Adaptive Theory for PCa - Part Two: Frameworks for treatment models, Eco-evolutionary Stability in mCRPCa, & AR is very adaptive

[cujoe]

It seems most major research about Adaptive Theory (AT) applied to PCa is now coming from Dr. Robert Gatenby, Co-Director, Center of Excellence for Evolutionary Therapy at the Moffitt Cancer Center in Tampa, FL. Here are two recent papers that attempt to lay the groundwork for mathematical models that could be used to formulate treatment programs for individual patients; i.e. are patient specific. And while the first model is not specifically based on AT, it would of necessity include and help define effective adaptive treatment regimes within the range of the model. Also included is a third paper from German researchers who look at AT as it relates specifically to the Androgen Receptor in PCa.

The first paper describes a conceptual mathematical framework for treatment models to be used by treatment boards in directing treatment programs for a particular patient. The second paper is an earlier one that is based on clinical results and likely informed the framework proposed in the first one. It specifically addresses AT (referred to in the paper as ‘evolutionary stable therapy’) when applied to the treatment of mCRPCa.

This first paper (co-authored by who else but our AT pioneer, Robert Gatenby) is extremely technical and definitely not for the mathematical-modeling novices among us. For those without any grounding in mathematical models or construction of algorithms, you may best skip the details sections and go to the Discussion section at the end. The first sentence in that section is:

"Here, we advanced the idea of a framework to support the decisional theory modeled on tumor boards' function to identify patient-specific clinical pathways."

The research team's "Key Objective" was:

"How to decide on the optimal treatment for a patient? Our approach aims to rate tumor-board-preselected optimal treatments with a Bayesian statistical tool rather than determine optimal treatment through externally specific indexes."

BTW, For those who are unfamilar with the term "Bayesian", here is what Merriam-Webster has to say about it:

Bayes·​ian | \ ˈbā-zē-ən, -zhən \

Definition of Bayesian: being, relating to, or involving statistical methods that assign probabilities or distributions to events (such as rain tomorrow) or parameters (such as a population mean) based on experience or best guesses before experimentation and data collection and that apply Bayes' theorem to revise the probabilities and distributions after obtaining experimental data.

And here Wiki's page on Bayes' Theorem:

en.wikipedia.org/wiki/Bayes...

The first paper is here:

Bayesian Framework to Augment Tumor Board Decision Making - JCO Clinical Cancer Informatics - Published online: May 11, 2021

ascopubs.org/doi/10.1200/CC...

The second paper, also co-authored by Dr. Gatenby, will be of more specific interest to PCa patients, as it used treatment outcomes of patients treated with abiraterone and focuses on the concepts that underpin AT when applied to mCRPCa in the clinic. It is also technical in nature and likely well above the pay-grade for most readers here. It is a very thought-provoking paper, as it challenges the treat-to-failure/resistence SOC practice that is still in mainstream use for PCa today. This is from the Introduction:

"For instance, a type of evolutionary therapy known as adaptive therapy uses drug holidays timed specifically to each patients’ disease dynamics in an attempt to intentionally maintain a sufficient level of drug sensitive cells [8, 11–14]. Upon withdrawing therapy, these sensitive cells can compete with and suppress resistant cancer cells, thus prolonging drug efficacy. Continuous or maximum tolerated dose therapies quickly eliminate the entire sensitive population resulting in treatment failure as resistance cells can now grow unchecked. Adaptive therapy clinical trials are underway in multiple different cancers including trials in metastatic castrate-resistant prostate cancer (NCT02415621, NCT03511196), in melanoma—NCT03543969, and in thyroid—NCT03630120."

The full paper can be found here:

Optimal control to reach eco-evolutionary stability in metastatic castrate-resistant prostate cancer - PLOS ONE - Published: December 8, 2020

journals.plos.org/plosone/a...

And, finally, this review paper on AR adaptability supports the need to be more creative than is the traditional treat-continuously-to-CR/failure SOC model that has been used for a generation or more. This is from one of the paper's figures is key:

"In general, due to accumulation of mutations, a tumor is composed of many cancer cell types leading to tumor cell heterogeneity. Cancer consists also of cancer stem cells (stem) and other non-cancerous cells (other, including cancer -associated fibroblasts and immune cells). Androgen-deprivation therapy (ADT) is mostly successful inhibiting the growth of androgen-sensitive PCa cells. However, castration-resistant cells may be selected by the treatment and accumulate. Treatment with AR antagonists and other therapeutic drugs, including chemotherapy and radiation, might select for drug resistant PCa cells leading to a more aggressive tumor (such as NEPC). Associated with the tumor evolution, during tumorigenesis PCa develops a variety of androgen bypass signaling."

The authors also suggest that senescent cells may play a sort of stealth role in promoting tumorgenesis. They go on to offer that senolitic compounds (which are known to be able to eliminate/reduce senescent cells) may be a new treatment avenue. This is a very comprehensive paper on the mechanisms involved with the AR function in PCa and a good read for those that want to deep dive into AR.

The full report is available here:

Androgen Receptor-Dependent Mechanisms Mediating Drug Resistance in Prostate Cancer - Cancers (Basel) - 2021 Mar 26

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

Much to consider as we all try to make decisions about the increasingly complex world of cancer treatment. I'm on a self-directed n=1 AT trial and am glad to be there. If I had gone the SOC route, I would surely be CR now and would have also had the QOL hit of ADT for the last 3 1/2 years. Dice roll, for sure - but so far, I'm way ahead at the AT gaming table. Chips Ahoy!

There is a short Part Three to follow in a few days. In the meantime, Stay Safe & Well - Capt'n K9

[cujoe]

Nal, Thanks for adding real world results to a still theoretical model. We both represent drastic departures from the SOC "norm". You are dealing with a much more serious hombre than I currently am. Therefore, your results are all the more "stood up" impressive.

As we both know, there are many other treatment mavericks out there (Patrick, et al) who are challenging SOC with varying levels of success - and failure. Each is a sort of solo pioneer looking for a way to keep the beast at bay - so that we may hang around long enough to kick off from a heart attack, speeding car, or just good ole-timey Old Age, rather than from our PCa.

Unfortunately, on June 01 I'll be meeting with my CLL oncologist just about the same time that you and Patrick are toasting with his latest selection of fine wine. I also have an appt on 10 June with my PCa doc, so that would be the next logical jumping off point for heading west. Not sure what else will be on my agenda then, but I'll keep you posted to see what you are up to - around then or later.

For now, here's a tune just for you:

youtube.com/watch?v=ye-Mwxu...(Not working as expected?)

Stay safe & well - K9

[cujoe]

I could take it out, but haven't in years. Sails are in storage and out of the weather, so any movement would be 100% diesel powered. At this point in time it is more an economical floating residence that a means of travel. However, my standard line is that "It is the ultimate form of waterfront property, since if you don't like your neighbor, you can move to a different slip, and if you don't like your neighborhood, you can move to a different marina".

I even considered getting an RV late last year, but by that time the market for them had gotten way out of line with reality. Plus, then I would have to find a place to keep it when not in use. One more complex mechanical device to maintain and lots of worry I don't need . . . Altho', traveling the warmer parts of the US would be a significantly better way to spend the winter months than hunkered down in the bowels of a 40 year old sailboat. Another thing to work on during the summer months ahead.

I do sometimes have to pinch myself to be reminded of how fortunate I am/have been to be able to do the liveaboard thing for17 of the last 22 years. It is some people's lifelong dream, so I try to make sure to never take it for granted. Sort of like being able to fish when you want in FL. Easy to forget that we get to enjoy activities anytime we want, while many people are only dreaming of doing them at all.

Sorry to miss the June 01 lunch, but I expect we will get together sometime later this year. 'Til then, take good care of yourself and Ms. Mary in your Home, Sweet New Old Home. Shalom - K9

[jdm3]

Good stuff. Thanks for the summaries of the papers. I have been intrigued with Gatenby's work for a while, but tend to glaze over when I try to get deeper into the math so settle with the takeaway that adaptive theory, biostatistics, and modeling are all possible weapons in the arsenal to complement and inform other care. All good stuff and may move the needle in the right direction.You may have seen this paper from Cornell talking about game theory.....

sciencedaily.com/releases/2...

Edited to add: I Just read your Part 1 so see you are all over game theory, Morganthaler, etc.. You da man!

[cujoe in reply to jdm3]

But not yet a SuperHero like you, who is a proven master of air, sea, and land. And has a sidekick who can fly with the birds and a daughter who masters the mountain trails and can light your lamp up bright.

Thanks for adding the Cornell link. I had seen that paper and meant to include it in the Part One post. Proof of concept that many heads are better than one (i.e., esp mine). BTW, I figured your technical mind would be loving all that theoretical math mumbo-jumbo?

Are you in your summer digs with garden planted or still hanging in your southern winterhaven?

Enjoy life wherever you are. Ciao - K9 terror

[cigafred]

Care to name a price for a recording of the lunch? Or maybe do a Buffett and auction off a place at the table, or two (one mute, one participating), proceeds to HealthUnlocked?

[cigafred]

Have the guest wear ablindfold.

[NPfisherman]

K9,

The evolution of treating PCa is happening at an astounding rate. In 2013, Maha Hussain did a study on intermittent vs continuous ADT. While survival rates were similar, there was improved QOL for intermittent...--see below:

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

However, many of the newer treatments were not available at that time. I believe that a study today might show a benefit for intermittent in survival and QOL. The article was interesting. Like you....our friend in the North has been off meds longer than on them... over 2 years off... Using supplements to kill senescent cells and increase apoptosis of PCa cells can lead to longer IADT vacations which is beneficial to us as patients.

Will IADT become part of the norm for Gleason 8 and below?? Stay tuned, boppers....stay tuned....

Fish

[cujoe in reply to NPfisherman]

Senor Pescado,

That's the study my Onco gave me when we discussed me doing IADT. Strangely enough, it worked to my favor that he was absent from my appt at the end of the first 3-mo cycle. That is how I started the 3 1/2 year vacation I'm currently still on. I get labs and my semi-annual visit in a couple of weeks, so we'll see if I can keep it going.

Excellent QOL is the benefit I've been able to reap so far and I hope I've also preserved the effectiveness of ADT if/when I need it again. Currently my post-ADT vacation has reached over 60% of the overall slightly greater survival of the continuous treated group while being able to maintain a "normal" QOL and T levels throughout.

It might not last forever, but it seems to be a much nicer road to be traveling than the one I would be on had I done continuous treatment or the normal induction period before cycling for IADT.

Any more fishing expeditions in your near future? Always keep the gear handy and the bait fresh. Later, Amigo

[NPfisherman in reply to cujoe]

K9 Terror,

I have been busy finishing my barn renovation project, so no new fishing plans... You have definitely run the table using your IADT plan.... It should absolutely work if you ever need it again because of the minimal exposure of PCa cells to ADT... I believe this plan works to delay castrate resistance, enhances QOL, and reduces risk for stroke and heart attack... The reality though is when you need ADT, then you need it, but the real conundrum is figuring out how long to do it.... There is AI for calculating that plan... In the meantime, enjoy the ride...

Fish

[cujoe in reply to NPfisherman]

Mr. Science,

100% agreement on my good fortune with my accidental treatment program. Dumb luck is sometimes our best friend. I guess what I keep thinking is: Why isn't the option of doing an early "text vacation" for good responders like me even considered/offered for such patients?

The risk/reward (based entirely on my own singular experience) would seem to favor QOL & extended OS for those having a similar excellent response to BOTH the initial ADT treatment and an equal interval test vacation. It is hard to imagine that a "good responder" would have his PCa gain much advantage during a 3 mo test vacation, while the opportunity to stay off ADT for an extended period of time (in my case, years) with recovered T and preserved QOL seems well worth the risk involved.

Up until the fall of last year, I was assured that I was holding steady with PSA labs actually falling to a post-surgery/IMRT of 0.02, but both my local lab and my cancer center are now only reporting <0.1, so if I keep getting that level of "undetectable" results, I will do a couple of walk-in ultra-sensitive labs per year to monitor any PSA creep - as I like Nal's idea that in addition to having the goal of "not letting any treatment fail", we should have a similar goal of "not letting a vacation fail". Interesting concepts to ponder as we all wait for those silver bullet treatments to show up.

With barns to renovate, a new greenhouse to maintain, and gardens to plant, weed and harvest, sounds like the only fishing you will be able to do is if/when you decide to build a fish pond on the property. Worms are good for the garden soil and fine fish bait.

Be Safe / Stay Well - K9

[NPfisherman in reply to cujoe]

K9 Terror,

Indeed, doing the USPSA is sound strategy to not letting a vacation fail. It is a strategy that Josh and I both utilize. I test again in a few months and have a plan formulated for the day that I hope never comes. In the meantime, enjoy life and good fortune...

Fish

[6357axbz]

This is a very good overview. Thank-you cujoe!

[cujoe in reply to 6357axbz]

Thanks. Glad to be able to find the time to do it. There's is one more Part (3) that might get posted later today. I also found a free Springer book downlad (PDF) that is a well-source of information on cancer. I'll also be posting that info soon. Stay Tuned & Stay Well - K9