What we are up against: Know the Beast

[MateoBeach]

One of my most useful quotes about cancer is the perspective: "Cancer is a meadow and not a cornfield." This highlights the diversity of sub-populations within a cancer and the interaction with the environment or ecology of the cancer micro-environment and interactions with non cancerous cells and the cellular matrix and resources.

Some time back I posted about "The Hallmarks of Cancer" in its updated and expanded form. The drivers and stages (phenotypes) of cancer progression. All underpinned by genetic instability (mutations) and inflammation. It provides a map of what must be addressed in order to delay or stop cancer's progression. The landscape, even where the roads are not yet defined.

Hallmarks of cancer: the next generation

pubmed.ncbi.nlm.nih.gov/213...

Recently we have had expansions on these and related themes in discussions in this forum. Such as with cujoe and others on cell dormancy and hibernation, and on cell senescence, signaling and senolytics.

Here is an excellent and expanded overview of both the landscape (ecology) of cancer, and how various factors interact in the "Hallmarks". And how diversity of cancer sub-populations, their interactions and their environment evolve. And how treatment strategies might best address them. Also how some treatment strategies (high dose chemo) can have detrimental effects. It explains how "adaptive therapies" (such as BAT) and intermittent or alternating therapies can be effective as well as immune interventions such as check-point inhibitors.

It is not too long nor too hard to understand. And can make some of these therapies more readily understandable. This comes from the "Frontiers" group of articles that cujoe previously posted. MB

The Hallmarks of Cancer as Ecologically Driven Phenotypes

frontiersin.org/articles/10...

[cujoe]

MB - While not yet with the time to dig into the article, your "meadow vs corn field" analogy is useful to those who have yet to grasp the "heterogeneity" of PCa. It is also a lead in to the oft-used analogy of treating weeds in the lawn, where the first weed-killer kills off 98% of the weeds, but the ones that then come back are resistant to the weed-killer#1 and come to dominate in the re-population. Take that through several various treatment cycles and eventually you have the = to CRPCa.

There is also a historical tale about the origins and later modification of The Hallmarks of Cancer that is useful to know and understand - both the original Hallmarks and the ones added later. The Hanahan and Weinberg papers are referenced in the text just above Fig 1 and are easily accessed via search. Here is a link to a short AACR article from earlier this year describing the additions.

New Dimensions in Cancer Biology: Updated Hallmarks of Cancer, Published January 21, 2022 by Silvia Licciulli, PhD

aacr.org/blog/2022/01/21/ne...

More comment later, but off the top, another insightful post by a fellow PCa patient, who is an MD with skin in the game. (The best kind of doc there is ~ For those who have been around awhile, the now-retired Snuffy Meyers is an example of the perfect MO wtih s-i-t-g.)

Dig deep and do it often. Ciao - K9

[NPfisherman in reply to cujoe]

Top Dog-- in the dog eat dog world of posting/replying on the PCa forum,

Indeed, the concept of weed killer and the results of tx as an analogy in treating Pca is most appropriate. The resistant survive, but that is where the story can change. Gaming Theory and the use of IADT that allows susceptible cells that grow faster to come back and inhibit the growth of the resistant PCa cells. If my use of "Enhanced IADT "(sequencing my Eligard, SBRT, and later abiraterone to utilize T flare) had been good (at least so far), then I do wonder about Pablo's "IADT on Steroids" (Sequencing BAT, SBRT, and use of Lu-J591) and how much more beneficial that will be in doing in the resistance and susceptible PCa cells.

The treatment paradigm is evolving so quickly and I think MO's are rolling with it. This time around, my treatment time may be only a year and then off to vacation. I am thinking of ending tx with a shot of T. Perhaps, you should talk with Pablo and/or Smurtaw in looking at a BAT/ Bicalutamide regimen. He and Smurtaw seem to be the BAT Brigade leaders (What do I know??).

The choices just keep coming. Patients need to realize the opportunities to change it up, and choose opportunities for QOL Continuous ADT is such a drag on the physical, mental, and emotional system.

Bon chance, mon chien,

An NP with s-i-t-g

[cujoe in reply to NPfisherman]

LadderFish, Duly noted! I am just beginning to develop, sort, and prioritize future treatment options. I'm waiting on Monday lab results to determine effectiveness of bical as a short-term bridge to something "better". No stone is as yet being left unturned, so the future is so bright (with possible alternatives), I gotta wear shades.

youtube.com/watch?v=nsRKleS...(Not working as expected?)

[NPfisherman in reply to cujoe]

DS,

The landscape is wide open as putting together alternatives like BAT, SARMs, vaccines,SBRT, IADT, Lu and AC, and sundry AR drugs-just to name a few-- offer a chance to whip together a witch's brew of treatment. The eye of newt is best if fresh, and don't choke on a wing of bat... You should seek the advice of the chemist--- Nalakrats. If only... Wish we all could !!!

DonP

[cujoe in reply to NPfisherman]

Yes, both The Master Chemist and The Amazing Researcher (who are sometimes seasonal compatriots in all things PCa-related) are sorely missed for their quality content contributions. Off-grid solicitation of advice will be sought as appropriate.

Steady on that ladder, Bro' = fish out of water? Safety first, windows second. Stay S&W ciao - k9

[NPfisherman in reply to cujoe]

K9 Terror,

Enjoy the visitation that you are receiving. Don't get pecked by the birds. Too foggy this am to be going up the ladder. Window in the afternoon. Yes, it would be good to have the two of them here...

Fish

[MateoBeach in reply to cujoe]

indeed the New Dimensions version of the Hallmarks is tracking our own ongoing research and integration of the science and the disease with rational new possibilities for orchestrating treatments. Or should I say “Navigating the landscape” of the cancer (There be dragons.) I’m excited to see the additions of epigenetic reprogramming, phenotype plasticity, senescent cell signaling, and microbiome effects into the overall picture. As well as resisting autophagy. You will learn much about the mechanisms of control of autophagy in Lane’s book about mitochondria, as they are the final common pathway for (necessary) cellular suicide.

I am going to enlarge the new graphic displaying the expanded Hallmarks and put it on the wall of my study/meditation room. Thanks for sharing the Sylvia Licciliuli summary. Excellent.

May the Albatross be with you Mariner.

[NPfisherman]

Pablo,

Thanks for posting... Our knowledge and understanding of how cancer grows and stopping that growth continues to evolve. Never...have we been in such a position where the disease is so well understood (Knowing the beast ), and yet.. stopping it is a whole other issue.... The plasticity of cancer cells, evolutionary response to tx, etc...

I watch the development of drugs like Metarrestin, which have the goal of blocking metastasis... (slowing it significantly would be great also), because it is not the primary that kills us... Can we get cancer to a stable/chronic disease state soon?? I believe so, and hope springs eternal...

The path ahead looks good and numbers do not lie.... when I started the journey, the ACS said my chance to be around in 5 years was 20%, now 32%, and rising with the significant number of new txs added...

Do we...know the beast?? We still learn more, but yeah... we know him.... Do we have his number?? Not yet... but stay tuned, boppers... stay tuned...

Don Pescado

[NPfisherman]

Smurtaw--A Leader in the BAT Brigade,

Sounds like a sound plan. Everyone needs a back up. The use of IADT to provide enhanced QOL and avoid the pitfalls of continuous ADT, when that is possible, just makes sense. Extending the viability of treatments using gaming theory and knowledge of CSC evolutionary pattern may give you some idea on a time frame.

nature.com/articles/s41467-...

Best of luck with the BAT, and may it never fail...

DonP

[No_stone_unturned]

Great read. Ty