Anyone used 3bp (3-bromopyruvate)?

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RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sun Mar 10, 2019 09:15 PM

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Sorry, JohnnyP, I suspect that there is no universal standard with these DVDs. Each hospital probably just rolls their own and it is a great mystery what button you need to push.

According to the rules of good technology, if an interested person can't figure it out, then its not the fault of the person but the fault of the technology. Might try the Readme file. Hopefully it would provide some idea of how to open the files.

Glad to see that you are carefully engaging with the information that you have been given.     

RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sun Mar 10, 2019 10:19 PM

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There is a great deal of very exciting research that I have been reading. Near the top of the list are studies that are considering genotype specific responses to treatment.

https://www.ncbi.nlm.nih.gov/pubmed/?term=29695106

The thread has taken a moderately strong anti-genetic stance along the lines that cancer is so genetically heterogeneous that specific targetting almost seems hopeless. Reports from the Cancer Genome Project tended to confirm this perspective, describing oncogenic mutations as appearing to occur almost randomly; without any obvious patterns or themes.

Yet, looking at somatic genotypes and relating them to responses might prove to be much more relevant. If we are talking about germline genotypes (article is not explicitly explicit on this question, others do note that it is germline genotypes that are under study), then we would have a stable genetic foundation from which to work. From the article above, we see in Figures 2 and 3 that mutations in BSG and SLC16A1 (MCT1) have substantial effects on survival in the context of multiple myeloma treated thalidomide patients. Other research has duplicated these SNPs and others in additional cancers.

{I checked the exome file of a family member and we hit the rs1049434 variant in SLC16A1 (MCT1), also hit a BSG variant that is ridiculously rare, with low quality, strand bias and not in dbsnp: I'm going to call that one a false hit. Also see quite a few variants in GAPDH, which is a gene of substantial importantance in cancer.}  

"BSG is implicated in response to treatment with immunomodulatory drugs (thalidomide and its derivatives)"

We are all well aware that MCT1 and BSG are also highly implicated in response to treatment with 3-BP. It would be an extremely important development for advancing 3-BP and for cancer treatment more generally if germline genotypes could predict treatment response/safety etc.. In effect, instead of trying to treat within the context of an ever changing genetic landscape, one would be able to take advanatage of the background genetic horizon -- which is fixed. 

This perspective would also reduce a concern that has been nagging me for some time: namely, what if a patient did have some very odd genetic variant that for example, constantly kept MCT-1 open in all of their cells. Human genetics is diverse, it should probably be assumed that such variants while rare likely do exist. If in this freak instance 3-BP had easy access to all cells, then saftey issues could  arise. By thinking, right from the start about genotype specific responses, efficacy and safety would be enhanced.

What is even more exciting about this approach (if it is in fact possible to generalize the concept) is that the entire library of cancer medicines could be categorized by genotype. After one were genotyped, one could walk into the clinic and the optimal medicines would be waiting for pick up. To date personalized medicine in cancer has mostly been hopeless because cancer does mutate constantly. In this version of personalized medicine, though, the focus is placed on what is staying the same and not what is changing.  

Finding germline variants that might predict exceptional 3-BP response would certainly be a game changer.

RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Wed Mar 13, 2019 01:43 AM

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Now this is interesting!

I have continued to look through a family member's exome file and I spotted some intriguing variants that I had initially overlooked. Surprisingly, I managed to overlook a rare 5utr variant in the MCT-1 gene (i.e., 3-BP's entry portal).

The other day I got all hand wavey when I suggested that these variants could be a real game changer for 3-BP. Yet, at the time, I was very unclear how one might go about translating such knowledge into actual value added for patients. How could we ever figure out what variants closed the MCT-1 doors, for example? While reading through

  http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.808

I noticed something very startling. Figure 1B shows the variants that shut down MCT-1! And these variants are in the same region as the variant I noticed in our exome file! My guess is that there is at least a 50% or better odds that one of the dots in the figure is actual our variant.

Given this, it is now ridiculously frustrating that they did not bother actually disclosing the identity of these SNPS. When you are in that situation (and you are consciously aware that you are in that situation), it is difficult not to know whether the dot does or does not represent your variant.

We really need expanded open access to full data reporting of scientific research.  

This is still hand wavey; now much less so compared with my last car hailing attempt: Here goes. One interpretation (probably the most intuitive) would be that those with one of the dots in Figure 1B that essentially shut down MCT-1 activity would not be favored candidates for 3-BP treatment. The variants largely stop 3-BP entry. This would be true in all cells, normal and cancerous. In order for the MCT-1 doors to open up, it would require that the mutation could somehow be unbroken, which does not seem likely. Fortunately, this would be a highly testable hypothesis.

Another possible interpretation is that those with these mutations would have normal cells that were resistant to possible dangers from 3-BP because they would block entry, though it would then not be obvious how 3-BP would then have access to cancer cells. 

If this were to all pan out, then those patients who likely would not respond to 3-BP treatment could be made aware of this even before treatment began. Those patients who likely would be good responders could also be preinformed on the basis of genotype results. This might allow a smoother clinical path for 3-BP.  

The technique that was used in this article is extraordinarily powerful. Randomly inserting mutations into the genome and seeing how this modifies genomic function might allow for a rapid unlocking of the meaning of the vast variation present in the human genome's (in particular, how it relates to cancer biology).

RE: Anyone used 3bp (3-bromopyruvate)?

by JohnnyP on Fri Mar 15, 2019 07:20 PM

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J:

We just spoke by phone with Shirley's radiation oncologist, who had ordered the PET scan.

He said no new tumors, but the SUV went up in the lymph nodes, but they are smaller.

He offered no explanation for that, saying he wasn't sure what to make of it.

I asked about the tumors in the bones.  He said the area he treated is stable, the ones in the ribs are painful but not to worry about because they are not weight bearing.

He asked how she is doing, saying he goes more by her clinical condition.  It's pretty good, and getting better every day, though she still needs a back brace, sleeps with back elevated at 45°, and can only walk short distances on her own.

We see her oncologist in about two weeks.  She will probably read to us from the written report and say "Well, what do you want to do?  You know, you're not doing all you can," etc. (since Shirley stopped the Ibrance due to side effects).

Medicare approved us for Faslodex, so I'm sure she will want Shirley to start taking it.  We told her we would wait to see how the scan came back before deciding.

Shirley's glucose reading is higher that it was months ago, which could account for the higher SUV.  She is eating a bit more, and she wants some carby things, so I give in.  She likes tuna salad or lunch meat on a rice cake.  The rice cake is only 7g so I let her have it.  I make tacos once in a while, not so good.  One 6" corn tortilla is 11g, then add the peppers and onions, etc., and sometimes I make two for her, knowing she can't finish the second one.

RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sat Mar 16, 2019 01:18 AM

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JohnnyP, it is gratifying that your wife and so many on D's forum are doing reasonably well while under metabolic treatment. As you know, for a few years we did not see patients who consistently maintained benefit even over the short term.

Now we have patients who are topping up chemo with anti-metabolic therapy (similar to what appears to be used at the Turkish clinic) and their response to chemo deepens. I would love to see us find a way to transition to a non-chemo metabolic treatment, as once chemo's effectiveness fades it then can be difficult to maintain the gain.

The internet is such a wonderful technology that can bring people with challenges together and through a collective process help them to overcome these challenges. I suspect that many cancer patients have heard of the ketogenic diet, many have tried the ketogenic and probably many have not been overly successful with the ketogenic diet. There are tricks involved and often people in difficulty do not have the time or energy to overcome these difficulties. Fortunately, you have been able to surmount these barriers and can see the benefits from getting over the hurdles.

Yet, it is still difficult to hear about the physical limitations that your wife is experiencing. It worries me to hear that she can only walk short distances, needs a back brace and sleeps with her back at a 45° elevation. Sometimes we can give up so much of our quality of life and then there is no more ground left to give up. At the same time, there is this endless ocean of research to be explored. It is especially frustrating when something as seemingly obvious such as diet (in particular the ketogenic diet) continues to be an open question in oncology. 

I am glad that you are very aware of her nutritional intake. Carefully considering exact food inputs is very wise. It is no longer uncommon for people to consume up to 100s of grams of carbs per day without qualms.

Perhaps you might arrange a consult with a medical nutritionist. Creating an anti-cancer diet that went beyond ketogenics and calorie restriction could intensify the anti-cancer effects that you have witnessed.       

 

RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sat Mar 16, 2019 02:11 AM

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Something exciting has caught my attention! After reading the latest 3-BP review article I noticed an additional article from China reported with my Google search. My Chinese is not very strong and I was not able to make it through the translation barrier, though I  noticed when I followed this link that there were actually quite a few more Chinese origin 3-BP articles that did not appear with a generic Google search. 

I then played around with the Google settings and was able to change the national search parameters. When I did this, I found an entire layer of 3-BP research at an international scale that I had been totally unaware. There must be dozens of PhD dissertations on 3-BP!

If I could figure out how to do a Web of Science type search on doctoral dissertations that included the search term "3-BP, 3-bromopyruvate" etc, then I could be more quantitatively exact about the trend I saw. As a qualitative quantification, I would say there is A LOT of such 3-BP research, most of it has been done in the last 5 years.    

Clearly, the online rhetoric about 3-BP is completely at odds with what I am seeing at university campuses worldwide. Nearly an entire generation of cancer researchers have embraced a metabolic perspective and more specifically a 3-BP focus. Collectively this research verifies and reenforces all the years that we have posted away on this thread, without appreciating the vast global academic interest in 3-BP that often is not published to pubmed.

It is not difficult to understand why students might choose to research 3-BP: 3-BP gives you a nice strong first hit against cancer, all you then need is even a modest (sub) additive (or better yet synergistic) second hit and you can do the funky chicken dance in the doctoral lounge end zone. How great would that be for a student with likely a smallish lab budget to report a largish anti-cancer result?

3-BP would be a highly attractive subject for doctoral students. It is a wide-open field in which one could rapidly find combinations that further enhanced 3-BP's effectiveness. The obvious glycolysis-OXPHOS 3-BP inhibition combo appears to be unpublished. Going to the lab would be fun! In fact, some of the universities that I saw online were actively promoting awareness and encouraging 3-BP research.       

It is uplifting to see this worldwide effort by the academic community. 

RE: Anyone used 3bp (3-bromopyruvate)?

by JohnnyP on Mon Mar 18, 2019 12:04 AM

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I told her we sould think about metformin.  I'm pre-diabetic.  My PCP may write a prescription for me...

If not, I could ask my cousin in Yuma to cross the border.  I have heard it's available without a prescription.

Until then we have ordered Berberine.  And she has agreed to take the nanocurcumin I bought, against the wishes of her oncologist.  When we asked her about it, she read the label and said "absolutely not to take it, it has anti-oxidants."

I am also looking in to HBOT but that's not covered by insurance.

My daughter said I may be able to get paid by the state as a caregiver, based on a conversation she had with someone at the state disability office.  She is looking into it for caring for one of her daughters that is deveopmentally disabled.  She said they told her it could pay up to $2k per month.  That would cover HBOT.

Did you read the paper on Metformin in combination with an old blood pressure medicine, Syrosingopine?  In short, it inhibits the cells from exporting lactate.  Link to 17 page pdf:

https://www.cell.com/cell-reports/pdf/S2211-1247(18)31806-0.pdf

RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue Mar 19, 2019 02:35 AM

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JohnnyP, it is encouraging to see that you are aware of a range of metabolic treatments. On D's forum we have been compiling a list of a great number of them: stiripentol, honokiol ... . There are close to an endless number of metabolic treatments.

I must admit that I had been somewhat neutral on curcumin, though posts on D's forum have mentioned success. The big problem is that so many patients never receive treatments that are properly formulated, at the right dose, combined in the right way. With these parameters carefully optimized, it would appear that many potential metabolic therapies might be effective. johan on D's forum mentioned combo nanocurcumin and berberine (and others).

I am especially excited now about dual glycolysis/OXPHOS inhibition approach using nanoformulations. When I look through the scientific literature, I see a great many articles that might have a mito drug (such as mito-HK, mito-VES, etc.) and these can have very strong anti-cancer effects. Recently, I saw reports for mito-HK and 2-DG or 3-BP and the results were even stronger. But what about, cyclo-dextrin 3-BP combined with nanoMG? This could be a super strong and very specific treatment.

The syrosingopine and metformin article that you noted was mentioned on D's forum a while back. It does look very strong, though the research is only at the cell stage. What  side-effects might emerge? Of course, the big problem with so many of these studies is that even years later there is no follow-up. We might never have any idea what could happen even in an early pre-clinical in vivo study; yet, these are long approved FDA drugs. It is very frustrating!

D was placed in this circumstance several times as he cared for his wife. He would give a treatment and it would not always be clear what might happen. It is a treatment frontier that many are not be comfortable with.      

It would be amazingly positive if you could receive the caregiver funding! Just think if you could save up 5 months of payments and then negotiate with Dayspring in order that they might accept another 10 (?) of these payments as collateral. Dayspring has reported a great deal of success and they have a range of metabolic treatments that they use including forumulated 3-BP along with ketogenic diet. It is very impressive that they are able to achieve this without chemo.  

JohnnyP, after now over 5000 posts, metabolic treatment makes more sense than ever to me. At this point, we could all just admit defeat and move along to the next onco-fad. Who could blame us? We tried!

But I just do not see it that way. For me metabolic medicine is just channeling what a great number of alternative practioners have said for a very long time. When you attain the awareness that all of these approaches converge onto broadly defined metabolics, you develop great confidence that this is the way forward. On top of that there is now a significant push to move treatments such as 3-BP etc. into clinical medicine. Perhaps mainstream medicine might catch up with what was known by alternative medicine a century ago. 

The true thought leaders must have understood metabolic medicine deceades and decades ago. I would not at all be surprised if Warburg would have recognized the rough plan. Yet, here we are and focused nanoformulated metabolic treatments are now being published that are bringing us very close to potentially highly effective treatment. I wasn't sure whether we would ever reach 5,000, though now, I am not sure whether we will even need to reach 10,000.    

RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Thu Mar 21, 2019 01:04 AM

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New article to be posted to pubmed talks of sorafenib and 3-BP. A while back on the thread a poster suggested that sorafenib might have potentiated 3–BP response in the liver patient. Honestly, at the time I thought that was competely nuts. I would look back on the thread to check, though we have reached the point where you can't find anything anymore, so I'll just leave it at that. 

The soon to be published article actually did find that sorafenib can upregulate HKII and then lead to more effective 3-BP response. When it is phrased in this way, it is highly consistent with many other metabolic treatments that we have encountered. Sorafenib is actually be a metabolic therapy! What it can do is upregulate glycolysis! Bascially, here again we are looking at a somewhat primitive dual metabolic combo that has notable anti-cancer effects. It is quite odd how many times that we see a metabolic effect pop up like that. How often do cancer drugs actually have treatment effects through their metabolic influences? 

When we translate vague statements into intelligible metabolic language, it becomes clear almost obviously true. I admit when posters have talked about their chemo, I am completely baffled. How does this relate to metabolics I wonder? With chemo X what happens when it encounters resistance? Often it is back to square 1. There is no overall strategy. Yet, with metabolics, the treatments start to fit together into a comprehensive rational strategy. For instance, here, sorafenib (hit 1), leads to upregulation of glycolysis through HKII, 3-BP (hit2) then knocks down the tumor. There is a strategy in which the cancer evasive response simply feeds into more pain for the cancer. We now seem to be reaching a knowledge base in which we could endlessly loop through metabolic approaches without there being an opportunity for the cancer to find a route to evasion.    

What should also be noted is that before the liver patient received 3-BP after undergoing sorafenib, an ethical review panel needed to carefully deliberate over whether 3-BP would be allowed. This occurred even though the patient had already went past the median response time, had no other lines of treatment available, and had a feeding tube lodged in his stomach. 

The ethical challenge that emerges now is that sorafenib by upregulating HKII expression also can lead to greatly diminished life expectancies. As shown in Figure 6 and elsewhere from the upcoming article, liver patients treated with sorafenib who developed high HKII had noticeably reduced survival in fact high versus low HKII patients had a 60% versus 10% 3 year survival. This would be a tragedy on a far greater scale that will never make the headlines. Sorafenib treatment causes patients to have elevated HKII which if not rescued by 3-BP treatment greatly reduces their survival. I am sure all of us would be interested in the explanation of how withholding 3-BP from these patients could be considered ethical. Given this latest research, it does actually appear that 3-BP's potential was actuated by sorafenib in the instance of the liver patient who had a very dramatic response to treatment.

 

RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Fri Mar 22, 2019 01:21 AM

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PMID:30880247
Another exciting chemo-metabolic article! They are popping up everywhere! This time the well known proto-typical chemo drug cisplatin. Once again they report that cisplatin potentiates a  metabolic pathway: OXPHOS. Even short term treatment, creates a stable long term upregulation.
As I noted in my post yesterday, one can start to see things circling back and back again to these central metabolic pathways. Cisplatin encounters resistance through the upregulation of OXPHOS [along with glycolysis downregulation] the upregulation of OXPHOS was then reversed with metformin.
The article from today and the one from yesterday and likely others might offer an explanation as to why we, the Turkish clinic and others have seen such strong results when combining with chemo and metabolic approaches. If chemo is actually a disguised form of metabolic therapy then adding other metabolic therapies that we are all highly aware of metformin, DCA, .... would likely amplify the benefits. This is what we have seen! Now, however, we would actually have understanding of how it was working and perhaps choose even better combinations.  For example, cisplatin upregulates OXPHOS, though in highly hypoxic tumor regions there is not a great deal of oxygen to drive OXPHOS, and at the same time cisplatin is pushing down glycolysis, thus including an anti-glycolytic would possibly be a rational strategy to stress the hypoxic tumor cells. Cycling through stressing OXPHOS and then glycolysis would also be worth considering.
 
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