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Loss and revival of androgen receptor signaling in advanced prostate cancer

pjoshea13 profile image
26 Replies

New Swiss paper[1].

These guys neatly sum up my negative feelings about the scorched earth approach to the androgen receptor [AR] axis. If you can't kill it, you make it stronger.

Anyone have access to the full text? Can't get to it via Sci-Hub.

"Targeting the androgen receptor (AR) signaling axis has been, over decades, the mainstay of prostate cancer therapy. More potent inhibitors of androgen synthesis and antiandrogens have emerged and have been successfully implemented in clinical practice. That said, the stronger inhibition of the AR signaling axis has led in recent years to an increase of prostate cancers that de-differentiate into AR-negative disease. Unfortunately, this process is intimately linked with a poor prognosis. Here, we review the molecular mechanisms that enable cancer cells to switch from an AR-positive to an AR-negative disease and efforts to prevent/revert this process and thereby maintain/restore AR-dependence."

Wondering if they mention BAT.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/334...

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26 Replies

Is this it?

nature.com/articles/s41388-...

pjoshea13 profile image
pjoshea13 in reply to

Yes it is - thank you!

Best, -Patrick

treedown profile image
treedown

So concern of over treatement can be added to success of same treatment. Whats one more target on my back.

pjoshea13 profile image
pjoshea13 in reply to treedown

Yes, & some would say it is cruel to mention it, but I do believe that "forewarned is forearmed".

-Patrick

treedown profile image
treedown in reply to pjoshea13

Nicely put. This particular issue weighs heavy on me right now.

pjoshea13 profile image
pjoshea13

OK - thanks to RSH1 we have the full text.

I'll just mention the BAT-like references.

[1] "Supraphysiological Testosterone Therapy as Treatment for Castration-Resistant Prostate Cancer"

"Blocking androgen signaling has been the focus of treatment for advanced and metastatic prostate cancer (PC) for the past 70 years (1). First-line androgen deprivation therapy (ADT), either through surgical or medical castration (luteinizing hormone-releasing hormone agonists and antiandrogens), holds promise for PC patients; however, the disease inevitably progresses to castration resistance (2). Second-generation ADT, abiraterone acetate (AA), and enzalutamide (ENZ), have been effective for a subset of patients with castration-resistant PC (CRPC) with relatively short median survival benefits (~3–5 months) (3–5). Concerted effort in the field, including evidence from our group, clearly demonstrates a sustained AR activity in the CRPC tumors including (1) amplification of AR, (2) AR mutations, (3) expression of AR splice variants that are constitutively active, (4) altered milieu of AR coactivators and corepressors, and (5) intracrine synthesis of androgens to support CRPC progression (6, 7).

"The addiction of PC to the AR signaling paradoxically creates a therapeutic vulnerability that has recently attracted increasing attention. While ADT causes regression of PC, high level of androgen can also inhibit PC progression. The concept of cancer suppression using excessive hormone therapy was introduced by earlier work from Huggins in 1940: “malignant cells can regress from too little or too much hormone” (8). In relation to PC, AR regulates proliferation as well as differentiation of prostate epithelial and cancer cells but it has not been established what conditions support one over the other. Interestingly activation of AR with excessive hormone (i.e., supraphysiological levels of testosterone; SPT) was shown to inhibit growth of CRPC in vitro by negative effects on proliferation and increased expression of some of the AR-regulated genes that are expressed in differentiated luminal epithelium, e.g., prostate-specific antigen. ..."

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

"Prostate cancer that progresses after enzalutamide treatment is poorly responsive to further antiandrogen therapy, and paradoxically, rapid cycling between high and low serum testosterone concentrations (bipolar androgen therapy [BAT]) in this setting might induce tumour responses."

[3] "Supraphysiologic Testosterone Therapy in the Treatment of Prostate Cancer: Models, Mechanisms and Questions"

"Since Huggins defined the androgen-sensitive nature of prostate cancer (PCa), suppression of systemic testosterone (T) has remained the most effective initial therapy for advanced disease although progression inevitably occurs. From the inception of clinical efforts to suppress androgen receptor (AR) signaling by reducing AR ligands, it was also recognized that administration of T in men with castration-resistant prostate cancer (CRPC) could result in substantial clinical responses. Data from preclinical models have reproducibly shown biphasic responses to T administration, with proliferation at low androgen concentrations and growth inhibition at supraphysiological T concentrations. Many questions regarding the biphasic response of PCa to androgen treatment remain, primarily regarding the mechanisms driving these responses and how best to exploit the biphasic phenomenon clinically. Here we review the preclinical and clinical data on high dose androgen growth repression and discuss cellular pathways and mechanisms likely to be involved in mediating this response. Although meaningful clinical responses have now been observed in men with PCa treated with high dose T, not all men respond, leading to questions regarding which tumor characteristics promote response or resistance, and highlighting the need for studies designed to determine the molecular mechanism(s) driving these responses and identify predictive biomarkers."

-Patrick

[1] ncbi.nlm.nih.gov/pmc/articl...

[2] ncbi.nlm.nih.gov/pmc/articl...

[3] mdpi.com/2072-6694/9/12/166

in reply to pjoshea13

As you probably know, I did 6 months of estrogen patch ADT. I've been doing SPT ever since. 400mg a week of T cyp. An AI to keep my E2 20-30. T is >2100. I'm using cabergoline to drop my prolactin (currently 1.1). Nice side effect is that I have good fat loss from the cab. I verified once. I need to do that again sometime.

I was using DHT blockers but stopped taking them about 4 weeks ago. My DHT has already gone up a lot (from 32 to 150). I'm having my PSA measured. An experiment of sorts.If my PSA or cancer progresses I'll go back on the DHT blockers. If it still gives me problems I'll go low T until (hopefully) things go back to "normal". Then SPT.

cigafred profile image
cigafred in reply to

As you know I have been struggling with the DHT question--so please let us know the result of this experiment. Many thanks.

in reply to cigafred

We're both struggling with the DHT question. I will let you know how it goes. I'm expecting some kind of answer, at least with PSA, in the next couple of weeks.

Justfor_ profile image
Justfor_ in reply to

I have been experimenting with my DHT as well. For 2+ months I had reduced Avodart to one every other day compared to daily. No remarkable change observed.

The absolute value went up from 0.46 -> 0.45 -> 0.48 ng/ml (normal range 0.03-0.65) and the DHT/tT ratio 4.06 -> 3.88 -> 4.15%. The only time my DHT doubled from this (0.93 ng/ml and ~9%) was at a time that I had run short of my statins for 8 days. This is another indication to my suspicion that my PCa is related to my familial hyperholisterolemia. During these 8 days my tCholesterol went from ~150 to 200. With no statins it climbs to 320-350.

LearnAll profile image
LearnAll

Patrick...Glad to see that more and more research is now openly saying that strong and continuous suppression of Androgens by lupron type meds and anti androgens...cause differentiation to androgen independent, more aggressive type prostate cancer.One more study in favor of use of Intermittent ADT and use of diet, herbs, spices ,immune modulators as supportive complementary substances..

Just wait.. more news is on the way that potent anti androgens like Zytiga, Extandi are more likely to cause castration resistance than old fashioned milder Anti Androgens like Bicalutamide.

The reason I keep insisting to our fellow members that we need to KNOW our Prostate cancer whether it is mild, moderate or severely aggressive...to prevent anyone giving us too strong androgen suppressors. Nail in the coffin of so called "soc" aka ..Sub-standard care.

pjoshea13 profile image
pjoshea13 in reply to LearnAll

My wife is on a drug for a cancer for which there is no cure. She is doing very well. When she asked how long she would have to be on it, she was told "Until it stops working."

It's the dirty little secret of palliative cancer meds. There will be treatment-emergent adaptations. You may buy time upfront, but there will be a cost at the backend.

For many there is no choice, but I feel that men here should ask about Plan B.

Apologies for sounding so grim on a delightful sunny day in western North Carolina.

Patrick

Schwah profile image
Schwah in reply to LearnAll

I understand the point you were making. However, it doesn’t seem to coincide with what I understand to be the science. Men with metastatic prostate cancer were found (in the Stampede and Latitude trials) to live 40% longer if they took Lupron and Zytega As opposed to lupron alone. The added survival times were huge. How can you reconcile that with what you are saying?

Schwah

Concerned-wife profile image
Concerned-wife in reply to Schwah

Excellent question

cigafred profile image
cigafred in reply to Schwah

Yes, excellent question. When I was at Tulane to talk about BAT while still castrate sensitive, they pushed in the direction of adding Xtandi/Zytiga to Lupron instead.

noahware profile image
noahware in reply to Schwah

In advance of LearnAll's own reply and independent of it, let me address his comment that "we need to KNOW our Prostate cancer whether it is mild, moderate or severely aggressive" in the context of extending survival.

The problem, of course, is that we often DON'T know or can't know. But if we suppose we DO know one man's cancer is HIGHLY aggressive, then we might also suppose he needs the most aggressive treatments. Perhaps he can double his survival from a year to two years. Does it really matter if the cancer is going to be made more resistant by treatment, or evolve into a more lethal variant? Well, no, not if the cancer was going to quickly kill him anyway in its "less lethal" form. And this certainly applies, too, if the cancer was causing pain or other symptoms: you need WHATEVER treatment works best NOW, as relief.

But if we suppose some other man's cancer is NOT aggressive, and he is without pain or symptoms, then could we suppose he might POSSIBLY not need the most aggressive treatments? Perhaps he is destined to survive many years with a less aggressive treatment. Does it really matter if the cancer is going to be made more resistant, or evolve into a more lethal variant, by way of instead pursuing a too-aggressive approach? Well, yes, it might, if the cancer now evolves to a variant that will more quickly kill him its "more lethal" form.

If he was an individual that might have lived ten years, it seems possible that some certain variations of over-treatment might actual shorten that survival. The fact is, the median survival benefit that appears in these studies appears when half the men are dead and half are still alive. The men in the WORST shape die right away regardless of which study group they are in, and sometimes it appears neither treatment regime was of any use at all to some of them.

But then there are also the men in BOTH study groups who survive well past the median. What do we actually know about how the two treatment regimes being studied impacted their extended survival? We know very little, both because the study has ended well before their lives have ended, and because the sample size has now been reduced to the point of being an under-powered study size.

So we have three categories of men in these studies:

1) early die-ers, who get no superior benefit from either treatment

2) middle die-ers, who DO get a statistically significant benefit

3) late die-ers, who do not reveal many details about relative harms/benefits

So what is the "typical" man? In any group, it is the eventual death of a SINGLE man that defines the half-dead/half-still-alive median point. Obviously, "most men" are not THAT man. He is "Median Man" and is used to represent all the men in his group.

So I see LearnAll's point as, how is it that we might determine how close to, or how far from, that "Median Man" EACH of us might be, so far as the nature of our individual cancers. Our docs can guess, but they can't always tell us. Plenty of stories around here about docs telling men they will be "early die-ers" and those docs being wrong.

I am not advocating for or against any particular treatment regime, for any particular man, as NECESSARILY better or worse. I am just pointing out that we don't know what we don't know.

I think this "not knowing" can go back, for example, to a decision to get an RP upon diagnosis: a man and his surgeon face three possible scenarios: 1) you get an RP that you never really needed (because your cancer was never destined to progress to being lethal), OR, 2)you get a life-saving RP that effectively cures you of a cancer that WAS destined to progress to being lethal, OR, 3) you get an RP that ends up being futile (because your cancer was already destined to progress to being lethal, even before and in spite of RP).

Schwah profile image
Schwah in reply to noahware

What you are saying sounds totally illogical to me. If a man had metastic PC disease, his cancer is aggressive to at least some degree. And with proof out there that Iggy here and zytega together reduce deaths by over 40%, for men with metastatic disease, it seems crazy to me to not avail oneself of that treatment regimen. At least not until some solid evidence comes out indicating that some subset of men with metastatic disease will live longer without this treatment, And some way of determining who falls into that subset.

Schwah

noahware profile image
noahware in reply to Schwah

"aggressive to at least some degree"

Yes, the mets appear to tell us that. But to WHAT degree? Because it is well documented that many men will die WITH their PC without even knowing they ever had it, and some of those men will have begun the metastatic process without it ever having proceeded to present symptoms. So that "aggressiveness" never manifested clinically, for at least some subset of men.

An interesting question would be: is it possible that some of these men who never knew that had cancer would have ended up with MORE aggressive cancer, had their cancer been discovered and subjected to a certain aggressive treatment? I don't see how we could say that is NOT possible.

The fact is, there will never be "solid evidence" in clinical trial form that comes out indicating that some subset of men with metastatic disease will live longer without a certain "better" treatment, for the reasons I mentioned.

I think it helps to actually look at a study's survival curve, and think about what you are seeing: right off the bat, men in BOTH groups start dying. And we KNOW the cause of their deaths.

But once we get well beyond the median survival points for both groups, you will see men in BOTH groups continuing to survive. Do we know what is "causing" then to stay alive? No. Among the possible "causes" of continued survival are the interaction AT LEAST two very important things: 1) the nature of the cancer, and 2) the nature of the treatment.

How would you know that the treatment that helps many men in the near term might not be harmful to SOME men, in the long term? To me, it seems much more logical to assume there IS such a subset. Why wouldn't there be, given the phenomenon of "resistance" selection and evolution that occurs across so many ecosystems in nature? Why would I assume the cancer-cell ecosystem is an exception to normal mathematics of population ecology?

Now, if you look at a study where most of the men are dead in three years and there is a clear statistical benefit for one treatment, where median survival is extended from 12 months to 18 months, for example, then you would certainly want that treatment... IF you have the kind of cancer that leads you to an expectation of a good likelihood of being dead in three years!

That might be a guy with very high PSA, very high Gleason, very heavy or visceral met burden, very symptomatic, who is very advanced in age and has very advanced cancer that has already initially proven very resistant to treatment. His outlook is not good, and he need have little concern if the best treatment NOW causes treatment resistance later.

But what if you are a guy with a relatively LOW Gleason, PSA and met burden? And you are a "great responder" to your initial treatment? You might then have reason to believe (or at least hope) that you are in the subset of men surviving well past the median length of survival in a group of men generically labelled "metastatic." You then might think that ways to avoid becoming CR could be important in the long run, because there might actually be a "long run" in your future!

And some way of determining who falls into that subset? That, as I said, is the problem. You can't know. Just as many men can't know in advance of an RP if it is providing cure that is BOTH definitive AND necessary. Of the three scenarios I mentioned, what do you suppose the true breakdown for "cure possible and achieved" vs. "cure not actually needed" vs. "cure hoped for but not actually possible" might be, for all the men who ever had an RP?

treedown profile image
treedown in reply to Schwah

Isn't the whole Gleason, Stage, etc an attempt to determine if the cancer is a dove or a vulture as Learnall calls it. I wonder if a man's reaction to the drugs he is treated with is any indication to what his treatment should be. Does a man who does well with limited side effects any indication of said use of aggressive drugs vs a man who cannot stand to be on even one of the drug options. I also note that for my level of disease NCCN states the "preferred" level of treatment is the most minimal. I can see that Drs are given a road map to follow and very few want to take alternate routes to their destination.

pjoshea13 profile image
pjoshea13 in reply to Schwah

With M1 PCa (distant mets) 70% will die within 5 years on SOC. ADT will have failed in the first 2 years for most.

ADT + Abiraterone has a longer mean-time to failure, so deaths are delayed - better survival for those otherwise fated to die within 5 years, say.

But failure of Abi potentially leaves one in worse shape than failure of ADT. You would need to follow all of the men through death to see the full picture.

With longer follow-up we will know more.

-Patrick

6357axbz profile image
6357axbz

Can we only see the Abstract?

pjoshea13 profile image
pjoshea13 in reply to 6357axbz

courtesy of RSH1:

nature.com/articles/s41388-...

Magnus1964 profile image
Magnus1964

After two decades of ADT drugs my cancer cells must be super charged.

MateoBeach profile image
MateoBeach

Here is a full text pdf from Naturenature.com/articles/s41388-...

Is that the right one?

pjoshea13 profile image
pjoshea13 in reply to MateoBeach

Thanks!

Tall_Allen profile image
Tall_Allen

A lot of misinterpretation is going on among several patients here. The data are telling us that as patients live longer with prostate cancer because of wonder drugs like Zytiga and Xtandi, the cancer may sometimes progress to an AR negative state. Typically, the opposite happens - AR amplification. That is why Lupron is always continued through castration resistance. It is hoped that the newest antiandrogens, Erleada and Nubeqa, will curtail AR overexpression. ARV110 is a medicine in clinical trials that was specifically designed to degrade the overexpression of the AR.

However, a minority of patients lose surface AR expression. For those patients, the goal is to recover the vulnerability of the AR to hormonal agents, or to target other surface proteins (like PSMA). Clinical trials of medicines like CPI1205 or CC-99011 may reverse the AR- condition. Medicines like Lu-PSMA-617 or AMG 757 target alternative proteins.

What patients should NOT do is slow down use of second-line hormonal agents. Use of these agents should not be limited by concern for the subsequent development AR negative prostate cancer. That would be like cutting off your nose to spite your face. They have been proven in multiple randomized clinical trials (STAMPEDE, LATITUDE, ARCHES, TITAN and ENZAMET) to delay the onset of castration resistance and to extend survival compared to ADT only or ADT+Casodex. Hitting it early and heavily has been proven to delay castration resistance significantly.

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