Evolutionary Dynamics in Cancer Treat... - Advanced Prostate...

Advanced Prostate Cancer

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Evolutionary Dynamics in Cancer Treatment Part 2: Extinction Vortex Strategies

MateoBeach profile image

Much recent interest in Adaptive Therapy is a strategy of applied evolutionary dynamics to alternate two different treatments, or on-off cycles of one treatment, to provide stabilization between susceptible and resistant sub-populations of cancer cells to compete and stabilize populations for more prolonged survival with the disease. Bipolar Androgen Therapy (BAT) and similar are examples. As is the cycling of abiraterone/prednisone vs continuous. (Gatenby et al.)

jonsmitchell.com/biol461/fi...

A whole different level of "Evolutionary Dynamics" is present in approaches that use Extinctions Dynamics in treating cancer with the intention of "cure" (= extinction) through principles that lead to species extinctions in nature. Some of these have been well studied and documented. The principles are very applicable to metastatic prostate cancer, yet seldom seem to be employed in current clinical practice.

The approach is using a "First Strike" and "Second Strike". Two (or more) different therapies are applied in sequence, administered when the cancer population is most reduced and vulnerable, but before resistant cells can become predominant. An "extinction vortex" is a sequence of events that lead small populations to become increasingly more vulnerable as they spiral towards extinction.

This is the opposite of using a therapy (chemotherapy, ADT etc) at the maximum tolerated dosage (MDT) and continuing it even after maximum results: NED, "No evidence of Disease". In APC this is most often an undetectable PSA. Yet if the treatment is continued, it inevitably leads to recurrence of resistant disease. We know this all too well. First castrate resistant to ADT, then to subsequent agents over time.

Extinction theory would call for administering a second strike, a second and different treatment at exactly the time of reaching NED or treatment nadir. When ADT, of ADT plus an advanced AR drug succeed in reaching "undetectable PSA", would be the best time, not to continue monitoring for the inevitable recurrence of resistant disease. But to undertake aggressive taxane chemotherapy at that time. Then start a third treatment perhaps as soon as that is complete. (Might be such as immunotherapy, Lu-PSMA if avid mets are present, etc. as individual circumstances, genetics, co-morbidities, dictate the best choices).

Here is an article reviewing this topic as relates to cancer treatments. food for discussion with your medical teams. An excerpt follows.

cancerres.aacrjournals.org/...

Eradicating Metastatic Cancer and the Eco-Evolutionary Dynamics of Anthropocene Extinctions

Anthropocene extinctions suggest a strategy for eradicating metastatic cancers in which initial therapy, by reduc- ing the size and diversity of the population, renders it vulnerable to extinction by rapidly applied additional perturbations.

The evolutionary dynamics of Anthro- pocene extinctions suggest eradicating metastatic cancers may be possible through a strategic integration of several therapies, each of which, individually, cannot achieve a curative outcome and, in fact, may only be mildly effective.

This potential curative strategy requires two or more steps guided by eco-evolutionary principles. The first strike applies a therapy that is effective in reducing the population even though prior clinical experience has determined that it is rarely or never curative. The second strike, following immediately after the cancer cell population decline, exploits the unique properties of small populations. As generally seen in background extinctions, an identical perturbation may result in entirely different outcomes in small populations compared to large groups of the same species (17). This is due to the vulnerability of small populations to stochastic changes in birth and death rates (17), decreased cellular heterogeneity, and Allee effects that adversely affect small populations (19, 22).

Application of this strategy requires an initially effective first line treatment or sequence of treatments that can significantly reduce the cancer population ideally to NED, similar to standard first line therapy in current oncologic practice. Importantly, first-line treat- ment does not need to be a magic bullet that eradicates the entire cancer population. Rather, by significantly reducing the size and diversity of the cancer population, it renders it vulnerable to extinction. Effective first strikes are reasonably common. For exam- ple, androgen deprivation therapy for metastatic prostate cancer reduces PSA to normal or undetectable in >90% of patients. Similarly, initial chemotherapy for metastatic pediatric fusion- positive rhabdomyosarcoma (31, 32) and for small cell lung cancer renders most patients NED. However, clinical experience shows that curative outcomes are rare as small surviving resistant clones eventually repopulate the tumor.

Our proposed strategy differs from standard oncologic practice because it changes treatment even as the tumor is responding well to the first therapy. As demonstrated in Figs. 5 and 6, the standard practice of continued application of the same agent(s) at MTD therapy until tumor progression following an excellent initial response is ineffective because the surviving cancer cells are resistant. Further- more, during tumor growth from NED to measurable disease, the cancer population increases in both size and diversity. Thus, application of second line therapy is too late to produce extinction.

Thus, we hypothesized curative outcomes may be achievable if, after effective initial therapy, new treatments are applied immediately after achieving NED. Figures 5 through 7 are consistent with the hypothesis but also find the opportunity for extinction is broader than expected. In fact, consistent with the concept of the extinction vortex, cancers that remain sufficiently large to be observable but are in decline are also vulnerable to extinction from a second strike. In contrast, as shown in Figs. 6 and 7, combining the first- and second-strike agents at the initiation of therapy is ineffective. However, if applied within an optimal window of opportunity when the cancer population is small and in decline, simulations found that addition of an even mildly effective second agent (killing only 20% of the surviving cells) consistently resulted in extinction of the cancer population.

33 Replies

I was just working on integrating an adaptive approach to Zytiga/Xtandi/Ketoconazole into mBAT.

Excellent writeup.

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

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

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

journals.plos.org/plosbiolo...

peterattiamd.com/robertgate...

moffitt.org/research-scienc...

MateoBeach profile image
MateoBeach in reply to RSH1

You are so far ahead of the curve! Thank you

Justfor_ profile image
Justfor_ in reply to RSH1

I am currently trying an adaptive cook-recipe of my own.

I started Bicalutamide in the hope that it rises PSMA on the way for a PSMA PET/CT.

Apart from Avodart and statines, I am naive to any other medication.

Two and a half years after RP it was evident that I was recurring, hence the need for the PET scan to guide my next move.

The Covid situation in Europe is ramping up and this made me cautious regarding anything having to do with hospitals for now.

Ten days of 50mg/day Bicalutamide and 10mg of Tamoxifene brought my PSA from 0.17 to 0.09 (almost half). I got some interesting numbers from Wikipedia about average PSA decline with dose, as well as decay half-times with dose. I lowered the dose from 7x50=350mg/week to 4x50mg/week. My calculations estimate that by next Monday (11 days since latest PSA test) my serum concentration will have reached equilibrium (i.e. net bicalutamide intake equals time decline of the accumulated) will be almost the same as that of the latest PSA test.

This is my actual target: Maintain a "quiescent" PSA of 0.05-0.06 by taking the minimal dose. I share the reasoning behind the papers that you posted and as such, I don't see any benefit for pushing it down to undetectable.

Will see if my estimations are valid and adjust accordingly.

RSH1 profile image
RSH1 in reply to Justfor_

Sounds logical. I'm using bicalutamide on the ADT portion of mBAT. I anticipate that mBAT will end sometime. If I use bicalutamide I'll likely steal your approach.

When you talk about Adaptive Theory--it is more than a principle, it is a compartment full of different Processes. You outline from your data an off-shoot of the back and forth Adaptive Approach, and have added another dimension. When speaking in these terms you are speaking my language--so to say. I am in an 8-month process of trying to teach my Doctors, the Adaptive Theory Principles. Mateo--you hit a home run today!Thank You,

Nal

MateoBeach profile image
MateoBeach in reply to Nalakrats

Thank you, Nal

Nalakrats profile image
Nalakrats in reply to MateoBeach

I will be adding Evolutionary Dynamics, into my studies/research--->relative to the Adaptive Theory Principle.

Nal

Thanks for pulling this together. I'd seen the work on non-metronomic dosing of Abi but not the subsequent modelling of the impact of second stage therapies. People often talk about throwing the kitchen sink at PCa, and some here speculate about the effectiveness of supplements, dietary modifications and even non-standard drug regimes such as Care Oncology's protocol etc, all having some measure of supporting evidence but not really standing up as proven cancer killers.

Perhaps this modelling of the impact of timing on the potential for second strike therapies to eliminate cancer cell populations, even if the stand alone therapy is well short of 100% effective, explains the anecdotal success in suppressing recurrence claimed by some ...

Good observation. Thanks

Mateobeach...I am currently using principles of adaptive therapy as my treatment. I will be meeting Dr Jingsong Zhang at Moffit within next 2 months to fine tune this adaptive approach. He is a pioneer of adaptive therapy and has published many research articles.

MateoBeach profile image
MateoBeach in reply to LearnAll

Looking forward to hearing what Dr. Jingsong has to say.

noahware profile image
noahware in reply to LearnAll

Are you planning intermittent abi monotherapy? If so, what are you thinking of (prior to the fine-tuning) as your most likely or most preferred on/off periods, and why?

LearnAll profile image
LearnAll in reply to noahware

Not planning...I am already doing it. My upper set point is PSA 10 and lower set point is PSA 4. I am using these points based on older research papers. A recent paper is suggesting 50% decline to stop. I am not able to know exactly what it means and therefore I am making appointment with researcher Dr JingSong Zhang.

MateoBeach profile image
MateoBeach in reply to LearnAll

You identified the conundrum: what criteria is best for timing cycling? The Gatenby article on cycling Abi went through extensive computer modeling exercise. Then they threw that out and just chose a 50% decline on an individual basis. So called Bayesian but it is just as good as any other until it can be refined and adjusted in the future. Your selection of 4 and 10 (60% decline) sounds as reasonable as any. Best of luck.

Dr Jingsong Zhang at MoffiIs he the Doctor that ran the trials for Gatenby?

He has published many papers about evolutionary dynamics .in last 5 years . not sure about Gatenby paper.

I understand the principles of this, but don't understand why the different treatments need to be applied sequentially. Why is that better than throwing everything in all at once?

MateoBeach profile image
MateoBeach in reply to TFBUNDY

Good question. It did not work in their simulations to start the combined therapies at the outset, just prolonged the time to failure. I think it may be due to the cancer getting a head start on creating resistance while in a state of being stronger and having a larger population, vs. letting the first strike do maximum damage first, then hitting it with the second at the nadir.

noahware profile image
noahware in reply to TFBUNDY

Good question. In the above text, the reasoning is that a "second strike, following immediately after the cancer cell population decline, exploits the unique properties of small populations. As generally seen in background extinctions, an identical perturbation may result in entirely different outcomes in small populations compared to large groups of the same species..."

So doing an "all at once approach" means ONLY acting upon a single, larger population, rather than acting once on the larger and THEN on the smaller.

I may have this wrong, so hopefully I will be set straight if I do... but hypothetically, suppose you have two different therapies that each, given alone, kill 90% of cancer cells. After one therapy, the population is at 10% of the former level; if the second therapy is then applied to that reduced population, and manages to kill 90% of it, you have only 1% left. The smaller population may be prone to not surviving. (I used these numbers just because the math is easy!)

The question remains, though: isn't it possible that applying the two treatments at the same time, instead of killing only 90% of cells, exhibits a synergy that manages to meet or exceed the 99% kill-rate of the sequential treatments?

Think of it in terms of human population. Yes, if there is a famine that kills 90% of the population, and that is later followed by a pandemic that kills 90%, the remaining 1% may be more prone to extinction than with either one alone. But why would we assume that both happening at the same time could not be just as lethal, if not more?

It sounds like the authors are claiming the sequential extinction events are what we see in nature's historical record, so that is what we might expect of cancer cell populations?

LearnAll profile image
LearnAll in reply to noahware

Well... the problem is if you kill 90% of one type...it leads to proliferation of other type which you need to kill again with some effective treatment.Using all treatments simultaneously kill all type of cells ..in one shot but the danger of repopulation of mutated cells rise/ Also side effects are huge too.

MateoBeach profile image
MateoBeach in reply to noahware

Good analysis. 👍

Nalakrats profile image
Nalakrats in reply to TFBUNDY

Then you missed the point of the paper. All at once, will usually fail--if not we would have many cured members on HU--there is a Molecular Bio-Chemistry subtly that you may be missing at the Micro-Environment of the Pca cell.

Nal

Thank you for researching this and writing up so clearly. It makes complete sense. I see my NHS doctor (I'm in the UK) in December. This is a crucial meeting for me as my PSA has reached its nadir. I was going to discuss BAT but hitting with AC225/LU177 or chemo now makes more sense. Then if successful to do BAT. I most likely will need to pay and go to Germany or India but ideally need my Medical Oncologist on board.

MateoBeach profile image
MateoBeach in reply to lcfcpolo

I read your profile and see you have assembled a comprehensive and (to me) very sensible treatment modalities, both SOC plus non SOC supports. And now have achieved a very low nadir. Congratulations. SOC would no doubt just continue this until it failed and resistant cancer takes over. Extinction strategy would call for doing chemotherapy right now such as docetaxel up to X 6. Then consider the Lu-PSMA if you have remaining significant PSMA avid sites on scan. They may have disappeared negating that by then. Provenge would seem a good choice. And perhaps overlapping it with the chemo could give even better immune response. (Termed abscopal effect.)Sorry about your pain from the absence of your wife from your life.

This I like but too complicated for me to follow.

Thanks for sharing this post - it definitely gives me something to work through and review with my team.

Great post. I would think a delayed second strike, several months after NED whilst still NED, although not ideal, is still merited with an approach using Extinctions Dynamics, right?

I would think that several months after reaching NED would likely still fit this model and be effective in progression towards extinction vortex. As long as recovery of the population has not progressed very far. Of course it has a large element of speculation unproven in clinical trials. So consider carefully and discuss with your most trusted MO.

Am considering a "second strike" after reading up.. MO says no; progress cannot be measured. I am visiting Brazil with reputable on-line pharmacies where most stuff can be bought without prescription. Abiraterone is what I think first of, but I fear it may be too close to my first strike drug, ADT,, to qualify as a second strike drug.. ADT is the only SOC drug I have used, quit two months ago. After all, both share the fate of resistance by progression of androgen independent pc cells.Your or anybody else's views on this would be appreciated.

I hope I am wrong since abi srems so "easy" but if not

chemo (despite statements of it being crazy when NED) or immunotherapy (desite only approved for MCRPC) is what comes to my mind.

I like your analysis PB. Agree that Abi+p may or may not be a true 2nd strike after LHRH ADT. Probably partially so as it extends action to testosterone producing cancer cells. Certainly has been shown to provide additional survival over ADT. And May not need to be combined with ADT since it blocks all testosterone production itself. I would use the cyclic adaptive approach, stopping when PSA declines by half and resuming when reaching starting level PSA. Of course that requires a measurable and rising PSA level, not undetectable.A true second strike would be to start some cycles of chemotherapy very soon after reaching undetectable. Surely that would be a very difficult decision to make at that exact time when things look to be going so well. Both for us, and for the oncologist, even though we know what will happen eventually. Still, chemotherapy will not kill us and can be stopped when side effects become too difficult. They are not going for maximum tolerated dose and duration endpoint necessarily in this approach. Maybe a few cycles would suffice? All unknown.

Immunotherapy with Provenge seems a fine choice too. Perhaps as a 3rd strike? No real downside to it except the horrendous cost since it is not covered until mCRPC is documented.

As for me, I am currently off all ADT and am taking high dose testosterone to restore muscle mass. Have Severe sarcopenia. 6 weeks on T-cyp and 4 weeks off currently. PSA is low and indolent 0.1 on this regimen. Expect to add degarelix to the off cycles if it breaks above 0.2 . I am adding a senolytic regimen starting next month with weekly Sirolimus 3 mg, Dasatinib 100mg for just 3 days every two months along with Quercetin 1,000mg and Fisetin to be determined.

Plan to discuss possible 2nd strike chemo with Jevtana with my MO in January.

This is immensely helpful, MateoBeach. I have ordered a 4-month supply of abiraterone lowdose 250 mg daily taken with food plus 2x5 mg prednisone daily.

As you write, abi is probably a partial second strike given that it hits testosterone producing pc cells which ADT doesn't. Also, although I have NED, testosterone has recovered sharply after cessation of ADT, being right in the middle of the referece range (it was close to the upper limit before ADT). To boot, I would have opted for abi in addition to ADT when starting, if the study showing benefit for the newly metastized had been available then.

So to me it seems a no-brainer to start abi now, if side effects are tolerable. My only uncertainty is the length. I opted for a single 4-month package, but maybe I should add a second package whilst still in this wonderful country (getting a postal parcel from Latin America or India thru customs is a major hassle). There is obviusly no standard for this when NED but if you have any gut feeling please let me know.

I am debating whether to order Jevtana as well, for a coming third strike. My MO is not as as approachable as yours I won't even suggest it. I know a nurse who can inject and have to find out if J can be done in a home setting. Are you thinking of Jevtana because of less side effects than Docetaxel?

I missed writing one additional strike option in my case: a PARP inhibitor plus Carboplatin, since I am BRCA2+.

Sorry to hear about your sarcopenia. I think it's not compounded by a current lack of exercise I believe I recall you are physically active.

I am waiting for a 2 mg package of Sirolimus/rapamycin, after weighing the pros and cons of going higher, but it is just a rough judgement in this experimentation we are doing. I recall you were thinking of 2 mg but see you have opted for 3 mg now.

I am feeling my way on Dasatinib, noticed a temporary slight 10 % increase in ALP after the 3day regimen, then it dropped again to the exact level where it has always been ever since the ALP flare after ADT/radiation. Probably a coincidence, or - an irrational hope I guess - could it be cancer cells dying...

Am inclined to do D+Q monthly, with Fisetin in the middle after I have figured out the latter but have also thought about bi-monthly as you are planning - is thst because of lessened side effects? I noticed a temporary drop in lymphocytes after D+Q will check that next time too.

It will be tough convincing MO plus changing my own mind-set, going all out on senolytics. But I suppose there isnt any contradiction between that and adding a second strike...

I want a Hess truck for Christmas............

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 11/24/2021 12:08 PM EST

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