Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel - MDA/UBA, 01.15.2021

[cujoe]

The following research out of MDA and University of Buenos Aires is quite perplexing to me, since it seems to indicate that the ketone bodies generated by a ketogenic diet or fasting would actually be creating fuel for prostate cancer, at least at some points in its progression to CR androgen independence. I would be interested in any comments from those more steeped in the biochemistry of cancer metabolism on the results presented herein:

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Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel - Estefania Labanca, Juan Bizzotto, Pablo Sanchis, Jun Yang, Peter D.A. Shepherd, Alejandra Paez, Valeria Antico-Arciuch, Nicolas Anselmino, Sofia Lage-Vickers, Anh G. Hoang, Mark Titus, Eleni Efstathiou, Javier Cotignola, John Araujo, Christopher Logothetis, Elba Vazquez, Nora Navone, Geraldine Gueron - medRxiv - preprint posted January 15, 2021.

(doi: doi.org/10.1101/2021.01.12....

ABSTRACT

Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis. Using PCa patient-derived xenografts (PDXs) we assessed the metabolic changes after castration of tumor-bearing mice. We found that relapsed tumors had a significant increase in fatty acids and ketone body content compared with baseline. We confirmed that critical ketogenic/ketolytic enzymes (ACAT1, OXCT1, BDH1) were significantly augmented after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT.

Increased ACAT1 and OXCT1 was also observed for a subset of PCa patients that relapsed with low AR and ERG expression. These factors were associated with decreased biochemical relapse and progression free survival. In summary, our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence.

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Note the ACAT1 & OXCT1 referenced above via the AR & ERG expression can be correlated back to the Movember Prostate Cancer Tissue Microarray Resource posted earlier.

The Abstract, full text, and PDF download are available here: Note this is a pre-publication document and has not yet been peer reviewed.

Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel

medrxiv.org/content/10.1101...

Most who are paying attention have become aware of the ability of advanced cancers to use various metabolic pathways for fuel, even robbing it from neighboring healthy cells. However, as various forms of fasting and dietary interventions get promoted to the cancer community, the science specific to individual cancer types and stages is lacking. This research seem to be looking to fill in some of that informational void for advanced PCa. The problem for the patient community is how to convert such basic research into actionable dietary/lifestyle changes that provide a beneficial outcome; i.e., into applied science we can actually use.

Insights would be appreciated. Be Safe / Stay Well - K9

[NPfisherman]

K9 Terror,

I think this has to do with the metabolism of tumors and indicators of progression to MCRPC. The increased fatty acids and ketone bodies, as well as enzymes, occurs after castration or initiating ADT. Is there a way to target these enzymes to prevent progression to MCRPC while on ADT?? Thus, eliminating the deadlier phase of our disease... The way around ADT seems to be these enzymes. I would guess the Movember research would be able to look at the levels of the enzymes and the rate of progression and correlate...

Thanks for posting...

Fish

[cujoe in reply to NPfisherman]

But my question is are the increases in keytone bodies via diet and or fasting aiding the cancer by providing a preferred metabolic fuel without the cancer having to work for it? I see evidence for and against ketogenic diet and fasting to achieve ketosis when it comes to cancers that are know to prefer fats at some point in their disease progression. What am I missing? Or am I? Deep weeds and no weed eater.

[NPfisherman in reply to cujoe]

I believe what we see here is all about metabolic reprogramming by the tumor. AR guides tumor metabolism and when that is suppressed, the work around begins. Some of what is essential at that point is fatty acids to provide fuel for metabolism. Controlling dietary saturated fat intake and cholesterol may help slow progression, but tumors can take fat and utilize it for fuel--an interesting article below:

cdrjournal.com/article/view...

The enzymes in your article play a key role in enabling tumors to use fatty acids and ketone bodies for fuel. I believe in IF and limiting certain food intakes, but ultimately. the tumor does what it needs to survive and grow. Would limiting these enzymes result in tumor regression and delay castrate resistance?? Likely, but can we starve a tumor to death?? I do not believe so, but by proper food consumption, we may slow this process down...

How many licks does it take to get to the center of a Tootsie pop??

Ask Nalakrats, for he is much wiser than me... LOL...

Fish

[cujoe]

When I was kid, I might have ventured a guess on the tootsie pop question, but that was long ago and far away.

I appreciate your response and see what you are getting at. That may be all there is to it, but as I have taken up fasting recently, I'm trying to decide if it is a good thing to continue or something that might actually be potentially bad for PCa due to it's appetite for fats.