Cellular Rewiring in Lethal Prostate Cancer: The Architect of Drug Resistance

[pjoshea13]

New paper below, [1].

I can't get to the full text, but the Abstract clearly describes the problem that has been articulated here: the danger of sophisticated palliative therapies that induce the emergence of cells that can't readily be managed.

We know the escape pathways that are commonly used, but we lack the means to block them.

These pathways are often mentioned in cell studies of polyphenols.

-Patrick

pubmed.ncbi.nlm.nih.gov/322...

Nat Rev Urol

2020 Mar 16[Online ahead of print]

Cellular Rewiring in Lethal Prostate Cancer: The Architect of Drug Resistance

Marc Carceles-Cordon 1 , W Kevin Kelly 1 , Leonard Gomella 2 , Karen E Knudsen 1 2 3 , Veronica Rodriguez-Bravo 4 , Josep Domingo-Domenech 5 6

Affiliations collapse

Affiliations

1 Medical Oncology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.

2 Urology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.

3 Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.

4 Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. [e-mail].

5 Medical Oncology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. [e-mail].

6 Cancer Biology Department, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. [e-mail].

PMID: 32203305 DOI: 10.1038/s41585-020-0298-8

Abstract

Over the past 5 years, the advent of combination therapeutic strategies has substantially reshaped the clinical management of patients with advanced prostate cancer. However, most of these combination regimens were developed empirically and, despite offering survival benefits, are not enough to halt disease progression. Thus, the development of effective therapeutic strategies that target the mechanisms involved in the acquisition of drug resistance and improve clinical trial design are an unmet clinical need. In this context, we hypothesize that the tumour engineers a dynamic response through the process of cellular rewiring, in which it adapts to the therapy used and develops mechanisms of drug resistance via downstream signalling of key regulatory cascades such as the androgen receptor, PI3K-AKT or GATA2-dependent pathways, as well as initiation of biological processes to revert tumour cells to undifferentiated aggressive states via phenotype switching towards a neuroendocrine phenotype or acquisition of stem-like properties. These dynamic responses are specific for each patient and could be responsible for treatment failure despite multi-target approaches. Understanding the common stages of these cellular rewiring mechanisms to gain a new perspective on the molecular underpinnings of drug resistance might help formulate novel combination therapeutic regimens.

[Garp41]

Patrick,

Have you found a good polyphenol supplement that "covers the waterfront"?

Doug

[pjoshea13 in reply to Garp41]

Doug,

I prefer a mix. They are structurally similar but different, with slightly different properties. They all have protective roles in the plants in which they are found, although I find it strange that this would translate to anti-cancer properties in humans.

Anyway, I just searched on <"PI3K-AKT" polyphenol> & got 272 PubMed hits:

pubmed.ncbi.nlm.nih.gov/?te...

IMO, crazy to be concerned about "drug resistance via downstream signalling of key regulatory cascades such as the androgen receptor, PI3K-AKT or GATA2-dependent pathways, as well as initiation of biological processes to revert tumour cells to undifferentiated aggressive states via phenotype switching towards a neuroendocrine phenotype or acquisition of stem-like properties"

& ignore such studies. True, at high doses they are unapproved & untested drugs. But they will never be tested.

& then there is the potential of Metformin to help against the "acquisition of stem-like properties":

pubmed.ncbi.nlm.nih.gov/293...

& so on.

IMO, with such poor odds that we are faced with, we need to tip the scale in our favor when we can. There are othe views, of course.

-Patrick

[Garp41 in reply to pjoshea13]

Thanks Patrick

[cesanon]

Patrick

This seems important, but I am not certain how exactly to digest it.

Do you have any conjecture on how this might inform patient decisions?

[pjoshea13 in reply to cesanon]

My own view, & I'm not trying to do anything more than to state it, is that:

(1) if I have a choice, better to delay non-curative therapies that induce unmanageable cells.

(2) one should take an interest in add-on drugs/supplements that might inhibit the use of escape pathways.

-Patrick

[cesanon in reply to pjoshea13]

"one should take an interest in add-on drugs/supplements that might inhibit the use of escape pathways."

It would seem that recurses back to the same issue? Does it not?

Isn't the blocking of pathways what is generating the use of new escape pathways?

So " add-on drugs/supplements" are no less likely to generate escape pathways than the more conventional treatments.

Unless you are talking about hitting all possible pathways at the same time?

[Schwah in reply to pjoshea13]

Except it seems like most the major clinical studies indicate earlier use of these therapies generally provide better outcomes than delayed use.

Schwah

[timotur]

This is another angle on other discussions here about "treatment emergent neuroendocrine PC" (NEPC), which is associated with using ADT + Zytiga early in HT. My take is, combo therapy accelerates T-deprivation and suppresses T-levels to an extreme and is related to tumor cells morphing to undifferentiated aggressive states via phenotype switching towards NEPC. In other words, there is higher risk/reward with combo therapy, and possibly shouldn't be done in less aggressive PCa-- i.e. lower Gleason or non-metastatic cases.

[Schwah]

If that’s the case then why did the studies show 40% plus survival advantages to early combining of Zytega and adt, chemo with adt and Xandi and adt? Aren’t you over thinking this ? The evidence seems pretty clear.

Schwah

[Flydoggy]

Can you share which supplements you are using in this regard?

[pjoshea13]

I can attest to the pot. A bottomless pot. I have only known one other man to use coffee at pharmaceutical levels. That man was impervious to caffeine. Could drink coffee from morning to night. Was clearly addicted, but seemingly not to the caffeine. His father, uncles & 2 of his brothers died young, but he is still going. Is my age but looks 20 years younger. Anecdotal of course.

-Patrick

[Claud68]

Maybe this is another reason, why treatments don't work and cancer cells don't die:

isbscience.org/news/2017/11...

[pjoshea13 in reply to Claud68]

A possible reason why men with a slow decline to PSA nadir do better than those with a rapid respons?

-Patrick

[Bjry in reply to Claud68]

Thanks for the article - really interesting. I stopped taking fish oil - I'll have to look at that again or are there better sources of resolvin?.

[Bjry in reply to Claud68]

I don't think I'm overreacting but the more I read about 'resolvins' the more impressed I get.

See this Japanese study with fish oil supplements:

oatext.com/DHA-enriched-sup...

Perhaps you should do your response as a stand alone post. Anyone who has had or is having docetaxel might be interested.

[Claud68 in reply to Bjry]

I posted this, so you'll find interesting answers :

healthunlocked.com/advanced....

[pjoshea13]

The cumulative intake of antioxidants that Nala takes is probably well into the pro-oxidant range. i.e. enough to generate ROS, rather than quench it.

-Patrick