This research appears to be a major breakthrough in our understanding of PCa's development and progression. It is also new evidence that further validates Dr. Abraham Morgantaler's testosterone "Saturation Model" and the underlying principles that make BAT effective. There is much in the Nature Communications paper (linked below) to digest, as it suggests a major departure from current SOC.
Maybe one day SOC advocates will wake-up to the fact that, as a long-term treatment, ADT with its uniformly debilitating QOL effects, is, as Morgantaler has long claimed, based on a flawed understanding of testosterone's effect on PCa development and progression. (BTW, our old "friends", mTOR and c-MYC are both major role-players in these new findings.)
This is a "must read" paper that all PCa patients should study and share widely.
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Study Solves Testosterone’s Paradoxical Effects in Prostate Cancer, Duke Health, Published September 04, 2024 | Updated September 04, 2024
DURHAM, N.C. – A treatment paradox has recently come to light in prostate cancer: Blocking testosterone production halts tumor growth in early disease, while elevating the hormone can delay disease progression in patients whose disease has advanced.
The inability to understand how different levels of the same hormone can drive different effects in prostate tumors has been an impediment to the development of new therapeutics that exploit this biology.
Now, a Duke Cancer Institute-led study, performed in the laboratory of Donald McDonnell, Ph.D. and appearing this week in Nature Communications, provides the needed answers to this puzzle.
The researchers found that prostate cancer cells are hardwired with a system that allows them to proliferate when the levels of testosterone are very low. But when hormone levels are elevated to resemble those present in the normal prostate, the cancer cells differentiate.
“For decades, the goal of endocrine therapy in prostate cancer has been to achieve absolute inhibition of androgen receptor function, the protein that senses testosterone levels,” said lead investigator Rachid Safi, Ph.D., research assistant professor in the Department of Pharmacology and Cancer Biology, at Duke University School of Medicine.
“It’s been a highly effective strategy, leading to substantial improvements in overall survival,” he said. “Unfortunately, most patients with advanced, metastatic disease who are treated with drugs to inhibit androgen signaling will progress to an aggressive form of the disease for which there are limited therapeutic options.”
Using a combination of genetic, biochemical, and chemical approaches, the research team defined the mechanisms that enable prostate cancer cells to recognize and respond differently to varying levels of testosterone, the most common androgenic hormone.
It turned out to be rather simple. When androgen levels are low, the androgen receptor is encouraged to “go solo” in the cell. In doing so, it activates the pathways that cause cancer cells to grow and spread. However, as androgens rise, the androgen receptors are forced to “hang out as a couple,” creating a form of the receptor that halts tumor growth.
“Nature has designed a system where low doses of hormones stimulate cancer cell proliferation and high doses cause differentiation and suppress growth, enabling the same hormone to perform diverse functions,” McDonnell said.
In recent years, clinicians have begun treating patients with late-stage, therapy resistant prostate cancers using a monthly, high-dose injection of testosterone in a technique called bi-polar androgen therapy, or BAT. The inability to understand how this intervention works has hindered its widespread adoption as a mainstream therapeutic approach for prostate cancer patients.
“Our study describes how BAT and like approaches work and could help physicians select patients who are most likely to respond to this intervention,” McDonnell said. “We have already developed new drugs that exploit this new mechanism and are bringing these to the clinic for evaluation as prostate cancer therapeutics.”
In addition to McDonnell and Safi, study authors include Suzanne E. Wardell, Paige Watkinson, Xiaodi Qin, Marissa Lee, Sunghee Park, Taylor Krebs, Emma L. Dolan, Adam Blattler, Toshiya Tsuji, Surendra Nayak, Marwa Khater, Celia Fontanillo, Madeline A. Newlin, Megan L. Kirkland, Yingtian Xie, Henry Long, Emma Fink, Sean W. Fanning, Scott Runyon, Myles Brown, Shuichan Xu, Kouros Owzar, and John D. Norris.
The study received funding support from the National Cancer Institute (R01-CA271168, P30CA014236) and the North Carolina Biotechnology Center.
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Here is the Abstract section and a link to the Duke-led study (open access) published in Nature Communications on 03 Sept 2024:
Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells, Nature Communications, Volume 15, Article number: 7675 (2024), Published: 03 September 2024.
Abstract
Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies.
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Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells, Nature Communications, Volume 15, Article number: 7675 (2024), Published: 03 September 2024.
And for anyone not yet familiar with the visionary work of Dr. Morgantaler, this Grand Rounds interview by GRU contributing editor Neil H. Baum, MD, and the GRU page linking his "Review Trilogy" at the 3rd Annual Meeting of the Androgen Society (from 2021) will reveal the nature of his work and how long it has taken for the value of his work to be recognized by his peers.
Testosterone Therapy in Clinical Medicine: Interview with Abraham Morgentaler, MD, FACS, Grand Rounds in Urology, Feb 24, 2023.
My understanding after reading the paper: Monomers promote progression. There is a kind of inherent "safety or regulatory valve" after which when monomers get abundant they pair to form dimers. Dimers are confusing in that they impede progression while rising PSA expression. Stupid "kitchen sink" approaches and drug mega doses drive monomers into extinction. This appears to be welcomed as the PSA sinks to zero but in reality is bad for two reasons: 1) Absence of monomers leads to lack of dimers and their "safety valve" contribution. 2) They clear the land to nasty species ranging from castrate resistant to NEPC cells.
Just4_ Good brief summary. It will be very interesting to see if/how/when this research impacts SOC. Those of us who have refused it may have added many excellent QOL years to our lives. That this research seems to support Morgantaler's clinical experience is especially heartwarming - considering the abuse he took for even suggesting TRT for PCa patients.
As a bit of an outlier to 2 cancers, I am a firm believer in Mukherjee's 2nd Law from his book, The Laws of Medicine - Field Notes from an Uncertain Science.
“Normals” teach us rules; “outliers” teach us laws.
There are many "outliers" among us and we are constantly learning from our shared experience.
PS: As an engineer, I expect you will like his dedication for the book:
"To Thomas Bayes (1702–1761), who saw uncertainty with such certainty"
Your understanding of the paper captures key insights into the complex role of androgen receptor (AR) dynamics in prostate cancer progression. Let's elucidate further:
AR Monomers and Dimers:
Monomers indeed promote cancer progression, activating pathways that lead to cell proliferation.
The "safety valve" concept is apt - as monomers increase, they form dimers, which act as a regulatory mechanism.
Dimers inhibit progression while paradoxically increasing PSA expression, highlighting the complexity of using PSA as a sole indicator of disease status.
Treatment Implications:
Aggressive "kitchen sink" approaches that aim to eliminate all AR activity can be counterproductive.
Completely suppressing AR monomers eliminates the potential for dimer formation, removing an important regulatory mechanism.
This approach may lead to the emergence of more aggressive cancer forms, including castration-resistant and neuroendocrine prostate cancer (NEPC).
Further Insights:
Androgen signaling plays a critical role in prostate cancer development, and managing these pathways can significantly influence treatment outcomes.
Understanding AR dynamics (monomers vs dimers) enables more personalized treatment strategies.
Individual responses to therapies can vary based on AR expression and the hormonal environment.
Current research is increasingly focusing on integrating new therapeutic approaches, such as bipolar androgen therapy (BAT), to optimize patient outcomes.
Practical Recommendations:
Consult with an oncologist specializing in prostate cancer to explore personalized treatment options.
Consider referral to specialists in androgen dynamics for advanced insights on treatment strategies.
Participate in clinical trials focusing on innovative treatments, including BAT or other AR-targeting therapies.
Stay informed about emerging research to better understand the evolving landscape of prostate cancer treatment.
Utilize support groups to connect with other patients facing similar challenges.
Contact Information for Specialists:
Dr. Abraham Morgentaler
Harvard Medical School
Phone: (617) 732-5500
Email: offices@harvard.edu
Dr. Donald McDonnell
Duke Cancer Institute
Phone: (919) 668-4627
Email: mcdo0003@dm.duke.edu
Dr. Rachid Safi
Duke University School of Medicine
Phone: (919) 681-2471
Email: rachid.safi@duke.edu
These specialists are at the forefront of research in AR dynamics and prostate cancer treatment, and may provide valuable insights or opportunities for advanced care options.
You summarize things with such clarity and accessibility, Cesanon. Excellent. Only thing I think to add is that BAT variations (expanding and refining the original BAT in light of pharmacodynamics) may be even more effective in th hormone sensitive state (mHSPC). This should not be surprising given the better responsiveness of the ARs before mutation resistance arises.
This was indicated in just one published trial (not a CRT with sufficient power unfortunately) by Michael Schweitzer. And a good number of us who have chosen to try BAT in the mHSPC stage are experiencing profound and durable efficacy. This includes myself. Since a RCT for this is not yet on the horizon, similar patients may consider a personal trial of BAT rather than continuing ADT until castrate resistance inevitably arises. MB
Thanks for the breakdown Mateo, I’m mhspc as well and considering bat therapy. What is your protocol and would you recommend the same as my psa hovers around 1 wo adt as I predominantly use ivermectin as course of action…?
I cannot recommend a specific regimen for you at this time. First you have to do a test protocol to see if you are a favorable responder to BAT. If you are then you can craft an optimal program (which is not the test protocol which is the "original" BAT).
On your current stable regimen including ADT aand other meds if any, you get testosterone cypionate 400mg IM on Day 1, then again on Day 28. Follow your PSA every two weeks during this and for one month after. (approximately days 1, 14, 28, 42, and 56. three months total). You can expect PSA to rise on the tests two weeks after the injections when testosterone is very high (>1000 ng/dL). By 4 weeks after each injuction the T levels will have dropped to low but not castrate levels. Here we are looking to see a stable to downward trend of PSA compared to baseline.
If PSA at the end of the month is significantly higher than at baseline, then you are not a favorable responder and you should drop/stop further BAT. If it is the same, or preferably lower than baseline, then you can consider refining the regimen to get maximal benefit from a modified BAT regimen. Happy to talk to you about that then if this is the case.
Now what you need to do is to find a physician willing to support you in the test regimen and prescribe the testosterone cypionate.
OK great thank you for the protocol, I have a cpl oncologists/urologists that have prescribed it in the past and were open to it when I mentioned it. I’m scheduled for a psma scan at the end of the month n will bring it up to them again and keep you posted, thanks again for all the info…
Thank you for sharing this article Cujoe. I've found it fascinating and I hope this research leads to fewer cases of castration resistant and NEPC versions of prostate cancer.
KocoPr - In the ~5 years that my "urologist" (sic) monitored my rising PSA, my T was never tested. So, the first T lab I ever had in my life was at my pre-op prior to my RALP at my cancer center. Testosterone was 127!! Granted, the blood draw was probably taken in the afternoon when T levels fall (*), but having tested it during the 5 years of monitoring would have likely been another indicator that the PSA rise was due to PCa.
(*) I now have over 40 T labs covering over 20 years. They are all entered into a master hormone spreadsheet and consistently show the significant difference between morning and afternoon labs, which can easily vary over 200 ng/dL when trending in the upper portion of normal levels. I now get all blood draws done by 9:30 AM for the sort of consistency needed to monitor hormones over time. While maybe not needed for hormone draws, I also fast until after the draw and make sure to be well-hydrated as well.
For some stupid reason they don’t measure T with PSA. Why don’t they just order a male hormone panel yearly? They do the CBC and CMP panels but neglect the hormones which are so important for cell signaling and translation.
Another thing they never measure is vitamin B and when they do it just B12 and not a panel like B12 panel to include homocysteine AND MMA (Methyl Malonic Acid). I had to specifically ask for it when my B12 levels showed good but i was suffering from peripheral neuropathy and tinnitus. Even my homocysteine was normal but sure enough my MMA was high which meant B12 was not being metabolized thus normal B12. Oh then i asked for B12 injections and they prescribed a synthetic and semi toxic shelf life stable cyanocobalamin. I found a compounding pharmacy to make bioavailable Methyl B12.
BTW, the more-absorbable methylated form of B-12 is available OTC as methylcobalamin. (At least in the US.) Being mostly WFPB, I have been taking 500 mcg sublingual tabs 2 to 3 times a week for years now with my target being to keep my B-12 in the low end of the upper third of the normal range. This form is a bit more expensive, but not enough to not want to use it instead on the more commonly available cyanocobalamin.
"...low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation"...
I wonder if rapamycin could be used to inhibit mTor early on.
Thanks for the read , BUT I will admit to being a Dumb-Ass and confirm report is above my retired no-income Pay Grade for understanding and so simply hope the following (my OWN devised Protocol) makes minimal sense ---
2014 - PSA RISE and PCP does DRE resulting in LUMP in Right Half of otherwise regular prostate. DO NOT HAVE BIOPSY due to training for Ironman Triathlon + Marathon and Long Distance Bicycling events coming up
2015 - Biopsy done & given Biopsy Results. Told Very Aggressive PCa so Urologist insists on beginning with ADT Drugs but I insist on a bilateral Orchiectomy instead of ADT Drugs
2015 - Have 2nd biopsy confirming GL10 confined to Right Half with lesser in Left
2015 - Cryoablation of Right Half
2015 - Opdivo+Keytruda+Yervoy combo injected into ablated Right Half + IRE of small spots of GL6 & GL7 in left half
2016 - BEGAN biweekly Cypionate Injections with *T* ≥ 1,600ng/dL after injections and down to *T* ≤ 500+/- ng/dL before next injection
2018 - PSA RISE, Axumin Scan showing recurrence in Left Half biopsy = GL6 & GL7 -- IRE Treatment following stopping of Cypionate resulting in *T* ≤ 2.5ng/dL. Remain OFF of Cypionate for months maintaining LOW PSA
2018 - BEGIN Cypionate
2020 - PSA rises have Pylarify PSMA and MRI after stopping *T* injections. NOTHING FOUND and *T* ≤ 2.5ng/dL remain off with LOW *T* AND PSA so begin *T* again
2024 - PSA rapidly RISES to 12ng/mL with immediate Pylarify PSMA showing 3 spots in LEFT HALF so immediate STOPPING Cypionate. 3 months pass before biopsy with PSA = 0.9 ng/mL and *T* = 45ng/dL right before biopsy that shows 3 cores of GL6 in Left Half
2024 - choice of treatment is Watchful Waiting while remaining OFF of Cypionate
2024 - 3 months after biopsy PSA = 0.04ng/ml and *T* ≤ 2.5ng/dL
Currently remaining OFF of Cypionate until next PSA + *T* + other Blood Work and if OK then back to Cypionate to resume rollercoaster of *T* ≥ 1,600ng/dL to *T* ≤ 500+/- ng/dL to REMAIN CSPCa
???? what say the EXPERTS ????
p.s. - remember I mentioned I'm a DUMB-ASS. Now this 74yo is going out for a 50 mile bicycle ride.
I’m circling (cycling) back to you on this very interesting thread because of your clinical situation of G6 with 3 PSMA positive spots in left Half of Prostate. With localized well identified disease Like that I would go for definitive treatment by radiation such as external beam SBRT or HDR Brachytherapy. And consider pelvic LN fields as well. At least discuss with RO. Perhaps short term adjuvant ADT in your case?
Even As someone who unfortunately just recently failed his B.A.T. Trial because of progression, I’m happy this option is starting to become more mainstream. The Q.O.L benefits are incomparable to ADT/inhibitor treatment. The disappointment that this didn’t work for me is second only to the original dx. I’m back to hot flashes every 40min, raisin balls, ejaculating dust, nausea at the onset of hot flushes, zero drive and limbido, crashing fatigue, short term memory problems and everything being harder at the gym. It’s crushing to go from almost feeling normal again back to hell. I wanted this to work for me so bad. I will adjust, because, well because it’s either I do or die, but I sure hope they keep at this and maybe find out why it fails some and helps others. It’s that important. Perhaps I’m younger than most ppl that get mPC at 48, but I can’t imagine that at any age it’s the SO of SOC is easily acceptable.
My mission as long as I’m here is to do whatever I can to contribute to the movement of a SOC less morbid than what is basically our only choice of survival. I pray and hope the next generation doesn’t have to suffer like we do.
Love it as affirmation to alternative methods and medicine validation!
Hate it because right now, I'm deep into SOC with an added genomic drug that's all working! Scared from the onset of hormonal therapy because of the knowledge of eventual resistance and progression as prescribed in the methodology given daylight in the study above, and others. Have ventured down the MED vs MTD with my MO and even BAT which he vehemently opposed for "Me" and "My" presentation of my PCa.
Question for me, as I'm approaching the typical threshold (in time) whereas resistance presents itself, is do I push for a change PRIOR to it happening? Man oh man... My brain will be in overdrive now, lol.
Some here know my story, a complicated mess. So always going forward is a conundrum! In any event I'm always appreciative of those who stay in the arena, searching and sharing these cutting edge avenues available to us all. Great stuff!!!
It appears to be the same one I posted yesterday - that I was excited by until I realized it was in-vitro and in mice, not humans. It's perhaps exciting info - but does it translate to human PCa? If it does - how long before the human trials begin?
Just wondering..
I think if you want TA's read on it - that thread has his response to being asked to review it.
3 replies on that thread and no TA... Wonder if his response was removed? Hmmmm?
Mice or men, cell structure research begins in the lab. Shall we discuss the dozens of cell types used for PCa research and only the few that translate to pharmaceutical use? How they look for the most common but not necessarily the less so? Identifying mechanisms of action is extremely beneficial as well. And yes, very few results translate from mice TO men, lol.
Doesn't make it any less interesting or valuable to venture down untraveled paths, identify new agents and methods to figure that this. If, and it's a big "IF" resistance mechanisms can be identified and counteracted, it would be a huge, very HUGE step in PCa therapy.
Anyways, it's all good stuff! Not sure why you lost excitement, there's some good stuff in that study!
Cross-linking posts between forums used to be frowned upon - at least between Malecare curated forums and this one. I always assumed that was in regard to linking from there to here? I think all regular readers here are fully capable of coming to their own conclusions about research related to PCa and health.
This reader isn't capable of understanding your last sentence. Is it an indirect way of pointing out that "guru" commentaries are not considered prime-time material here?
great study and exposition Yes every patient with APC should Read's it and understand the Major points. Absent that, if facing progression, whether HS or CR, it is certainly worth a personal trial to know if One Is a favorable responder to BAT or not. Those still hormone Sensitive (ADT STILL WORKS) seem to do even better than the CR on BAT. MB
I am wondering if it is the same mechanism that (evidence so far) makes intermittent ADT at least as good as continuous ADT in HSNMPC, for example:
Intermittent Versus Continuous Androgen Deprivation Therapy for Biochemical Progression After Primary Therapy in Hormone-Sensitive Nonmetastatic Prostate Cancer: Comparative Analysis in Terms of CRPC-M0 Progression
Stefano Salciccia1 ∙ Marco Frisenda1 ∙ Antonio Tufano1 ∙ … ∙ Susanna Cattarino5 ∙ Alessandro Sciarra4 alessandro.sciarra@uniroma1.it ∙ Alessandro Gentilucci4 … Show more
Received May 4, 2023; Revised June 26, 2023; Accepted August 18, 2023; Published online September 8, 2023
Graham - It has been suggested that IADT would "outperform" continuous ADT, if no "induction period" (i.e., 12 to 18 months of continuous ADT) was used before starting the cycling. The notion being that the heterogeneity of the cancer has already advanced during the induction period and, thus, the loss of full effectiveness of the on-off cycling in an adaptive sense.
Moffit got better results (in the best responders) in their small (16 patients) in-house PCa trial using the adaptive approach of treating for a 50% reduction from PSA nadir and then re-treating when PSA doubled. Rinse and repeat. The cycles varied for individual patients as further evidence of the individual nature of PCa, esp. as progression occurs. (As Moffitt was using PSA exclusively for the cycle duration determinant, I wonder if, in view of the Duke research, they have cyclical T labs results that could now be correlated to see how T cycles relate to those of PSA; i.e., did the two best performers have robust T- rebounds on the off cycles that might explain their superior responses?)
Here is a link to the full report of the trial results (complete with data for each on the 16 trial participants):
Evolution-based mathematical models significantly prolong response to abiraterone in metastatic castrate-resistant prostate cancer and identify strategies to further improve outcomes, by Jingsong Zhang, Jessica Cunningham, Joel Brown, Robert Gatenby, Department of Genitourinary Oncology, Moffitt Cancer Center and Research Institute, United States; Department of Integrated Mathematical Oncology, Moffitt Cancer Center and Research Institute, United States; Department of Biological Sciences, University of Illinois at Chicago, United States; Cancer Biology and Evolution Program, Moffitt Cancer Center and Research Institute, United States, eLife - Research Article, Evolutionary Biology Medicine, Jun 28, 2022.
When dissonance is present, in addition to trying to reduce it, the person will actively avoid situations and information which would likely increase the dissonance.”
― Leon Festinger, A Theory of Cognitive Dissonance
So the question is if my PSA is slightly rising on both T and ADT cycles does this mean BAT is failing?
I think we don't know because it does not show if c-MYC is being suppressed but does show I am having more Androgen receptor activity.
Will my AR convert to more Dimers?
How do we know when the scale is tipped to favor more dimers vs monomers?
Presently all we can rely on is scans and unfortunately PSA rise.
Any Ideas?
I just finished my first 30 day ADT cycle of my new cBAT protocol and was surprised my PSA didn't drop down more than it had. But still shows Orgo/Daro still working.
I am presently on my 2 month High T cycle with every 2 week cypionate injections. Hopefully this resets the Dimer:Monomer ratio.
Koco - One of our resident BATers can maybe add some insight to your results. However, you might also consider using my personal trend "algorithm", which says that 3 lab results sequentially in the same direction define a trend, while, importantly, a fourth one serves to "confirm" it. Using that criteria, it will be your next result that might suggest consideration of a change in your current BAT routine.
And, altho' he is no longer active here, this presentation (Aug 23, 2023) by Russ Hollyer (and his internally linked book) may be useful in formulating any changes to BAT cycles and/or ADT drugs that you might consider.
Thank Cujoe! I am PCL warrior and have Russ’ book. I reference it often.
I like your trend idea. I think with BAT and this new info on AR dimers and monomers i am hoping two months of high T will repopulate the AR dimer:monomer ratio. There just no way to measure these AR without a biopsy and a lab that can do it.
as long as ADT brings PSA down that’s the trend i will have to go by.
Little doubt that we all would benefit by better diagnostic (and treatment) "precision". But outside of clinical trials, it can be difficult to get a doc to authorize any form of it. (as you note.) I'm seeing my MO tomorrow and will bring up CTC testing again. (He did get me into the STRATA trial back in July 2017. That CT was a "matching trial" that tested for a wide range of cancer-related mutations known at that time. Zero mutations! in a family with near universal multi-generational cancer. But the test criteria was not-PCa specific, was on tissue from my 2013 prostatectomy, and the mutations in my cancer have surely changed since 2013.)
We are all pulling for you to get your BAT program perfected for best outcome.
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