Why does PCa stay dormant in bones for so long, and then emerge so fiercely?

[Blackpatch]

I noticed one of my countrymen, Bjry, had posted a paper just published by researchers from Peter Mac and other Australian institutions that seeks to answer this question, only to be met with resounding silence.

So then I figured it must just be that you've finally got some good weather over there and our out enjoying the sun... at an appropriate separation, of course.

Anyway, for whatever reason, this work seems to have gone unremarked, yet from discussions I have had with Peter Mac R&D staff, this is perhaps right up there with the very big breakthroughs that will one day form the basis for "curing" metastatic PCa - they are pretty excited... so here's a link to a slightly more user-friendly description of the work...

pcfa.org.au/news-media/news...

Nobody should be taking false hope, but there are established drugs out there that will be trialled very shortly on the basis of this work, so keep watching this space.

Stuart

[LearnAll]

Immune system is the key to ultimate treatment ...indeed !

[pjoshea13]

Hi Stuart,

Yes, dormancy is a big issue. Nalakrats wrote about it some time back. I don't know what percentage of men here have mets, but the subject is perhaps of little interest to them. However, the lack of response to Brjy might be due to COVID-apathy. The site is moribund at the moment.

When I was treated at T6 last year, my radio-oncologist said that the cell that started the lesion was probably there at diagnosis - 15 years earlier.

A big question for those who do not have mets, is how to keep dormant cells asleep. Is it possible that treatment wakes them up?

Best, -Patrick

[noahware]

I think the short and simple answer is, PC as a process is (USUALLY) one that proceeds slowly, in a manner similar to aging itself.

One might ask: why does "old age" often seem to be dormant so long, and then emerge so fiercely? I have known so many people that, aside from getting grey and weathered, seem much younger than their chronological age. Then it seems like a switch is flipped, and in a relatively short time they become "old" without necessarily having a specific disease (like cancer) that has aged them so suddenly.

Aging, like PC, seems to be very heterogeneous in how it manifests in different people.

[Kuanyin]

I'm sorry but I disagree with you and Patrick about waiting until our "distraction" with Covid-19 passes. Here, in the US, we have several governors who have jumped the gun re the new normal. The information regarding the virus grows more muddied and confusing by day as well as the proper instructions for dealing with it. We are are told that Covid-19 may be a seasonal guest, yearly. I have gotten a vaccination, as advised every year for flu, only to be told that the vaccines are only 40% effective. Whatever information you have regarding Zombie Cancer Cells, if you don't want to post now, I, for one, would appreciate seeing it via Messenger. Thanks.

--Kuanyin

[Tall_Allen]

There are many reasons for slow progression at first, immune response is just one reason. If you have monitored the covid-19 epidemic, you may be used to seeing exponential curves. These are ubiquitous in biological systems. As you may know, there was almost no growth from December to late February, then it exploded. The same thing happens with metastases. Very slow initial spread - it can be years between detection of the first met and the second and the third. Then detection accelerates. I stress the word "detection." The met has to grow to a certain size (at least 4 mm - millions of cells) before it is detected.

The primary reason is the "seed and soil." The cancer cell is not only the seed, but it also prepares the soil. The microenvironment in which it grows has to be conducive to growth. The cancer changes the microenvironment by releasing extracellular vesicles that changes the phenotype of healthy tissue. When there are few "seeds" around, this is a slow process. But as the soil becomes a better environment for seed replication, the process accelerates. This is the primary reason why detection is slow at first (the flat part of the exponential curve) and accelerates later.

IMHO, immunotherapies will have limited ability to interfere in this process because prostate cancer signals the development of Tregs and macrophages that shut off immune response. Immunotherapies will always fighting an uphill battle. The adaptive immune system will always eventually shut down any immune response. Much more promising are FAPI-based therapeutics that alter the tumor microenvironment.

pcnrv.blogspot.com/2019/12/...

[Kuanyin in reply to Tall_Allen]

Good call TA. Just a cursory review of some of the literature on FAPI-based therapies indicates how complex such a strategy would be. This is what I have indentified so far:

Possible Strategies of Use to Target TMI (Tumor Microenvironment for Cancer Therapy).

1Targeting the Estracellular Matrix

2Targeting Tumor cell dervived exosomes

3Targeting chronic inflammation

4Avoiding neovascularization

5Inhibiting macrophages recruitment and differentiation

6Activating anti-tumoral activity of the immune system

7Targeting Cancer-associated fibroblasts

8Targeting Hypoxia and acidosis

Certainly not just a matter of "three different supplements"! In any case, where to begin?

--Kuanyin

[Blackpatch in reply to Kuanyin]

Look, at the risk of being unkind, have you read the paper that gave rise to this post?

Frankly, I’m a little bewildered by all the replies received - these researchers, from Australia’s premier cancer R&D labs, are saying they have elucidated the signalling mechanism that controls dormancy/awakening of PCa in bone, and that they have been able to reverse the effect of this signalling with drugs that were developed for other purposes.

The responses all seem to rehearse the existing state of posters’ knowledge rather take account of the newly reported results....

[Tall_Allen in reply to Blackpatch]

I'm sorry I don't share your excitement, but I did read it. It is based on a lab study, not clinical evidence. I wish I had a nickel for every such "breakthrough" study I have read. They put out these press releases to raise money for their charitable foundations, and I hope they are successful at that. I ignore all such studies, and suggest you do too - they are not meant for patients - they are part of an ongoing dialog among researchers.

HDAC inhibitors have been looked at for a long time. If you want to read more about it, here are a few more lab studies to whet your appetite (note the dates!):

spandidos-publications.com/...

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

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

sciencedirect.com/science/a...

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

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

cancerres.aacrjournals.org/...

erc.bioscientifica.com/view...

(I have dozens more)

There have been some early clinical trials that showed little or no activity in prostate cancer or other solid tumors, which is why there isn't much excitement among researchers:

clincancerres.aacrjournals....

link.springer.com/article/1...

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

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

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

However, a Phase II clinical trial demonstrated some activity when combined with Casodex, although toxicity was high:

clincancerres.aacrjournals....

And there is a Phase I clinical trial combining it with Xtandi:

clinicaltrials.gov/ct2/show...

I hope it proves useful, but we are a long way from knowing that.

[rust]

You can't treat what you can't see hence the need for best imaging radiotracers possible (in research) also applies to the body's natural immune response. Cancer cells become unnoticed like the terrorist or foreign invader dressed in civilian clothes that DS Charles Morgan warned about at Fort Bliss in 1985 - - "PRIVATES the wars of the future will be fought in the streets against an enemy dressed indistinguishable from civilians".

[Blackpatch in reply to rust]

Well, actually, it’s quite clear from the paper that you COULD treat what you can’t see, if these guys are right and they have discovered the signalling mechanism that wakes dormant PCa cells, and found ways to turn them off for good....

[Bjry]

Hello Stuart,

I was surprised by the lack of interest in what seemed to me to be a potentially significant breakthrough. As you have generated a better response than I did I'll include the link to the full article;

embopress.org/doi/10.15252/...

Hope this doesn't kill your post!

I am very interested in any information you have on trials based on this research. I see my oncologist on 3 June and I intend to chase it up with him.

[jimreilly]

A little off the subject--the metaphors used are interesting but maybe confusing--the immune system "seeing" the cancer cells, or "recognizing" the cancer cells (also it's easy to get confused with treatment providers being able to "see" or detect the cancer cells). I assume another way to describe what happens with the cells is that some substance is produced or becomes available to the cancer cells that blocks some kind of a chemical reaction from happening that would destroy the cancer cells or at least prevent them from multiplying, or multiplying quickly. Or maybe there's some kind of subtractive process--instead of "blocking" as a metaphor, maybe some substance is "removed" that makes such a reaction possible. As a definite non-scientist I am interested in the language and metaphors and how they makes things seem more or less clear or precise, at least to easily confused me.