easier.

Using SERMs is a bit complicated. In some cases they act differently depending on the tissue involved. Some binding to ER-alpha is necessary for long term health and not all SERMs are tested for how much they act as an antagonist to ER-alpha or to ER-beta in the prostate. You don't want to use any that block ER-beta.

Using SARMs becomes a bit problematic. You have to reach the equivalent of superphysiologic levels of T (SPT) in order to effectively treat PCa, and to do that with SARMs would require lots of money and years to get FDA approval. Also, the big question with regards to androgens are what their effect is on mAR and what it is on iAR. Right now, T and DHT bind equally well to mAR, but DHT binds ~10 times more strongly to iAR than T does. This allows BAT to work when you amplify iAR so that you achieve a great imbalance of iAR binding vs. mAR binding which you can use SPT to take advantage of. Ideally, all of the drugs which block iAR would be checked to see what their effect is on mAR. If iAR is blocked but not mAR, then SPT would be expected to kill ~60% of the PCa each month. Right now, flutamide is known to block iAR but not mAR and bicalutamide is known to block both. There is a single article that suggests that enzalutamide may block iAR but not mAR, but this should be tested directly before I would believe it. Right now it is possible to use T alone by using a 5AR inhibitor to prevent it from creating DHT or mostly DHT (without a 5AR inhibitor, 90% of T is converted to DHT within the prostate), so it is possible to manipulate the treatment of PCa by creating imbalances in the iAR-mAR ratio. For PCa to thrive, there has to be a relative balance in the iAR-mAR ratio.

[cujoe in reply to edfriedman]

Hi again - and thanks for the very prompt & thoughtful reply.

Off the top, is there a reason you prefer finesteride over the more-broad-acting dutasteride as a 5-ARi?

Thanks In advance for a reply,

Ciao, cujoe

[edfriedman in reply to cujoe]

Dutasteride has a half-life of 5 weeks. This makes it unsuitable for BAT type treatment. However, if using long term SPT with 5AR inhibitor such as Dr. Leibowitz did, then it is quite suitable.

[cujoe in reply to edfriedman]

Ahhh. Now I remember . . . our lost FPC contributor, smurtaw aka Russ Hollyer, being all over drug half-lives and making that same point. Thanks for the reminder.

I pretty sure you are in some contact with Russ at CancerHackerLab. I'm watching things there as a model for future patient-to-researcher collaborations. Great Idea and seems to be getting up to speed pretty fast. I was pleased to see that you are a participant there and expect your insights are well received by that audience. Russ was our most prolific poster until the content police ran him off. Your old-time acquaintance, Patrick O'Shea, has for the most part picked up the slack here.

Lots of very smart people pushing the edge of the science, your work definitely puts you in that group. As patients with an essentially incurable disease, we all owe people like you a large debt of gratitude for advancing our understanding of the complex interactions that contribute to the development and progression of PCa.

So, A hearty "Thanks" on behalf of all of us PCa patients for your many years of thoughtful research and continuing contributions to unraveling the many mysteries of our common disease.

May you forever Stay Safe & Be Well,

Ciao - cujoe

[cujoe in reply to edfriedman]

You said:

"Right now, T and DHT bind equally well to mAR, but DHT binds ~10 times more strongly to iAR than T does. This allows BAT to work when you amplify iAR so that you achieve a great imbalance of iAR binding vs. mAR binding which you can use SPT to take advantage of."

Seems this is the key insight that needs to be considered with any treatment approach using BAT.

[edfriedman in reply to cujoe]

I agree 100%, but almost no doctors are aware of the importance (or even the existence) of mAR.

I should also point out that it is astronomically against the odds that a gene that upregulates a protein will mutate in such a way as to downregulate that protein. This is especially unnecessary in the case of iAR, since just increasing mAR will in almost every case downregulate the proteins that iAR upregulates.

[Scout4answers in reply to edfriedman]

Are you available for consultation on BAT? or Can you recommend an Urologist or MO that is up to speed?

[edfriedman in reply to Scout4answers]

I am not a physician and can only offer theoretical advice, not practical advice. Unfortunately, I don't know of any physicians who are doing BAT the way in should in theory be done. However, Russ Hollyer seems to be doing it the best from what I've seen reported...

[Scout4answers in reply to edfriedman]

Thank You

[KocoPr]

Thanks so much Patrick. I’m HSPC and start BAT IN 4 days.

After a year on orgovyx and daro i just stopped daro for a 7 day clearing then inject T- prop for two weeks then back on daro for 2 weeks then 2 weeks off of both. All the while staying on orgovyx, and testing T,E2,, and PSA. Rinse and repeat.

I will also be taking letrozol during high T to combat my high unmetoblized estrogens. I still need some small doses of E2 patch to keep my E2 between 10 and 20.

I am still confused if i should even bother with orgovyx.

I plan on changing over to a longer T cycle like Mateobeach does but first want to see how I respond to BAT.

This BAT article you posted is the holy grail of good BAT efficacy in some and not in others. Now our researchers have a definitive focal point to work with , and us warriors more confidence and ammunition to try BAT.

Any input by all you BAT experts is much appreciated.

[Scout4answers in reply to KocoPr]

Very interested in your BAT progress Koko Let's hope you are one of the positive responders. I like you thoughts about moving on to Mateo's protocol if you are a BAT responder.

[KocoPr in reply to Scout4answers]

yes and i reserve the right to jump back to Russ’s protocol anytime as needed. That’s the beauty of not being in a BAT trial. One needs to be flexible.

So I will be doing Russ’s pBAT for a few cycles and start working like Russ does to longer High T cycles as needed. Keep the beast fed but caged!

[Ramp7 in reply to KocoPr]

All the best to you. I started BAT in January of this year after meeting with Denmeade in person. The first hurdle is determining if you are indeed a responder. God Speed.

[KocoPr in reply to Ramp7]

Thank you and good luck for your BAT.

Better chances of not having a higher MYC expression while still HSPC.

[Cooolone]

Thank you for posting!

[MateoBeach]

I read this article with great interest yesterday since I am on long-cycle BAT successfully for over two years with mHSPC. It provides a foundation for 1. Why BAT works and for whom. 2. Why BAT can lead to its own failure (resistance). And 3. How alternating BAT with cycles of enzalutamide or similar ARSI can maintain sensitivity and success with longer term BAT programs.

Basically, those men with high levels of androgen receptor activity (AR) respond best to SPT or BAT with a decrease in MYC oncogene activity. However, over time the high dose testosterone causes down-regulation of AR and consequent rise again of MYC recovery. Thus resistance to BAT/SPT emerges.

Alternating SPT with enzalutamide causes recovery of high AR expression and can restore or protect response to BAT. This is the basis for the STEP-UP clinical trial which uses 8 weeks (56 days) of high testosterone (SPT) alternating with 8 weeks of daily enzalutamide 160mg/day. Much more sensible approach IMO than standard 28 day BAT regimen.

A remaining question is how long actually does it take for enzalutamide or similar darolutamide to restore high AR activity? Does it really take two months? My own regimen is three months of high SPT alternating with one month of castrate T via Orgovyx and darolutamide. Would like to find research on the time course to high AR activity recovery in BAT programs. Paul

[Ramp7]

A lot of excellent information.

[MateoBeach]

This closes the loop for the theory of alternating ARSI such as enzalutamide with cycles of very high testosterone in modified BAT regimens:

We know BAT can restore sensitivity, in many, to enzalutamide from the RESTORE and TRANSFORMER trials. This paper you cited shows how ARSIs such as enzalutamide (and likely others) may in turn, maintain or restore sensitivity to BAT. Appears to be an auspicious circle.

Currently being explored in several of our personal regimens as well as in the STEP-UP trial. May that we continue to rapidly refine it. MB/Paul