evolutionary theory for Pca resistance

[podsart]

thought there was some discussion of adapting evolutionary theory to help postpone resistance to ADT; perhaps some using some form of it

anyone know about this or who has had experience with it?

nature.com/articles/s41467-...

[cesces]

The mathematical theory is that to slow the evolution of your PCA cells (or Covid variants for that matter) you attack it in overwhelming surges, with gaps in between instead of spreading the attack's intensity and varying munitions over time.

It appears that evolving standards of care, by design or by experience, are adapting this approach.

[Tall_Allen]

It remains an interesting hypothesis. The mathematical models are too complex for widespread use. And the evidence in those years has all been on the side of more intensive use of hormonal therapies. BAT, which is similar in some ways, has so far shown no oncological advantage. I haven't seen any large scale clinical trials since that article 6 years ago, and, of course, no one would do anything like that outside of a clinical trial.

[cesanon in reply to Tall_Allen]

"The mathematical models are too complex for widespread use. "

You can't do it exactly

But the switch from sequental escalation of meditications to concurrent administration of multiple medications is consistent with the mathematical models.

[Tall_Allen in reply to cesanon]

nonsense.

[cesanon in reply to Tall_Allen]

It's consistent with the models that I have read about in the past.

And I remember when the insurers would only permit one medication at a time and permit you to move on to the next only after passing some criteria.

I remember I always wondered if it was better to slowly ramp up or hit is back all at once to the smallest poplluation and let it start growing back again.

It was never intuitively obvious to me which route would best suppress an evolutionarily evolving biological agent.

When those studies came out... it sort of became obvious. LOL

Anyways, those are the mathematical models I was talking about.

[Ribotom in reply to Tall_Allen]

I work down the hall from one of Gatenby’s collaborators. I could ask whether a larger trial might be planned. I believe that the first author J Zhang is still working on this approach.

Note also that the Zhang and Gatenby Nature paper has a link for a “Matters arising” response from H. Mistry, who disputes their conclusions.

[Tall_Allen in reply to Ribotom]

I'm skeptical but open to proof. I'd love to see an expanded trial.

[Ribotom in reply to Tall_Allen]

Yeah, I read the Mistry dissent and he has good points. In my mind this approach is not yet proven useful. A larger trial would be great but obviously will take time.

[Ribotom in reply to Tall_Allen]

There is also a preliminary small (16 patient) study they have published with metastatic castration sensitive PCa:

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

Still just a small study and likely one can raise objections similar to those made by Mistry to their 2017 paper.

[Tall_Allen in reply to Ribotom]

No control group, but if you hear thay are expanding it, please let us know.

[podsart in reply to Ribotom]

thanks

[podsart]

Does this view make sense:

We know all current Pca therapies eventually lead to resistance and a slide to the lethal form of Castrate resistance Pca.

SOC has evolved in terms of different monotherapies to multiple therapies being given simultaneously. Regardless, resistance emerges, as the Pca continuously adapts to the different pressures its subjected to. All biosystems exhibit this, just look at COVID and its mutations, in response to the pressures put on it.

This evolutionary article uses 3 basic Pca cell types: 1) T+= requires exogenous androgen, 2) TP = testosterone producing cell, and 3) T- = cells that are androgen independent and resistant to abiraterone. We know that the AR ligand and associated signaling is more complicated, with different AR mutations, including the infamous ARV7 slice mutation.

They chose Zytiga rather than Xtandi, which has different modes than Zytiga, using AR signaling inhibition as well as being an antagonist. Of course, the mechanisms of Pca are very complex, way beyond the simplifications of the model in this article. But it captures the tradeoffs of pressuring the Pca into some form of control with the SE of that pressure forcing the Pca to adapt. In this model’s view, the energy tradeoffs of the 3 types of Pca cells mean that the T+ sensitive cells are needed for a dynamic balance to avoid, especially the T- cells from proliferating and driving towards resistance.

Given that we don’t really fully understand the full dynamics, there is natural fear that not putting sufficient pressure to control typical Pca growth [especially those with hi Gleason/aggressive forms], we may never be able to regain control. On the other hand, Darwinism, within the tumor microenvironment, says that constant max pressure, may be a self-defeating strategy.

Interestingly, this fear which may be why the article highlights what it calls a lengthy “induction” period for the intermittent ADT example of “metronomic” of zytiga at predetermined period leads to a suboptimal solution. Guess that longish hi pressure upfront already damages the possibility of a good “evolutionary” solution.

[Ramp7 in reply to podsart]

Thoughtful response.👍

[Tall_Allen in reply to podsart]

There is no doubt that evolutionary selection pressure competes against gross reduction of cancer volume. All the evidence so far is on the gross reduction side -- getting the biggest reduction in tumor volume, reducing as many clones as possible, has a much bigger effect than reducing selection pressure. For example, Xtandi+ADT outperforms ADT alone, Zytiga+ADT outperforms ADT alone, Erleada+ADT outperforms ADT alone, Docetaxel+ADT outperforms ADT alone, Nubeqa or Zytiga+Docetaxel+ADT outperforms Docetaxel+ADT. By "outperform" I mean delays castration resistance and increases survival. Also, intermittent ADT does not delay castration resistance any more than continuous ADT. BAT has not been shown to increase survival.

[podsart in reply to Tall_Allen]

thanks for a real world assessment of "evolution selection pressure" versus the impact of "gross reduction of volume impact"

[podsart]

thanks; as Tall_Allen says, nothing substantial has come from this in 6 years. Unless fully cured upfront, we all are on this slide [some faster- some slower] towards the castrate resistant unfortunate state. this solid tumor cancer seems to elude all our multiple best efforts.

[maggiedrum]

Seems to me that BAT therapy may be one application of what they are proposing. Keeping the cells confused so they never fully develop the resistance mechanism. just a thought

[Painful123 in reply to maggiedrum]

I want to agree with you on BAT, and I am trying to learn. But I am confused with what Allen wrote above : "BAT has not been shown to increase survival".

[maggiedrum in reply to Painful123]

Tall_Allen has shown to be a valuable information resource on evidence based trials and results. I admit that I have not attempted to double check what he presents. In fact, I am pretty amazed that he has the time and resources to present what he does. So I can't comment as to the accuracy of. his comments.

I was not trying to support the efficacy of BAT therapy on cancer survival. I just don't know. But from I have seen that is one of the tenets that have been made in support of the therapy. I'm not an expert on evolutionary influences from therapy but I have often doubted that it would work the way it has been proposed. I have a hard time imagining how it would push a cancer cell (actually a group of cells) to develop resistance to cancer progression through this means.

I have seen how many folks on this forum praise it to high heaven. I often think that this is a phenomena of wishful thinking. I have not been interesting in learning more about it as I could since I cannot tolerate the ADT to start with.