CRPC - causes and prevention of - Advanced Prostate...

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CRPC - causes and prevention of

Scout4answers profile image
44 Replies

This is the first time I have seen this explanation of why we become CRPC, do we know this to be true? This sounds like Gatenby's theory of killing off the weeds in a field allowing the non effected weeds to prosper.

Does radiation kill these cells as well?

This excerpt came from an NIH paper that Magnus referenced in another Post about Imimpramine Antidepressant

Although castration-resistant prostate cancer (CRPC) as a whole, by its name, refers to the tumors that relapse and/or regrow independently of androgen after androgen deprivation therapy (ADT), untreated tumor, even in early-stage primary prostate cancer (PCa), contains androgen-independent (AI) PCa cells. The transformation of androgen-dependent (AD) PCa to AI PCa under ADT is a forced evolutionary process, in which the small group of AI PCa cells that exist in primary tumors has the unique opportunity to proliferate and expand selectively and dominantly, while some AD PCa cells that have escaped from ADT-induced death acquire the capability to survive in an androgen-depleted environment. The adaptation and reprogramming of both PCa cells and the tumor microenvironment (TME) under ADT make PCa much stronger than primary tumors so that, currently, there are no effective therapeutic methods available for the treatment of CRPC. Many mechanisms have been found to be related to the emergence and maintenance of PCa castration resistance; in this review, we focus on the role of inflammatory signaling in both PCa cells and the TME for the emergence and maintenance of CRPC and summarize the recent advances of therapeutic strategies that target inflammatory signaling for the treatment of CRPC.

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44 Replies
Tall_Allen profile image
Tall_Allen

Of course, evolutionary pressure drives castration resistance, but it occurs whether or not AR-targeted medicines are used, and it occurs faster in the absence of those medicines.

Scout4answers profile image
Scout4answers in reply to Tall_Allen

Do we know if radiation kills the Androgen independent PCa cells?

Tall_Allen profile image
Tall_Allen in reply to Scout4answers

It kills all rapidly dividing cells.

Scout4answers profile image
Scout4answers in reply to Tall_Allen

I will take that as a yes, you have also said that Gleason scores do not matter at this point. Because The cancer would have to start over?

Tall_Allen profile image
Tall_Allen in reply to Scout4answers

Because once it is metastatic, therapy is not based on Gleason score.

CountryJoe profile image
CountryJoe in reply to Tall_Allen

For those men who opt to remover their testicles, are they also headed for CRPC?

Tall_Allen profile image
Tall_Allen in reply to CountryJoe

Yes.

CountryJoe profile image
CountryJoe in reply to Tall_Allen

Thank you TA

tennis4life profile image
tennis4life in reply to Tall_Allen

"but it occurs whether or not AR-targeted medicines are used, and it occurs faster in the absence of those medicines." Disagree wholeheartedly. (With all due respect) can you furnish evidence for this? TY

Tall_Allen profile image
Tall_Allen in reply to tennis4life

This has been well known since 1941 when Huggins and Hodges published their Nobel Prize winning study.

aacrjournals.org/cancerres/...

Their work greatly reduced metastasis suffering and increased life span by depriving the AR of androgens. All research since then has delayed progression by developing stronger AR and testosterone blockers.

tennis4life profile image
tennis4life in reply to Tall_Allen

Thanks for your reply TA!

tennis4life profile image
tennis4life in reply to Tall_Allen

Still don't see where untreated Hormone Sensitive PC becomes castrate resistant if left alone. (And/or occurs faster with no ADT)

Tall_Allen profile image
Tall_Allen in reply to tennis4life

Genomic breakdown is a characteristic of cancer. There are always some metastatic cells that are castration resistant from the start. It is why some men never achieve undetectable PSA after initiating ADT, and why ADT is never curative in metastatic men. Some metastatic PCa cells are always castration resistant.

LATITUDE and STAMPEDE (which is ending recruitment, BTW) discovered that completely cutting off all sources of testosterone with abiraterone+ADT from the testes and the adrenals slowed down the occurrence of castration resistance and extended survival. Similarly, complete androgen blockade with enzalutamide (STAMPEDE, ARCHES) or apalutamide (TITAN) slowed the development of castration resistance and death.

It is also why castration resistance occurs at the same time whether or not intermittent or continuous ADT is used (SWOG-9346). The TROG 03.04 RADAR trial examined the duration of hormone therapy in high-risk men treated with radiation. Of course, some had occult mets from the start. They found that, after 10 years of follow-up, men treated with 18 months of ADT survived longer, and reached castration resistance later compared to men treated with 6 months of ADT.

tennis4life profile image
tennis4life in reply to Tall_Allen

Very helpful. Makes sense now. Thanks for taking the time with me!

Nebula777 profile image
Nebula777 in reply to Tall_Allen

Your response to "Still don't see where untreated Hormone Sensitive PC becomes castrate resistant if left alone. (And/or occurs faster with no ADT)" didn't answer his point. You quoted results from 3 different Phase III trials, none of which used "no treatment with ADT" as a control arm. That would be unethical unless you were studying men with Gleason scores <7. All of these trials had control arms using ADT. And in the TROG trial, all men also received radiation therapy (and some zoledronic acid) in addition to 6 versus 18 months of ADT. Just because the TROG trial showed "time to development of castrate-resistant disease was decreased in the 18-month ADT group (HR 0.63, p = 0.004)" doesn't answer the point he made. This string of comments started with a question about the causes and prevention of CRPC. The points made focused on the cause. While you make a good point about castrate-resistant cells being present from the start (before initiation of ADT), plenty of published peer-reviewed articles show certain types of resistance mechanisms in CRPC are rare before treatment with ADT. That implies treatment with ADT and the subsequent lowering of androgens creates pressures at the cellular level to induce resistance and help create the formation of CRPC. In all fairness, you should acknowledge it is a mixed bag as to why CRPC occurs, some of which is related to treatment with ADT regardless of pre-existing castrate-resistant clones.

Citations for articles discussing ADT induced resistance mechanisms.
Tall_Allen profile image
Tall_Allen in reply to Nebula777

The original work establishing that androgen deprivation vs no androgen deprivation was done in 1941, as I said.

aacrjournals.org/cancerres/...

After that, it would be unethical to have a clinical trial where no ADT is given.

The point I was making in citing the many Phase III trials is that there is what is called a "dose effect": more powerful hormone therapy causes castration-resistance to occur later and for survival to increase. Far from "a mixed bag", it is consistent across all studies.

As I said, "Of course, evolutionary pressure drives castration resistance, but it occurs whether or not AR-targeted medicines are used, and it occurs faster in the absence of those medicines."

Do you have any evidence that that is not true?

PCaWarrior profile image
PCaWarrior

CRPC occurs in response to ADT. Cells dominate that can live without androgens, and, once they are dominating, they send signals to the androgen feeders to join their tribe. And of course some of the remaining androgen feeding cells upregulate and mutate their ARs. We're making their food scarce so they must adapt. This has been well studied. As many MOs state: every second on ADT is another second towards CRPC.

Scout4answers profile image
Scout4answers in reply to PCaWarrior

I have heard this said before do you have a reliable source or a randomized test result?

PCaWarrior profile image
PCaWarrior in reply to Scout4answers

Various studies. Conversations with my MO. Consults with others. Biology.

"Given enough time, prostate cancer cells can adapt to the changing environment. Those cells unable to adapt will die. Prostate cancer cells respond to the low testosterone conditions by markedly increasing the level of the AR glove to catch any testosterone that remains after therapy (Figure 2). Levels of the receptor can increase 100-fold or more. These cells fine-tune the level of the AR until they find the “sweet-spot” that allows them to grow again despite the low level of testosterone in the body. As ever more intensive hormone therapy is given, the prostate cancer cells further adapt. Castration resistance is not unexpected, it is the inevitable outcome of chronic, prolonged exposure to AR blockade."

onlinelibrary.wiley.com/doi...

"Several pathways are involved in the development of CRPC: (i) androgen receptor

(AR) amplification and hypersensitivity, (ii) promiscuity-causing AR mutations, (iii) mutations in coactivators, and (iv) intratumoural and alternative androgen production"

mdpi.com/2227-9059/11/3/826...

You could always ask your MO for their opinion.

Purple-Bike profile image
Purple-Bike in reply to PCaWarrior

The first study linked to in your post shows a statement without reference, and I believe it's similar in the second link. Not much compared to the Latitude, Stampede and other studies mentioned on this thread showing a longer time to castration resistance with longer time of androgen deprivation therapy.

Given that I quit ADT after 10 months, and just five months after met-directed radiation, I wish what you indicate is true but I fear it is not. My PCa is undetectable 18 months after quitting ADT and time may tell if I was foolish or not.

PCaWarrior profile image
PCaWarrior in reply to Purple-Bike

Denmeade made the statement. I believe that he knows a few things about prostate cancer.

PCaWarrior profile image
PCaWarrior in reply to Scout4answers

I was researching olaparib and found this:

dovepress.com/enzalutamide-...

"The adaptive response to androgen deprivation pressure

In recent years, scientific knowledge about PC biology and growth has substantially improved. Nowadays, it is well established that the progression from HSPC to CRPC is not determined by a true ADT resistance, but by an adaptation of PC cells to a microenvironment with reduced testosterone levels. In fact, notwithstanding the deep decrease in serum androgen levels caused by ADT, PC cells could synthesize androgens and could modify AR in a way that even low androgen levels could activate it.

The mechanisms responsible for this phenomenon are related to the selective pressure of ADT and include AR gene overexpression, AR gene mutation, AR variant of splicing (ARsv) expression, upregulation of transcriptional coactivators and overexpression of enzymes able to induce the production of androgens.19,21"

If PC cells aren't subjected to a low testosterone environment, then how and why would they adapt to it?

Spyder54 profile image
Spyder54

so what do we do to avoid non androgen cells from proliferating??? Guys that are metastatic and go on vacation have clearly learned it does not work, nor does it postpone the ultimate hormone resistance.

BAT/mBAT guys may have part of the answer. They believe that when on High T, you are allowing the Androgen sensitive PCa cells to come back into the dominant position, then after 2 or 3 months on high T you smash them back into Senescence with ADT2 for 30 days, or until PSA undetectable again, then REPEAT. We have a lot to learn as we are just sending out the first few N=1’s these past 3-5 years. It is early days. 4 Doc’s have told me NO to BAT. I’m watching closely, it appears to have some traction, but not with mechanical 30 days up, 30 days down. Too rigid. Need to set and follow parameters. Mike

Scout4answers profile image
Scout4answers in reply to Spyder54

Oligometastatic found only in 2 adjacent lymph nodes. MO and RO said a cure is possible as they radiated complete lymph chain below the two that lit up. Planning a vacation late this year 27 months of ADT and 18 months after Radiation. Goal to remain HS as long as possible.

Sort of no mans land with BAT as no MOs will approve it until CRPC.

Nusch profile image
Nusch in reply to Scout4answers

We have a similar bio. After IMRT/VMAT RT in 03/2022 I will stay on Lupron at least until 03/2024. This week I’ve done a PET/CT showing PC in full remission and all bones and organs are free, too. PSA undetectable and Testo under 10. Wishing you the very best for your vacation, I will probably try mine in 2024.

Scout4answers profile image
Scout4answers

Can you please elaborate

Boywonder56 profile image
Boywonder56

The Low T makes everybody so b*****

PCaWarrior profile image
PCaWarrior in reply to Boywonder56

We used to be men. Now that we are post-menopausal women, we need to learn how to operate.

Nusch profile image
Nusch in reply to Boywonder56

Do you exercise? For me working out is helping a lot. Running, gymnastics, weight lifting helped to form my body again.

anony2020 profile image
anony2020 in reply to Nusch

The SE kind of hinders consistent exercise. Does anyone take cold bath or shower when you have hot flush?

Nusch profile image
Nusch in reply to anony2020

No, sorry, no experiences with bath. But sometimes I wake up in the morning and think, I can’t exercise today. Then I give it a slow start and it’s getting better with every minutes.

dhccpa profile image
dhccpa in reply to Nusch

Yep, the key is to push forward.

Anthonyve profile image
Anthonyve in reply to Nusch

That’s my experience too. 👍

Exercise, especially strength training, works.

Scout4answers profile image
Scout4answers

You keep acting in a very childish way Nal.

I appreciate it when you are helpful and Lord knows you have been helpful to me personally.

I am at a loss to understand your other behavior. It keeps getting you kicked off of here, I am starting to understand why. I wish you only the best and appreciate your knowledge and that you share it with us.

I truly wish you would maintain your Dr. Jekyll persona and leave Mr. Hyde at home.

j-o-h-n profile image
j-o-h-n in reply to Scout4answers

Nal? Here? Get me some Holy Water.............

Good Luck, Good Health and Good Humor.

j-o-h-n Sunday 04/02/2023 12:33 AM DST

PCaWarrior profile image
PCaWarrior

Correction: retired old women. The man part left as soon as we went on ADT.

Justfor_ profile image
Justfor_

Undetectable, which I am currently at, is a big No-No for me. Low stable PSA is my goal, the key word here being stable and hence, inevitably, measurable. The typology of cells will evolve with time, no mater what, but it is absolutely silly to speed-up this process in exchange of a short time living in the chemera that undetectable is next door to "cure".

Mw921000000 profile image
Mw921000000

hmmm this is interesting. I might be misunderstanding but does this say there’s No successful treatment of MRCPC? Please correct me if I’m wrong lol.

dhccpa profile image
dhccpa

I think he was just asking about the process. At the moment, Big Medicine does seem to be struggling with the answer.

Btw, welcome aboard!

Scout4answers profile image
Scout4answers

PLEASE BE AWARE THAT THIS POSTER (RAZORS EDGE) JOINED THIS FORUM ON MARCH 30 2023 AND HAS NO PROFILE AND HAS NOT MADE ANY POSTS ANY OPINIONS ARE SUSPECT. Probably another reincarnation of you know who>

anonymoose2 profile image
anonymoose2

Just thinking outside the box gentlemen and I say that very loosely 😂

What if CRPC isn’t PC cancer at all but a derivative of another cancer of the groin? Kind of like testicular cancer or penis cancer? A hidden cancer living in harmony with PC and only shows it growth after the PC is so damaged from the ADT? A cancer that could show PSA but it’s not officially a PC. Any case studies of “ANY RISE” ever so light but shows an increase from Testicular or penis cancer? Remember it’s possible if any groin cancer is in and near to the prostate it could very well aggravate the prostate and make the PSA rise. I mean if sex and a bicycle seat can raise PSA why not a hidden cancer surrounding the PC cells?

Have a blessed day.

maggiedrum profile image
maggiedrum

I'm not a genetics or evolution expert but evolution has been a long time interest of mine. What I got out of the OP's except was that castration resistant PCa cells may, or do, already exist before ADT or other treatments are started. If that is the case you cannot say that ADT "causes" castration resistance. What it does is kill the competition so that the castration resistant cells done have anything holding them back by not having to compete for space, food, or other factors necessary for both of them to proliferate.

On the other hand, and both may exist at the same time, the hormone sensitive cells may actually react to the hormone therapy (as in a cell will change it biochemistry via a DNA, or protein, or cell membrane change directly in reaction to the lower T levels). It is also possible that these changes could happen independent of hormone changes, i.e. spontaneous mutations in DNA or cell chemistry.

Scout, you touched on a subject that is near and dear to my heart as it is the basis for a chemotherapy with ADT clinical trial in which I participated in 2004. I was newly diagnosed as metastatic prostate cancer with Mets to T3 and L2 of my spine. From the writings of my Research Professor Medical Oncologist which he penned about 2003:

“As a working hypothesis, investigators suspect that the transformation from an androgen-dependent to an androgen-independent phenotype is mediated by expansion of an androgen-independent clone already present at the time of ADT that continues to grow while androgen-sensitive clones are being suppressed. It is thus desirable to bring treatment to bear on the androgen-independent component while the corresponding tumor burden remains minimal and prolong the time to hormone resistance. Investigators view the androgen-independent component as analogous to "microscopic residual" or "micro-metastatic" disease, for which adjuvant chemotherapy has been shown to be effective in other contexts, even when the same drugs had little or no impact on survival in the setting of more advanced disease.

Chemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone is present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy could be effective initial treatment for locally advanced or metastatic prostate cancer. This study examined the efficacy and safety of chemohormal therapy approach.”

When Dr. Robert John Amato passed away of Glioblastoma on September 6, 2018, no one has picked up his research; although as recently as August 2022, it was discussed by the Medical School Oncology Professors of a major medicine school. A Houston Doctor of the Year in 2014, Dr. A dedicated his life to eradicating and giving the gift of more time to those who suffered from it. He was recognized as one of the world’s leading experts in genitourinary cancer and he was loved by all.

I am here today because of his efforts.

Gourd Dancer

JRPnSD profile image
JRPnSD

Is there a reason we continue to use castrate resistant.and castrate sensitive terminology???..rather than hormone resistant/refractory pc (HRPC)...and hormone sensitive pc (HSPC)? These are much more accurate than these archaic and offensive terms.

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