"... we will review those strategies and drugs that are able to resensitize cancer cells to previously used treatments through the use of "hinge" treatments with the objective of obtaining an oncological benefit.
"Some examples are: bipolar androgen therapy (BAT) and drugs such as indomethacin, niclosamide, lapatinib, panobinostat, clomipramine, metformin, and antisense oligonucleotides.
"All of them have shown, in addition to an inhibitory effect on PCa, the rewarding ability to overcome acquired resistance to antiandrogenic agents in CRPC, resensitizing the tumor cells to previously used ARSis."
Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy
Belén Congregado Ruiz 1, Inés Rivero Belenchón 1, Guillermo Lendínez Cano 1, Rafael Antonio Medina López 1Affiliations collapseAffiliation1Urology and Nephrology Department, Biomedical Institute of Seville (IBIS), University Hospital Virgen del Rocío, 41013 Seville, Spain.PMID: 37189723 DOI: 10.3390/biomedicines11041105
Abstract
Since prostate cancer (PCa) was described as androgen-dependent, the androgen receptor (AR) has become the mainstay of its systemic treatment: androgen deprivation therapy (ADT). Although, through recent years, more potent drugs have been incorporated, this chronic AR signaling inhibition inevitably led the tumor to an incurable phase of castration resistance. However, in the castration-resistant status, PCa cells remain highly dependent on the AR signaling axis, and proof of it is that many men with castration-resistant prostate cancer (CRPC) still respond to newer-generation AR signaling inhibitors (ARSis). Nevertheless, this response is limited in time, and soon, the tumor develops adaptive mechanisms that make it again nonresponsive to these treatments. For this reason, researchers are focused on searching for new alternatives to control these nonresponsive tumors, such as: (1) drugs with a different mechanism of action, (2) combination therapies to boost synergies, and (3) agents or strategies to resensitize tumors to previously addressed targets. Taking advantage of the wide variety of mechanisms that promote persistent or reactivated AR signaling in CRPC, many drugs explore this last interesting behavior. In this article, we will review those strategies and drugs that are able to resensitize cancer cells to previously used treatments through the use of "hinge" treatments with the objective of obtaining an oncological benefit. Some examples are: bipolar androgen therapy (BAT) and drugs such as indomethacin, niclosamide, lapatinib, panobinostat, clomipramine, metformin, and antisense oligonucleotides. All of them have shown, in addition to an inhibitory effect on PCa, the rewarding ability to overcome acquired resistance to antiandrogenic agents in CRPC, resensitizing the tumor cells to previously used ARSis.
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Very interesting review, Patrick. Here is a link to the full text below. I find the discussion of BAT very good in particular. And the mechanism of dasatinib on SRC. I take intermittent dasatinib as part of my periodic senolytic regimen. Epigenetic mechanisms and drugs targeting them are also emerging treatments coming into our view. Paul M/B
El Pablo - In my just finished second reading of Tripping Over The Truth, Christofferson makes a big point about the large and mostly unexplored treatment possibilities within the vast array of existing drugs. The fact that many have been in use for decades provides safety profiles unknown in any new pharma products. The hurdle lies in the fact that most are off-patent and therefore inexpensive to end-users - thus no incentive to do the testing required by FDA to allow their unrestricted use for off-label purposes; i.e., a sort of financial Catch 22.
It seems a bit of a no-brainer to me that this would be a perfect application for AI. I have already seen a few examples where it has been used to search for possible drug combos, but the challenge of getting such basic research into the clinic still remains. The more Fish's "The Science Is Coming" seems to happen, the farther behind our antiquated system for implementing basic science into practice looks to be.
So true, K9. Looking at my own regimen I currently take several repurposed meds that have decent research support for being beneficial in PCa, not to mention healthspan. Currently these include:
atorvastatin, doxazosin, aspirin, celecoxib, Metformin, Sildenafil, testosterone (BAT), Dasatinib, Rapamycin, melatonin, D3 with K2 (winters), Quercetin, Fisetin, theracurmin, EGCG, Sulforaphane, resveratrol, NMN or NR, CoQ10, Nattokinase-Serrapeptase, Omega 3 fish oil, a-Lipoic acid, l-Carnitine, Multi Vite plus B12/ methyl folate, Ca/Mg , Probiotic, Inulin/FOS, psyllium, whey protein, creatine, BHB salts and occasional Osterine. (!)
Vs only 3 meds approved for SOC and take them in a very non SOC schedule. Orgovyx (1 month out of 4), Nubequa (1 week only at half dose when starting Orgovyx) and Xgeva every 6 months currently.
That is indeed a very interesting book. Have you picked up Peter Attia’s book just out? “Lifespan”. Much better than I expected and puts his approaches in perspective. Audiobook was good.
For example, I now recognize that when I was on fully ketogenic diet and lost so much fat, that I was also losing muscle mass as protein was being harvested for amino acids for gluconeogenesis to meet minimum brain glucose requirements. Led to my sarcopenia. Much more conscious about getting adequate protein now. Eating low carb but not fully keto, probably 50gm or up to 100gm/day of whole PB carb sources.
El Pablo - Thanks for sharing your comprehensive list. You beat me by a supplemental country mile, but we share a large portion of the the same ones. I am about to post two research review articles that add support for many of the ones we both take. Look for it to show up later today.
I'm in the home stretch of the multi-day fast, so posting about diet has me thinking about small quantities of"healthy food" for later today - or if I decide to stretch it, tomorrow morning. No matter how you prepare them, water, tea, and hydration essentials provide only the most minimal measure of culinary satisfaction; i.e., no chef's hat and apron are required. (I'm currently drinking a fine mixture of water, baking soda, magnesium bisglycinate powder, a few drops of ionic zinc with trace elements, and a tiny bit lemon extract to make it all palatable. Delicious concoction, if you don't have anything else in the house to drink and you have starved yourself into ketosis.)
Ciao - The K9 Terror - who is only fierce when chasing fast cars and equally fast-running females - and maybe also when severely undernourished!
The only one I know who can beat you guys is Nalakrats. He takes so many, he has to take the last handful in the middle of the night. (He will verify that.)
Speaking of AI - Alan Turing, the father of AI, who has been dead for 69 years, never seems to have expected AI to do more than give the appearance of human intelligence. I wonder what AI would make of our various lists? Given the intelligence of those who compiled the lists, why aren't the lists identical? Would we humans ever agree to scrap our lists in favor of one produced by AI?
& how would we respond to being told by AI that using testosterone was like throwing gasoline on a fire? lol
Interesting consideration, Patrick. AI would need very big data, such as all of the clinical history data from every cancer patient to look for new meaningful correlations, patterns and combinations. Perhaps that may be coming, but is not here yet. Google’s AI engine allegedly has access to all of human knowledge that has ever been written! But what about that which has not been written, or at least released from HIPPA restrictions? Paul
PS Thanks for the melatonin info. Great article on cellular and metabolic pathways. I’m increasing my dose from 20 to 50 mg.
Would you care to elaborate on why you do these in this manner: 3 meds approved for SOC and take them in a very non SOC schedule. Orgovyx (1 month out of 4), Nubequa (1 week only at half dose when starting Orgovyx)
No measurable effect for me. Though my long cycle BAT probably also promotes higher blood counts. And I only take dasatinib for 3 days, 100mg, along with Quercetin and Fisetin in higher doses as part of my occasional (3X/year) senolytic regimen. Paul
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