Intro: "Development of resistance to anti-androgen therapy limits the usefulness of second-generation androgen receptor (AR) antagonists including enzalutamide and abiraterone in castration resistant prostate cancer (CRPC) patients."
{We know what they mean - both drugs target the AR axis - but only Enza is an AR antagonist.}
"Studies indicate that overabundance of EZH2 in localized prostate tumors increases the risk of biochemical recurrence after surgery, as it activates AR by enhancing methylation, resulting in the suppression of tumor suppressor genes and activation of oncogenes."
Avid readers of past posts will remember that methyl is an excellent target. PCa cells suck up the stuff. The universal donor in the body is SAM (SAMe). (A byproduct of the transaction is homocysteine.) The key dietary methyl donor tends to be folate (or folic acid), rather than methionine. Folate recycles homocysteine back to methionine, which then converts to SAM. However, there are essential cofactors involved in the process.
One such cofactor is vitamin B12. Some aging men lose the ability to take up B12 from the gut (the stomach ceases to produce intrinsic factor [2].) This 'problem' can be protective against the methylation of tumor suppressor genes. Outright B12 deficiency is dangerous, but B12 injections (or sublingual uptake) might stimulate indolent cancer.
{One sign of poor B12 status is elevated homocysteine. This has been associated with cardio issues, but intervention to lower homocysteine (via B12 & other cofactors) does not reduce risk.} Which suggests that homocysteine is an artifact rather than a player in cardio events.
{Note that a vegetarian/vegan diet is often deficient in B12. Diets that are deficient in essential nutrients can (often unintentionally) inhibit proliferation.}
Novel Approach to Therapeutic Targeting of Castration-Resistant Prostate Cancer
Eswar Shankar 1 , Daniel Franco 1 , Omair Iqbal 1 , Victoria El-Hayek 1 , Sanjay Gupta 2
Affiliations collapse
Affiliations
1 Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA; College of Arts and Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
2 Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA; The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA; Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA; Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA; Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA. Electronic address: sanjay.gupta@case.edu.
PMID: 32097843 DOI: 10.1016/j.mehy.2020.109639
Abstract
Development of resistance to anti-androgen therapy limits the usefulness of second-generation androgen receptor (AR) antagonists including enzalutamide and abiraterone in castration resistant prostate cancer (CRPC) patients. Recent genomic studies reveal that AR-regulated genes contribute to CRPC emergence. Several reasons for the development of resistance towards anti-androgens have been hypothesized, including intracellular testosterone production, androgen overexpression, somatic mutations of AR resulting in a gain of function, constitutive activation of AR splice variants, imbalance in AR regulators, and bypass of AR in CRPC progression. Recent findings suggest that epigenetic alterations are involved in the deregulation of AR signaling. Overexpression of enhancer of zeste homolog 2 (EZH2), the enzymatic member of the polycomb repressor complex PRC2, has emerged as a key activator of AR in CRPC. Studies indicate that overabundance of EZH2 in localized prostate tumors increases the risk of biochemical recurrence after surgery, as it activates AR by enhancing methylation, resulting in the suppression of tumor suppressor genes and activation of oncogenes. This apparent association between EZH2 and AR in activating target genes by cooperative recruitment might play a critical role in the emergence of CRPC. Our hypothesis is that combination treatment targeting EZH2 and AR may be a novel efficacious therapeutic regime for the treatment of castrate resistant prostate cancer, and we propose to investigate this possibility.
What is your view on the concept of epigenetic alterations (especially methylation) regarding food / nutrition? If I understand the concept correctly, food which contains a high amounts of folate or folic acid / TMG (Betaine), should be avoided.
A look at tables which contain the amounts of folate or folic acid / TMG (Betaine) identify the following as ´suspicious´:
Chickpea, Beans, Quinoa, Brussel Sprouts, Lentils, Spinach, Field Salat, Rye, Broccoli, Beetroot, Oatmeal, Walnuts, even Avocado …
If living in a country where grains are fortified with folic acid, it is difficult to avoid an over-sufficiency of folate. So I would target B12. Avoid supplements; eat less meat).
I stay clear of beets but am not concerned about others on your list.
I think it was prudent of countries that did not follow the U.S. lead. The FDA did not consider the effect on cancer patients who were protected due to folate insufficiency.
Hi Patrick, I am often late to this posts because I find them using the search feature. Here's my situation - Background: 4-5 years ago got cancer, had GERD also, 2 years ago I started to get really bad stomach problems and the doc gave me PPIs, which made it worse. I told her after 5 weeks that I wouldn't take PPIs anymore because they made the pain worse, plus it's bad for the heart. None of the supps like slippery elm, marshmallow root, aloe vera really did much but when I started taking 3-4 varieties of probiotics pre day, the tummy started to get better and pain subsided. Then 1 year ago I got sick (maybe covid) so they gave me prednisone, then Augmentin, then Levaquin! and then I was all messed up. I went to functional med doctor and did all the blood tests etc. My numbers weren't too bad except for a few of them. One that stood out was B-12, which was at 2,000 (normal range is 400-1000 I think). The do said that maybe I was not absorbing the B12. This week - trying to get some energy, I eat a 5oz grass fed steak, started taking 100% RDA of chelated iron (18mg), small doses of Mega-Mag (mag chloride) and the RDA (400mcg) of methyl folate and I di notice more energy this week. I've read that the Mega-Mag might help activate HCL in the gut and increase my intrinsic factor so I could get some B12 in me and get more energy. For the last few years I didn't eat the red meat at all and I didn't want to take the methyl folate or the iron because those were reported to help the Prostate cancer grow faster. Can you play a balancing act with these 100% RDA amounts, which are far less than many of the supplements out there? Or are any amounts too much based on your theory in this post? Or could I thread the needle with just a little mega-mag daily (.5-1ml daily) and pop a folate and iron once or twice a week? I'm not even sure if the theory that I'm not absorbing the B12 is true but it makes sense because my long dormant EBV flared up after the covid? and Levaquin poisoning. This was shown in the blood tests. The doctor also showed candida and get my a prescriptions for that. these are all signs of gastritis and a damage gut so the intrinsic factor was most likely damaged as well. Anyway, this is an exciting topic for a Friday night lol. I wanted to get your thoughts? I'd kind of like to get other people's thoughts as well but I thought you'd have good insights into it.
I found this also: Magnesium Chloride... In addition to its functions as an electrolyte, chloride combines with hydrogen in the stomach to make hydrochloric acid, a powerful digestive enzyme that is responsible for the breakdown of proteins, absorption of other metallic minerals, and activation of intrinsic factor, which in turn absorbs vitamin B12.
Using other magnesium salts is less advantageous because these have to be converted into chlorides in the body anyway. Many aging individuals, especially with chronic diseases who desperately need more magnesium, cannot produce sufficient hydrochloric acid.
Chloride is a highly important and vital mineral required for both human and animal life. Without chloride, the human body would be unable to maintain fluids in blood vessels, conduct nerve transmissions, move muscles, or maintain proper kidney function.
This wasn't one of my most popular posts, judging by the solitary Swiss respondee, so thanks for taking an interest.
I'm a fan of magnesium & take a "triple" form, none of which involves chloride.
Can one be deficient is chloride? Apart from table salt, where do we get it? "Foods with higher amounts of chloride include seaweed, rye, tomatoes, lettuce, celery, and olives."
When I was injecting B12 14 years ago, my PSA quickly rose. I had no hesitation in ceasing supplementation & wasn't concerned about a possible absence of intrinsic factor. I was thinking in terms of 5 year survival. I still put PCa first although B12 deficiency can lead to bad situations that can't be reversed. I really should pay more attention to my increased risk of dementia, etc. I would like to die of old age, due to no particular cause, but PCa dominates my thinking. E.g. should I be taking lithium to prevent or slow Alzheimer's disease? [1] & so on.
Yours is an interesting case, but I don't have answers. I can barely take care of myself, it seems.
thanks Patrick, I understand. I've been terribly busy this week and last working on whether to and where to get scans for possible radiation. My new local doctor sprung this on me without forewarning even though my Duke MO has been saying no for four year. I suspect the Oriole study results are driving things. I'm probably going to fly into the epicenter of the LA variant of covid in order to get a free PSMA PET scan and then see if radiating might be possible and advantageous. Don't know if it's useful for you, but very good video here: urotoday.com/video-lectures...
He says early on that PSMA increased the % of oligo cases. That is counterintuitive to me. My view, when a bone scan showed oligo mets, was that I didn't want a closer look that might find more mets, because I might then exceed the limit & not be treated.
I assumed that that treatment of what can be seen via old-style imaging would be good, regardless of small mets elsewhere. They might be dormant, e.g.
But, if a PSMA scan showed only one or two other mets, it would be good to have them zapped too.
I'm lucky, here in Asheville, to have a radio-oncologist who will now zap what I want.
He did L5 6-7 years ago & would have done S1 2 years ago, had I asked, but S1 was very small & only became a problem because I didn't have enough castrate days on my 28-day BAT cycle. With 2mg DES & a 2 month cycle, S1 is probably invisible now (& I have had no pain for >18 months).
Whether or not I have oligo disease is not something I'm interested in these days. For others, "oligo" opens up the prospect of "cure". I have gone for "maintenance" rather than "cure". That's because I'm hoping the BAT will be good for many more cycles, & perhaps because I do not expect to be cured after 17 years.
It wasn't too long ago when doctors said: if you have one met, you have a lot of mets - you just can't see them. T_A pours cold water over the subject.
Good thoughts Patrick. I look at some things in life as black and white and others with shades of gray. With cancer treatment I use the shades of gray scale, which conflicts with many of the black and white doctors, who when you press them with new findings that appear to have benefit, they throw out the same old analogies. Their analogies are often appropriate and relevant/accurate but sometimes they are wrong, and if a patient doesn't try something new, then they will never know if it helps. It's like playing at the casino or at the lottery, the odds can be against you, sometimes greatly so, but you certainly have no chance of winning if you don't play. TA does poor cold water on things but sometimes a cold shower is a good thing. I like hearing both sides and then deciding what I think. I'm not like today's media, where they only allow one directional ways of thinking or else they go into cancel mode.
What bothers me most about this forum is how some guys are trying numerous things, like BAT, or on-demand radiation and then when I write to JHU about BAT, I get no response, or if I call to talk to a radiation oncologist at Duke, they want to maybe an appt. for me 10 weeks from now. Maybe it is better to have a medium sized medical care facility instead of a huge one. I'm happy for the guys getting the treatment they want but I'm disappointed in how the care so widely varies and how they are so specialized. The MOs don't even know when I'm talking about 1/2 the time regarding radiation or other things. One MO didn't even know what Metformin was. Literally, he had never even heard of that drug.
Specifically regarding my situation, even though my doubling time is very rapid, I wonder if there is a slight possibility that the doctors are wrong about it being throughout my system due to the fact that when it initially started rising rapidly in 2015, when it got to a psa level of 38, it just stayed there for 6 weeks before I started Lupron. Maybe there is a chance that the cancer is content were it is and hasn't gone any further. As I write this, I feel silly because it's been five years since then so maybe it was content then, but by now it most assuredly progressed to other locations. Regardless, it does seem like spot radiation like you are doing is beneficial in some men, in addition to ADT and other MO drugs and treatments.
I also thought about what you said yesterday. maybe it is good if I dont absorb too much B12 due to concerns over cancer growing faster with B12 in the system but the next question would be, where did they find the B12 in the cadavers, in the blood or in the tissue? My blood levels were through the roof but maybe that's where they were in the autopsied bodies as well. In the meantime I think I'll try to increase the intrinsic factor, the iron and the folate a little bit so there is less chance of anemia and possibly more energy. I looked at photos from 2017 and I look like Casper, due to anemia, which isn't really there right now. These are the conversation I try to have with doctors, who then start typing and ignoring me😬
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Why does BAT work in so few?
Can melatonin control AR amplification and therefore help mCRPC drugs work better and longer? 
Thymoquinone (found in negella sativa and monarda fistulosa plants) may target some castration resistant and/or metastatic prostate cancers
CRPC at 58 - next step
