Testosterone metabolites inhibit proliferation of castration- and therapy-resistant PCa.

[pjoshea13]

New German paper [1].

I mention elsewhere how in normal prostatic cells, the presence of growth-stimulating dihydrotestosterone [DHT] induces an enzyme for its rapid clearance, & that a DHT metabolite - 3beta-adiol - is the natural ligand for an estrogen (!) receptor, ERbeta.

ERbeta is the estrogen receptor found in normal prostatic epithelial cells. It resist the growth-promoting influence of ERalpha, found in the stroma. Unfortunately, ERbeta is lost in PCa & ERalpha takes it place.

"Cell lines were treated with testosterone, dihydrotestosterone (DHT), R1881, and the androgen-metabolites 3β-androstanediol and 3α-androstanediol. 3β-androstanediol {3β-adiol} or 3α-androstanediol {3α-adiol} significantly reduced proliferation in all cell lines except the BPH-1 and androgen receptor-negative PC-3 and markedly downregulated AR and estrogen receptor alpha (ERα). Whereas ERβ expression was increased in all cell lines except BPH-1 or PC-3. In summary, 3β-adiol or 3α-adiol, as well as DHT and R1881, significantly reduced tumour cell growth in CRPC cells. Thus, these compounds represent novel potential therapeutic approaches to overcome drug-resistance in CRPC, especially with regard to AR-V7 function in therapy resistance. Furthermore, these data confirm the tumour suppressor properties of ERβ in CRPC."

What is remarkable here is that the introduction of T/DHT could affect the ERalpha:ERbeta balance in those cells. Perhaps this happens in BAT therapy too?

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/296...

Oncotarget. 2018 Mar 30;9(24):16951-16961. doi: 10.18632/oncotarget.24763. eCollection 2018 Mar 30.

Testosterone metabolites inhibit proliferation of castration- and therapy-resistant prostate cancer.

Bremmer F1, Jarry H2, Unterkircher V1, Kaulfuss S3, Burfeind P3, Radzun HJ1, Ströbel P1, Thelen P4.

Author information

1

Institute of Pathology, University Medical Center, Göttingen 37075, Germany.

2

Department of Experimental Endocrinology, University Medical Center, Göttingen 37075, Germany.

3

Institute of Human Genetics, University Medical Center, Göttingen 37073, Germany.

4

Department of Urology, University Medical Center, Göttingen 37075, Germany.

Abstract

Novel treatments for castration-resistant prostate cancer (CRPC) such as abiraterone acetate (AA) or enzalutamide effectively target the androgen pathway to arrest aberrant signalling and cell proliferation. Testosterone is able to inhibit tumour cell growth in CRPC. Estrogen receptor-beta (ERβ) binds the testosterone-metabolites 3β-androstanediol and 3α-androstanediol in parallel to the canonical estradiol. In the prostate it is widely accepted that ERβ regulates estrogen signalling, mediating anti-proliferative effects. We used the prostate cancer cell lines LNCaP, PC-3, VCaP, and the non-neoplastic BPH-1. VCaP cells were treated with 1 nmol/L testosterone over 20 passages, yielding the cell line VCaPrev, sensitive to hormone therapies. In contrast, LNCaP cells were grown for more than 100 passages yielding a high passage therapy resistant cell line (hiPLNCaP). VCaP and hiPLNCaP cell lines were treated with 5 μmol/L AA for more than 20 passages, respectively, generating the AA-tolerant-subtypes VCaPAA and hiPLNCaPAA. Cell lines were treated with testosterone, dihydrotestosterone (DHT), R1881, and the androgen-metabolites 3β-androstanediol and 3α-androstanediol. 3β-androstanediol or 3α-androstanediol significantly reduced proliferation in all cell lines except the BPH-1 and androgen receptor-negative PC-3 and markedly downregulated AR and estrogen receptor alpha (ERα). Whereas ERβ expression was increased in all cell lines except BPH-1 or PC-3. In summary, 3β-adiol or 3α-adiol, as well as DHT and R1881, significantly reduced tumour cell growth in CRPC cells. Thus, these compounds represent novel potential therapeutic approaches to overcome drug-resistance in CRPC, especially with regard to AR-V7 function in therapy resistance. Furthermore, these data confirm the tumour suppressor properties of ERβ in CRPC.

KEYWORDS:

3a-androstendiol; 3b-androstendiol; AKR1C1; AKR1C2 and AKR1C3; castration resistant prostate cancer

PMID: 29682196 PMCID: PMC5908297 DOI: 10.18632/oncotarget.24763

[FCoffey]

Thanks. The full paper is available at

oncotarget.com/index.php?jo...

The work was performed on 2 prostate cancer cell lines, grown in the lab.

This is almost certainly relevant to what happens in BAT. OTOH, were it that simple most or all men on BAT would see their cancer shrink. It hasn't worked that way; although the early results are quite promising they are not that good. What is certain is that essentially 100% of the men on BAT report large improvements in quality of life.

[pjoshea13 in reply to FCoffey]

Thanks for the link, but it didn't come across clean. I did find the paper & maybe the link below will work for those interested:

oncotarget.com/index.php?jo...

ADT induces gain of function via multiple copies of the AR &/or via AR amplification. I recall from old studies that reintroduction of T will deal with the first problem.

With amplification, the AR contains multiple copies of its instructions. It's always seemed like a bad idea to use BAT when amplification is present. Better to start using BAT well before CRPC.

-Patrick

[FCoffey in reply to pjoshea13]

The way this site treats links continues to frustrate me. Anyone know how to make a real HTML link on this forum so that it looks like Follow this link and clicking it opens the linked URL?

The point about BAT before CRPC is a good one. My oncologist and I recently discussed how the tendency to limit many clinical trials to men in the final stages of their journey seriously distorts the results. Immunotherapy doesn't help all that much in the last 6 months of life, but has been shown to lengthen life when given earlier, even if markers like PSA don't seem to improve.

Same with BAT. The theory is sound; the clinical trials very promising, but castration is still the default despite the horrible quality of life impacts and nearly inevitable failure to full on CRPC.

[rust]

Research continues to support benefits of BAT and until sufficient contradictory evidence appears I hope that more clinicians are open to the idea. I am concerned that we as a society are too conservative in progress towards new treatment options that are in opposition to long established beliefs.

[pjoshea13 in reply to rust]

Rust,

Physical or chemical castration has been the norm for as long as I have been alive (70 years). Many people assume that this proves that testosterone in the prime mover in PCa, & disregard the fact that castration is merely palliative & fails quite quickly.

In the old days, when male life expectancy tables were dismal, & a diagnosis came late (no DRE & PSA screening back then), a 2-year respite was a significant benefit.

In the modern era, when so many men are diagnosed at an age where the actuarial tales show perhaps another 20 years for healthy men, the castration paradigm is looking outdated.

-Patrick

[FCoffey in reply to pjoshea13]

Castration, chemical or surgical, offers genuine benefits to men in intense pain from bone mets. It made sense to use it when there weren't any other options. It may still make sense in those particular cases, but most men are diagnosed today at a far earlier stage.

What has happened is that castration has morphed from palliative treatment in late stage cancer to the first line of treatment for men with locally advanced disease or distant metastases. The evidence that this helps men is slim at best, the evidence that it hurts men is ample and growing. Besides the many severe toxicities associated with castration, we now understand that it actively promotes the development of CRPC.

The castration paradigm isn't merely outdated; it is disgraceful that so many men are harmed by this ineffective and brutal treatment.

[curious-mind]

I see you points about the dangers of ADT, but what should I tell/ask my dad's oncologist who is treating him for Stage IV PCa with a few bone mets? The mets were identified three years ago, when ADT3 was deployed along with Zytiga + Avodart, metformin and aspirin, he's now been undetectable for over a year, the mets (as of 6 months ago) have dissipated.

He's lost muscle mass, but other than that feels fine.

His oncologist doesn't want to touch the protocol, since "you shouldn't get off a winning horse". Do I ask for stoppage of ADT and a move to BAT? I would support any therapy that would give my dad the best chance at longer meaningful survival with this disease, but it just seems to hard to find out what to do. The conversional wisdom is ADT for life, but then again I'm reading lots of insight that suggests otherwise...

Arthur

[pjoshea13 in reply to curious-mind]

Arthur,

"The conversional wisdom is ADT for life" - true enough - but "life" is optimistic. Most men on ADT alone become resistant within 18-24 months. Zytiga + Avodart & metformin should extend effectiveness, perhaps significantly, but, depending on age, one shouldn't expect the protocol to be effective forever.

The problem with resistance is that the PCa cells will have evolved to a state where they are difficult to manage. A potential benefit of BAT is that the monthly testosterone [T] shots interfere with the adaption to very low T levels. BAT might delay CRPC indefinitely in some men.

You might want to get an opinion from someone at Johns Hopkins who is involved with BAT. Dr. Sam Denmeade heads up the research.

-Patrick

[curious-mind]

Thanks, Patrick for the info, we'll definitely start looking BAT up. Is it accurate to say that if my dad stays undetectable, this delays the progression of the disease, since it means the number of actual PCa cells in his body is too low to create a dangerous number of CRPC cell mutations?

We're hoping that every month or three that he remains undetectable is buying him time in the future, when new therapies might emerge for CRPC.

Lastly, is it possible to use BAT when someone is already CRPC?

Thanks,

Arthur

[pjoshea13]

Arthur,

Most of the changes that occur on the way to CRPC are induced by ADT, so it seems reasonable to delay when the PSA doubling time is long.

Some CRPC men do respond well to testosterone:

"A randomized phase 1 study of testosterone replacement for patients with low-risk castration-resistant prostate cancer.

ncbi.nlm.nih.gov/pubmed/192...

Denmeade's latest published study is:

"Bipolar androgen therapy in men with metastatic castration-resistant prostate cancer after progression on enzalutamide: an open-label, phase 2, multicohort study."

ncbi.nlm.nih.gov/pubmed/292...

-Patrick

[curious-mind]

Thanks, Patrick, will read up those papers.