Page 450-460

Quote | ReplyDear finder, I am excited about your earlier comment of having a tumor sample and that you had the intent of sequencing it. This could be of substantial importance. We have been locked into the dismal logic circuit for the last few years that some people might benefit from 3-BP some of the time, though it has not been clear who those some might be. Having some way to select for the responder class would completely change the conversation. The above mention of the R337H mutant might also help identify a responder group. If it were possible to produce an endless stream of 3-BP responders based upon some genetic feature or otherwise we could finally get past arguing about its efficacy.

Any progress in moving this forward?
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon Apr 24, 2017 09:43 PM
Quote | ReplyAnother topic that our thread has not thought of enough is AZD3965. Astra Zeneca is developing this MCT-1 inhibitor along with a biomarker for MCT-1 expression in circulaing tumors.

PMID: 25281618
Figure 6C shows that high MCT-1 expression patients had the worst outcome.
"high MCT1 expression was associated with worse prognosis (P = 0.014)."PMID:24277449
This would appear to have considerable relevance to the devleopment of 3-BP. AstraZeneca is now doing a fair amount of the leg work to move MCT-1 drugs into clinicalpractice. It will be very interesting to see how they might incorporate 3-BP into their strategy. For example, they will use MCT-1 as a biomarker of response to their drug what would they do if they had a patient with especially high MCT-1 activity? Might be reasonable to first treat with 3-BP and then with AZD3965. AZD might not be interested in pursuing this , though some of their patients might be.Quote | ReplyShare    Emad-Ly

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

by Emad-Ly on Tue Apr 25, 2017 02:29 PM

Quote | Reply

On Apr 23, 2017 10:17 PM Jcancom wrote:

Emad, you mentioned above about blood transfusions. Is there a leak?

As you said concurrently managing these other surrounding issues can be just as important as when treatment needs to be interrupted to do symptomatic fixes markers can head in the wrong direction.

If this were a GI bleeder, anyone on the thread have suggestions for that?
no the reason for blood transfusion is the low blood counts

also i feel somehow that cancer become more aggressive after transfusion

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

by Emad-Ly on Tue Apr 25, 2017 02:55 PM
Quote | ReplyToday the tumor marker results

it was 608 4 weeks ago , now it is 611

the first week we did nothing , so i can make sure the tumor marker even climbed more than 608, it progressed very very fast from 322 to 608 in 5 weeks

now it looks stable after we stopped the progression

but also the outcomes are not good , after 1.5 years on chemo + DCA , my mother continuously need blood transfusion because of low blood counts

neuropathy is becoming worse

and all the good results we had in months , all just gone simply in 5 weeks

i can see now when doing blood transfusion after less than 3 days of chemo, you will totaly lose the chemo effect

that was a very bad mistake that cost us a lot

so now , 3-Bromopyrovate + Salinomycin will be next

i will share our results here from now on , hope this community hear good news from me in the coming days

thank you all

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

by Jcancom on Tue Apr 25, 2017 07:07 PM
Quote | ReplyEmad, please let us know what is happening!

Admittedly guidance from a web forum might not be the most ideal venue, it has to be better than how 3-BP treatments have been managed in other instances.

I greatly hope that this combo will help your mother.          Best Wishes for Success!
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue Apr 25, 2017 11:09 PM
Quote | ReplyI can't wait to see what happens with AZD3695!

In Figure 6B of PMID:24277449 the lower right red dots represent the patients that would be expected to be responders to 3695. Of note is that all of the black dots above the red dots would have highish MCT-1 expression but also highish MCT-4 expression and would thus not be expected to be good responders. Yet, for 3-BP the only main requirement is high MCT-1 levels, though it is not clear how high is high enough. All the dots to the right of the vertical line at 8 would be potential responders. From the figure it does appear that there would be a fair few in this treatment group that perhaps would benefit from 3-BP.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue Apr 25, 2017 11:13 PM
Quote | ReplyProbably a good idea that those on our thread brace themselves in advance for what 3695 might command as a marketed pharmaceutical in terms of cost and revenue.

A million dollar drug? Multi-billion dollar revenue?

Would not want to put anything on the table for where this might go.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue Apr 25, 2017 11:45 PM
Quote | ReplySomething else of note from the above reference, the research knocked down MCT-4 expression and 3695 worked even better. MCT-4 could act as an escape route to vent lactate. This could also thwart 3-BP's effectiveness. AZD might be motivated to also develop a MCT-4 inhibitor to boost their MCT-1 inhibitor. If this were to be done, then this might be another boost to 3-BP treatment.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by finder on Wed Apr 26, 2017 08:35 PM
Quote | ReplyDear Emad-Ly,

I am sorry to hear that your mother's situation is worsening. The increase of 608 to 611 is in itself not problematic, it is within the error range of these tests. What is the marker? The blood transfusion thing is something which I would not advise, so short after chemo. As is the use of antioxidants in combination with chemo. You simply eliminate the mechanism by which the medication is supposed to work. The combination of chemo with DCA can be very dangerous due to interference of the mechanisms that they work with. The neuropathy is indication that the DCA treatment is causing problems. Did your mother receive vitamin B supplements?

I give these remarks, but I am not a medical doctor. I do not pretend to be a medical doctor, whatsoever.

Strength for your mother and you.

kind regards,

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

by Emad-Ly on Fri Apr 28, 2017 11:58 AM

Quote | Reply

On Apr 25, 2017 11:07 PM Jcancom wrote:

Emad, please let us know what is happening!

Admittedly guidance from a web forum might not be the most ideal venue, it has to be better than how 3-BP treatments have been managed in other instances.

I greatly hope that this combo will help your mother.          Best Wishes for Success!
Thank you always Jcancom

of course guidance from a web is not a good idea , I'm always cautious and careful whenever i use new things

I will always share whatever happens

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

by Emad-Ly on Fri Apr 28, 2017 12:14 PM

Quote | Reply

On Apr 27, 2017 12:35 AM finder wrote:

Dear Emad-Ly,

I am sorry to hear that your mother's situation is worsening. The increase of 608 to 611 is in itself not problematic, it is within the error range of these tests. What is the marker? The blood transfusion thing is something which I would not advise, so short after chemo. As is the use of antioxidants in combination with chemo. You simply eliminate the mechanism by which the medication is supposed to work. The combination of chemo with DCA can be very dangerous due to interference of the mechanisms that they work with. The neuropathy is indication that the DCA treatment is causing problems. Did your mother receive vitamin B supplements?

I give these remarks, but I am not a medical doctor. I do not pretend to be a medical doctor, whatsoever.

Strength for your mother and you.

kind regards,

finder
Thanks finder

sorry i didn't mention the marker , its CA15-3 (metastatic breast cancer)

actually i think the markers declined , when the result was 608 we did chemo after 5 days from that , and the markers was increasing super fast before that , so i think it reached higher results before (maybe to 650 or more)

also doing the blood transfusion after just 2 days from chemo is the biggest mistake

regarding DCA + chemo , im doing like Dr Akbar Khan said , we are not using it with chemo , im using it before chemo and after few days from it to avoid any interference

and im using DCA + chemo for more than 1.5 years , actually the best response we have is when i give a good dose of DCA before chemo , not with chemo

but when we stop DCA , the chemo stops working

also im giving B vitamins to my mother almost all the time , it really helps , but both chemo + DCA are causing neuropathy so after a while the side effect will increase

i totally understand that you are not in a sitiuation to give any advice

but really the information you all are sharing is very helpful

you all are helping and i wish that you all continue to let this thread alive , and with the great info you have , its our own responsibility to decide what to do

I wish you the very best

Sincerely

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

by Jcancom on Fri Apr 28, 2017 01:58 PM
Quote | ReplyVery exciting research!

PMID:27026010
Perhaps we should start thinking about 4-PB!I have been wondering for a while about whether there are other chemicals that might make it through MCT-1. There must be others. Perhaps these other chemicals might have even more promising properties than even 3-BP.
The part about 4-PB crossing the BBB through MCT-1 was a real stunner. Possibly a drug class could be developed that selectively opened up MCT-1 at the BBB. Selectively open MCT-1 at the BBB and then selectively open up MCT-1 in cancer cells. Sounds promising. You would not want to do this without a follow through if it were to only allow lactate to flood the brain, though with an analog of 3-BP it could be a useful combo. Wonder if upregulated MCT-1 at the BBB is related to brain mets.Quote | ReplyShare    finder

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

by finder on Fri Apr 28, 2017 06:08 PM
Quote | ReplyDear Emad,

thanks for your clarifications to your previous remarks. They make much more sense now. And I think (my personal opinion) that you have carefully evaluated the consequnces of the various treatments, and made a well considered, wise descision on how to apply the different treatments. I can only wish you and your mother the best.

kind regards,

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

by Jcancom on Fri Apr 28, 2017 09:56 PM
Quote | ReplyLactic acid is enormously harmful to cancer patients.

"Lactic acid suppressed the proliferation and cytokine production of human cytotoxic T lymphocytes (CTLs) up to 95% and led to a 50% decrease in cytotoxic activity. A 24-hour recovery period in lactic acid-free medium restored CTL function."

PMID:17255361Normally, humans produce 1 mol lactic acid per day. Below article used dialysis with maximal lactic acid removal of 1 mol per day.   RLC [rate of lactic acid clearance]

"RLC was also increased ((3.46 ± 1.46), (10.38 ± 5.50) and (24.53 ± 14.69) mmol/h, P < 0.05 respectively)..."

Tumors would add more lactic acid, though perhaps there could be a way of moving down lactic acid with dialysis. Might be especially helpful in ACT.

PMID:24824239
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sat Apr 29, 2017 02:47 PM
Quote | ReplyEmad, could always stack the deck.

PMID:25957999Very exciting! You would know prospectively and non-invasively what the expectation of 3-BP response would be. What an enormously powerful technology. Why guess, when you could know? From the MCT-1 research, 3-BP might be a 25% roll, with ctDNA you could roll as many times as you wished and then choose the bullseye. Almost not sporting.

Further, with a comprehensive view of the existing ctDNA one has insight into the evolution of cancerome and what therapies would be helpful. With this omniscienceinto cancer, the endless argumentation concerning the effectiveness of various treatments such as 3-BP and many others would no longer be sustainable. The conduct of clinical trials might also need to be reconsidered. Real time treatment protocols?
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### RE: Anyone used 3bp (3-bromopyruvate)?

by finder on Sat Apr 29, 2017 08:13 PM
Quote | ReplyDear Jcancom,

an exciting development. But it is about expression of genes in circulating tumour cells. This means that these cells do not neccesarily reflect the genetic make-up of the solid tumour. Gene expression is a very complicated thing, and no conclusions are to be drawn from other cells/tissues but the target.

kind regards,

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

by Jcancom on Sat Apr 29, 2017 11:18 PM
Quote | ReplyI have been trying to understand how beta oxidation specifically in the peroxisomes might fit into the picture.

"...the amount of MCT1 at peroxisomes is much lower than the one of MCT2. Furthermore,MCT1is also present at the plasma membrane and, surprisingly, at the nucleus." Another article talks of MCTs being present on the surface of the mitochondria. PMID:25639644

I arrived at this line of thinking from beta oxidation of very long fatty acids occuring in the peroxisome which produces ROS instead of ATP [thought there might be potential to AMP up ROS in the cancer cells which are catalase deficient].

Firstly, I find it noteworthy that MCT1 is present in all of these different organelles. Has the 3-BP research talked of this before? An open MCT1 at the nucleus would give 3-BP free access to the genome {and posibly other sensitive locations}.

Secondly, the MCT2 at the peroxisomes in prostate cancer might open up treatment targets.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by finder on Sun Apr 30, 2017 06:27 PM
Quote | ReplyDear JcanCom,

I am afraid that at this moment, we do not even know the function of MCT1/2 at the cellular level, let alone on the subcellular level. Cellular and molecular modelling are still in their infancy and we do not really have a clear sight on any regulation mechanism in the sense that we are able to integrate knowledge from genes, proteins, RNA, iRNA, whatever. The number of interactions is currently beyond our capacity to model. Let alone understand.

What strikes me, as a biologist, is the wide bandwidth of physiological parameters that still allow to have a "normal" life. Which is in complete disagreement with the thermodynamic law of entropy.

kind regards,

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

by Jcancom on Sun Apr 30, 2017 09:21 PM
Quote | ReplyMan, where did this come from? !!!

https://www.neonctech.com/

NEO218

perillyl alcohol

PMID:28450161
3-BP might actually be moving to the clinic!
perillyl alcohol
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sun Apr 30, 2017 10:13 PM
Quote | ReplyThis is ridiculously exciting!

They have developed a 3-BP conjugate that does not need MCT-1? I cannot wait to see it in vivo.

It is not totally clear to me what motivated them to do this. 3-BP is a very toxic chemical, the fact that it can enter cancer cells with a degree of selectivity with an open MCT-1 pathway and an assist from tumor acidity makes it a plausible therapy. I would love to know how cancer cell selective NEO218 might be. Appears the clinial path for this could be intranasal targeting brain cancer?

This is a preprint, here's a typo:   "highly resistant to 3-PB, whereas MCT-1-positive" [3-BP not 3-PB]
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sun Apr 30, 2017 10:30 PM
Quote | Reply"perillyl alcohol in cherry and spearmint"

"Limonene then serves as a precursor to a host of other oxygenated monocyclic monoterpenes such as carveol, carvone, menthol, perillyl alcohol and perillaldehyde"

"Furthermore, because of its pleasant citrus fragrance, d-limonene is commonly added to cosmetics, soaps and other cleaning products. Thus, human exposure to monoterpenes through the diet or environment is widespread."

Is perillyl alcohol GRAS?
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sun Apr 30, 2017 10:58 PM
Quote | ReplyPerillyl alcohol has already been through 15 clinical trials involving over 600 patients and another trial this time in Glioblastoma Multiforme using intranasal delivery is underway. Some of the earlier trials used up to 16 gram oral dosing which caused some side effects.

I thought perhaps they were be thinking of intranasal with POH-3-BP, though that might not be necessary if they dosed more down in moderate mg dose range.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sun Apr 30, 2017 11:40 PM
Quote | ReplyOh my!!!

http://www.businesswire.com/news/home/20170426005840/en/PreS

People! We have been sleeping on this one!

3-BP is now in motion! Finally!

Wonder what the formulation will be for Prescience?

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

by Jcancom on Sun Apr 30, 2017 11:46 PM
Quote | Reply"The Company’s newest lead compound, PS-102, is a novel formulation of a particular halopyruvate called 3-bromopyruvate. PreScience has tested 3-bromopyruvate in numerous animal models and in limited human trials (through compassionate use protocols), and it has shown very high efficacy and tolerability. The data suggests that PS-102 will be effective against most, if not all, types of cancers, including pancreatic, lung, and breast cancer, because it attacks a fundamental component of the metabolic pathway of tumors. The Company already holds an IND for one formulation of 3-bromopyruvate (PS-101), and anticipates submitting a new IND application for PS-102 in 2017, with enrollment of a Phase I study targeting pancreatic cancer in 2018."

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

by Jcancom on Sun Apr 30, 2017 11:49 PM
Quote | ReplyStrange part is they have not changed their web page yet.

Anyone have any patent info on their new formulation- PS-102?

I think almost everyone had given up on this ever going anywhere. Will be interesting to see if they are truly serious about this or whether it is just meant to be a scuttle job.

Including MCT-1 expression with other biomarkers used for possible selection (if this were still required) would show  good faith.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Sun Apr 30, 2017 11:58 PM
Quote | ReplySo we finally see some money on the table.                            OK, bidding starts at 2 million.                                            In for a penny, in for a pound.

"$2 million Series AA Round. Proceeds of this round will fund the Company to a Phase I clinical study."
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 12:00 AM
Quote | ReplyThings are about to become much more interesting! Everything is now in motion and we'll have to fasten up for the ride for the next few months.Quote | ReplyShare    peggyznd

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

by peggyznd on Mon May 01, 2017 12:22 AM
Quote | ReplyDo note that the discussion is about Phase I trials in 2018.  No reference to the previous compassionate use studies and the success or lack thereof.  Wish that there was more information, and fear that this may be like so many others, something that never really leaves the lab.

I don't think it will be a few months, and also wonder if the older patent issues will come to haunt this study.

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

by dumbcritic on Mon May 01, 2017 12:01 PM

Quote | Reply

On May 01, 2017 2:30 AM Jcancom wrote:

"perillyl alcohol in cherry and spearmint"

"Limonene then serves as a precursor to a host of other oxygenated monocyclic monoterpenes such as carveol, carvone, menthol, perillyl alcohol and perillaldehyde"

"Furthermore, because of its pleasant citrus fragrance, d-limonene is commonly added to cosmetics, soaps and other cleaning products. Thus, human exposure to monoterpenes through the diet or environment is widespread."

Is perillyl alcohol GRAS?
Sadly it didn't work out when this was used orally.

*Based on the collective outcome of the above-mentioned animal studies, POH was formulated in soft gelatin capsules and tested in a number of phase I and II cancer trials, where it was given orally three to four times each day for several months [99,100,101,102,103,104,105]. However, the results were disappointing. Because a high dosage was needed (gram quantities), patients had to swallow a large number of capsules, which caused unrelenting intestinal side effects (nausea, satiety, eructation, vomiting) and fatigue. Although toxicities were fairly mild to moderate, some patients found the unremitting nature of the intestinal problems hard to tolerate and withdrew from treatment [101]. In addition, contrary to what had been documented in experimental animal tumor models, the antitumor activity of POH in patients was unconvincing. As a result, oral POH as an approach to cancer therapy was abandoned [106].* https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037741/
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### RE: Anyone used 3bp (3-bromopyruvate)?

by dumbcritic on Mon May 01, 2017 12:10 PM

Quote | Reply

On May 01, 2017 2:58 AM Jcancom wrote:

Perillyl alcohol has already been through 15 clinical trials involving over 600 patients and another trial this time in Glioblastoma Multiforme using intranasal delivery is underway. Some of the earlier trials used up to 16 gram oral dosing which caused some side effects.

I thought perhaps they were be thinking of intranasal with POH-3-BP, though that might not be necessary if they dosed more down in moderate mg dose range.
Here is some data for NEO218 http://www.cancerletters.info/article/S0304-3835(17)30275-6/fulltext
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### RE: Anyone used 3bp (3-bromopyruvate)?

by dumbcritic on Mon May 01, 2017 12:13 PM

Quote | Reply

On May 01, 2017 3:49 AM Jcancom wrote:

Strange part is they have not changed their web page yet.

Anyone have any patent info on their new formulation- PS-102?

I think almost everyone had given up on this ever going anywhere. Will be interesting to see if they are truly serious about this or whether it is just meant to be a scuttle job.

Including MCT-1 expression with other biomarkers used for possible selection (if this were still required) would show  good faith.
*Anyone have any patent info on their new formulation- PS-102?*

It's an oral version. In the patent (US 9492417 B2) they cite some preclinical data.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 01:26 PM
Quote | Replycritic, this is the best day in the history of the universe, EVER!

Yeah!

It'll take me a while to digest the patent that you noted and it is from 2009 so I am not sure whether there is anything new here. I thought maybe that they had an entirely new uptake strategy. I suppose that since this is now going mainstream we are going to have an entire scientific ecosystem that will arise to nurture 3-BP forward. Might also aleady be able to leverage some of the tech that is in development for other similar products.

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

by Jcancom on Mon May 01, 2017 01:30 PM
Quote | ReplyThe article you noted on perillyl alcohol- 3-BP really opens things up. As described it sounds even better than perhaps even PS-102. POH-3-BP does not need MCT-1 (WOW!) that is very startling.

There are now a whole bunch of questions that need to be answered. In particular, how is it entering cells? 3-BP due to its way of entering cells has a certain safety associated with it. If POH- 3-BP has found some other sneaky way of entering cells this could get very interesting.

With all this horsepower under the hood there will probably going to be quite a few who will want to amp this one up. I am very anxious to see what they might do to amplify the 3-BP effect. If there were one or two more such amp ups, 3-BP could be massively massively powerful.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 01:39 PM
Quote | Replycritic, with the oral POH, that was truly heroic giving 16 GRAM dosing. Are there other pharmas that have ever went that high? It almost seems ridiculous.

What I was thinking, though that with the POH-3-BP formulation if you were talking more about perhaps dosing somewhere in the 50 mg ball park those dosing issues disappear for oral administration.

Also very excited about the intranasal brain cancer results. Whoa! We've had  glioblastoma multiforme patients on our thread before and it seemed so hopeless. The POH clinical results with nasal dosing for GBM appear fairly strong. Would this help with other types of brain cancer? The latest article used several GBM cell lines to test POH-3-BP. Will be very very interested in seeing what intranasal POH-3-BP might do.

This is awesome!

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

by Jcancom on Mon May 01, 2017 01:45 PM
Quote | ReplyI think some readers of our thread might have misread the recent press release. Here it is again in a more abbreviated form.

"...3-bromopyruvate ... has shown very high efficacy and tolerability. ... data suggests that... (it)... will be effective against most, if not all, types of cancers, including pancreatic, lung, and breast cancer,..."
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 03:39 PM
Quote | Replynothing to lose,

PMID:27598140Quote | ReplyShare   Jcancom

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

by Jcancom on Mon May 01, 2017 03:47 PM
Quote | ReplyAnyone able to access ACD/Lab’s BBB Penetration Module software (Advanced Chemistry Development Inc.)? I would love to see what the read out was for 3-BP.

http://www.acdlabs.com/products/percepta/portal/
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 06:10 PM
Quote | ReplyThis is such an exciting development!

Metabolic cancer drugs are not like the others. With 3-BP you can know within minutes if it will work or not. Patients in any clinical trial could be pre-screened on the basis of whether they will be responders or non-responders. Perhaps they could also have a category for those patients that will essentially vaporize their tumors.

This level of predictive power does not exist for other cancer drugs. Even in those who have specific gene expression it can take years and years to sort out who will actually respond. With 3-BP response will be known before treatment. Doesn't this make it too easy? 3-BP will under these clinical conditions have to be found to be successful.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 06:20 PM
Quote | ReplyThere are some points from the Neonc article that could use highlighting.

Many 3-BP articles (including this recent one) talk about the enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). What is of particular interest is that this is the first enzyme in the so called pay back phase of glycolysis.

Up till now in the investment phase ATP is spent to pass through hexokinase and phophofructokinase and now it's time for payback for all this investment. Time to cash the dividend cheques. But there are no dividends! 3-BP attacks glycolysis at its weakest point. Attacking GAPDH means that the cell will spend 2 ATP without a payback. This could explain why a rapid energy crisis quickly ensues.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 06:26 PM
Quote | Reply"In vivo, 3-BP has shown therapeutic potential in a number 98 of animal tumor models [6, 28-30], although liver toxicity was noted [31]." I found this a somewhat odd quote from the article. Typically when one provides a reference one expects that the reference provides some confirmation of the statement; the reference is accepted usually without further verification as supporting evidence.

However, when reference [31] ("although liver toxicity was noted [31]") was checked at the back of the article the title was "Aerosolized 3-bromopyruvate inhibits lung tumorigenesis without causing liver toxicity,".
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 06:27 PM
Quote | ReplyAlso from reference [31]

"Due to the known liver toxicity of 3-bromopyruvate in animal models given large doses of 3-bromopyruvate, confirmed in this study, we decided to test the chemopreventive activity of aerosolized 3-bromopyruvate in the same lung tumor model. As expected, aerosolized 3-bromopyruvate similarly significantly decreased tumor multiplicity and tumor load by 49% and 80%, respectively, at a dose of 10 mg/mL by inhalation. Interestingly, the efficacy of aerosolized 3-bromopyruvate did not accompany any liver toxicity indicating that it is a safer route of administering this compound."
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 06:54 PM
Quote | Replycritic, I was just reading the 3-BP Stateside thread on Team Inspire and the last post mentioned a post that you made on our thread last August about Neonc and Perillyl Alcohol. Wow, you've known about that one for a year? It was not clear from the Inspire thread, though have they been talking about POH-3-BP for almost a year? I am not sure whether I remember this one before.

This thread is now completely unsearchable so I thought it would be easier to ask you directly.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Mon May 01, 2017 07:57 PM
Quote | Replyfinder, any word on the German investigation.

These recent developments might complicate the filing of a final report.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by finder on Tue May 02, 2017 05:56 PM
Quote | ReplyDear Jcancom,

I do not think that the DOJ in Germany is following the scientific literature for 3BP. They have other problems.

kind regards, finder
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### RE: Anyone used 3bp (3-bromopyruvate)?

by finder on Tue May 02, 2017 06:11 PM
Quote | ReplyDear Jcancom,

As for the combination of 3BP with perillyl alcohol, at this moment I have not seen a chemical formula how such a molecule would look like. The things that I have drawn using available information, do not really make sense. If we assume that the core of the activity of 3BP is its excellent function in a nucleophilic pyruyilation reaction of cysteines and methionines in enzymes, combined with the selectivity impinged by its slipping into cells with high MCT-1 expression, then adding a molecule such as perillyl alcohol, does not make sense. PA in itself is known to permeate membranes of cells, abolishing the selectivity of 3BP. But I may be mistaken, have not been following al developments lately.

kind regards, finder
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 07:18 PM
Quote | ReplyDear Finder,

page 31 Figure 2 of PMID:28450161

Condensation reaction with 3-BP's hydroxy tail.

From what I can tell they ran the software that I mentioned above on a library of cancer therapeutics and 3-BP just popped out of their search. This would be an unbiased search. I do not see how else they would have been lead to it.

There are quite a few open questions as you said. The large advantage with 3-BP is that it does have selectivity through MCT-1. POH-3-BP apparently doesn't need MCT-1, do you now only have a toxic molecule that doesn't have selectivity. Really want to know what the answer to that question is.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 07:27 PM
Quote | Replyfinder, article also discusses pyruvylation by 3-BP and NEO218 (POH-3-BP). Also see Figure 10A

"... whether both 3-BP and NEO218 would be able to covalently pyruvylate GAPDH protein. The 451 amino acid sequence of GAPDH contains 4 cysteines (in rabbit at positions 150, 154, 245, 282), and their thiol functionalities represent potential candidates for nucleophilic  addition. ...   with 3-BP, all 4 cysteines were altered by the addition of pyruvate; in the case of incubation with NEO218, the same four residues revealed attachment of pyruvate-perillyl alcohol moieties (Fig. 10A). Taken together, the above results indicated that 3-BP and NEO218 caused inhibition of GAPDH enzyme activity via alkylation of its cysteine residues, in particular active site Cys-150  (equivalent to Cys-152 in human GAPDH), which is known to be most critical for enzymatic function."
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 07:34 PM
Quote | ReplyThought I should repost that one as a sound bite. People have an ever decreasing attention span so might as well get to the point.

"... 3-BP and NEO218 caused inhibition of GAPDH enzyme activity via alkylation of its cysteine residues, ... active site ... Cys-152 ... GAPDH ... most critical for enzymatic function."

Just to be clear 3-BP attacks the most critical active site of GAPDH? GAPDH is the first enzyme in glycolysis where cells actually get energy payback? Meaning that with a disabled GAPDH enzyme the cancer cell is actually producing negative energy? How many minutes could a cancer cell survive making negative energy?
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 07:50 PM
Quote | ReplyDear Finder, I am greatly interested in hearing your thoughts about what technology could/will be available to select 3-BP responders prospectively now that we are within the context of planned 3-BP trial/trials.

We have talked about this constantly on thread, though now it appears that we are actually heading for the clinic. For me this is a critical question. If it is possible to prospectively select those who will be responders, then the entire rationale for conducting 3-BP clinical trials is called into question. Why bother?

Clinical trials have always been needed because prospectively predicting the result to a high degree of certainly was not possible. Thus, clinical trials that last for years and years often ending without a clear result.

With 3-BP it would seem conceivable to easily predict outcome before patients were therapuetically dosed. Might  radiolabeled 3-BP be of use?
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 07:57 PM
Quote | ReplyMore Science Fair Winners.

“Enhanced CpG Activated Macrophage Killing of 3-Bromopyruvate Pre-treated 4T1 Breast Cancer Cells”

Florida Atlantic University
Category: Health & Medical Sciences

Basically what I am seeing here is remember to put "3-Bromopyruvate" into your science fair entry and then go pick up your trophy.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by peggyznd on Tue May 02, 2017 08:02 PM
Quote | ReplyThis goes to the heart of what a clinical trial can do. In the Phase I of a trial, the basic issue is safety.  Assuming that there is rationale from the lab and subsequent animal studies, and the required safety measure, proper consents and so on are in place, a Phase I trial could be approved, perhaps for 20-40 patients.  If there was also some benefit to the patients, that would be a reason to be ready to go into a Phase II trial which would test the dosage levels, and perhaps with a mix of patient types.  Since the issue with 3-BP and its efficacy in various tumor types would be of interest, this could be a more of a 'basket'type trial, with a mixture of patients with various cancer types being tested.  Maybe there would be only solid tumors, but a mix of them.

WHen there is good evidence of any decent response and without serious side effects which can be managed, there is a possibility of FDA approval at that time.  This was the case for high dose interleukin2 for metastatic kidney cancer, as there was simply nothing else shown to be effective.  It was a pretty low bar.

If 3-BP were to get to a Phase II stage, and yet not show efficacy or benefit, but still prove to be safe, then it might go into larger trials on Phase III, which could be tested against a mix of cancer types and the various approved medications.

Of course, the quick answer to "Why bother?" is that none of the testing that might prove who would respond has truly been done, although there is always an attempt to find the potential responders.  Trials might include only those with certain cancer types, patients of a certain age, those previously treated or not treated, and with any specific treatment or drug.  But to ask seriously, "Why bother?" is a barrier to planning out the kind of trial that might lead to an early approval.  In the US, once a drug is approved for use in one indication, it can often be used in an 'off-label' use.

But, as we have recently seen in Germany, the lack of controls of the use of this or any other drug, approved or not, can endanger the ongoing use of the drug, and not least of all, the patients.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 08:20 PM
Quote | ReplyPeggy, Thank you for your response.

The press release talked of the first 3-BP phase 1 being for pancreatic cancer which seemed somewhat unexpected, even though this is what has been posted to the Prescience Labs webpage for a number of years. I would have thought that they would have went with a basket approach also.

My "Why bother?" comment was directed at the fundamental premises behind the philosophy of clinical trials. In both published patient reports of 3-BP the responses that occurred happened rapidly. Within hours, within a day.

Metabolic medicine raises concerns for me about the entire methodology of clinical trials. Up till this point clinical trials have not been conducted with the expectation that responses could be generated perhaps in minutes. Trials with 3-BP might introduce innovative approaches to clinical trial managment.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 08:36 PM
Quote | ReplyTo be more specific consider PMID:24636230 Figure 3B first 3BP treatment of 1 mg/kg IV. The patient's LDH falls over 1000 U/L within 24 hours (probably more like 3-4 hours tops).
Translate this into a clinical trial and give perhaps a subtherapeutic dose of 0.25-0.5 mg/kg. Wait a few hours and see whose LDH levels have declined a few hundred points. These responders are then entered into the trial. There is no great high tech involved here and this is not the entire story as some of them will become 3-BP resisters, there are other technologies that would be much more effective.
However, for illustrative purposes this highlights my concern. Basically, the selection round has found the responders. Clinical trials have typically been conducted in order to search out the responders. With a pre-treatment round you have already found them. "Why bother?" seems to apply. Of course, you could also use whatever response criteria that you liked. For example you might say we want the 1% of patients with the most extreme 3-BP response.
You are now dealing cards to yourself face up with the ability to choose which cards you want. Clinical trials have never been conducted on that basis before.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 08:43 PM
Quote | ReplyThe reason that this line of thinking has emerged is because that is how metabolic medicine works.

The immune cancer drugs that are so much the rage now can take years for clinical trials to find the separation. Typically PFS is no difference from control.

With 3-BP you can shut off the energy supply to the cancer cells which would be expected to have immediate consequences. At some point an IPO might emerge, will be very interested to see how the money interprets this perspective. What I am seeing is that 3-BP lets you self deal the cards to yourself resulting in almost no risk of failure.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by peggyznd on Tue May 02, 2017 08:47 PM
Quote | ReplyI am confused about the use of LDH as a biomarker of response to the 3BP, which might well be correlated as you suggest, but that is still a surrogate for the response from the tumor.  This potential to lower the LDH in the patient population would simply be an 'inclusion' requirement, just as age, previous treatment so on.

Perhaps you could find a study which shows that LDH lowered by 3BP is indeed correlated with tumor death/shrinking etc.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 08:57 PM
Quote | ReplyAs another implementation of a 3-BP trial one could specifically search out the total responders. In Figure 3B noted above, the patient's LDH level decreased from 4500 to 12 after 3-BP paracetamol combo.

Notably, "no treatment (except supportive treatment) was given when acute conditions were present."

So, now you conduct a clinical trial only with those responders whose LDH levels fall by 99.7% or greater. Before starting such a trial remember to have riot police on site, things probably could get interesting when patients with no respiratory capacity have near 100% reductions in tumor metabolism within minutes of 3-BP treatment.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 09:03 PM
Quote | ReplyI have been around that merry go round about LDH before.

As a quick and easy measurement it surely has its purpose, though there would be no reason why a similar though more specific marker could also be used. It would show the same result, though there would then be no argument.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 09:19 PM
Quote | ReplyWould the FDA allow this?
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 09:54 PM
Quote | ReplyPeggy, in your above post you noted that LDH could be used as an inclusion. To your knowledge would the FDA accept such an inclusion?

Would the FDA allow a clinical trial for 3-BP that had the inclusion that patients would need to demonstrate a 99.7% or greater reduction of LDH on 3-BP pre-loading?

I am not sure if they would. Making such a concession would mean that the trial was unfailable.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Tue May 02, 2017 10:06 PM
Quote | ReplyFrom the Prescience Labs website,

"The planned Phase I study will evaluate the dosing regimen of the drug to determine the maximum tolerated dose (“MTD”)."

This refers to the planned Phase I study with PS-101 not for PS-102. However, this has always struck me as an enormously bad idea. 3-BP is considered a metabolic poison, searching around for the "maximum tolerated dose" would on the surface seem to be an extraordinarily dangerous thing to attempt. The first sign that you had reached the MTD might occur when ATP production stopped.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Wed May 03, 2017 12:51 PM
Quote | ReplyMore excitement.

dibromopyruvate and propionic acid.

http://journals.plos.org/plosone/article/file?id=10.1371/jou
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Wed May 03, 2017 12:56 PM
Quote | ReplyAn exploration of the 3-BP chemical universe really needs to be done.

We have: 3-Bromopyruvate, dibromopyruvate, tribromopyruvate, 3-bromo-2-oxopropionate-1-propyl ester (3-BrOP), dibromo-2-oxopropionate-1-propyl ester, tribromo-2-oxopropionate-1-propyl ester, propionic acid among many others.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Wed May 03, 2017 05:20 PM
Quote | ReplyDo INDs become part of the public record?
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Wed May 03, 2017 05:35 PM
Quote | ReplyStill thinking about whether an inclusion could also be turned into an outcome measure. Only allow predetermined responders into the trial?

This would be different from a similar use of genetic screens in that with a metabolic screen an exact predetermination of response is conceivable (it would be a quantitative measure). The genetic trials (e.g. BRAF mealnoma) have had strong results, though they were not able to select only the extreme responders.

The 3-BP trial could also be done in patients with very severe illness. Could this be filed as an orphan indication?
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### RE: Anyone used 3bp (3-bromopyruvate)?

by peggyznd on Wed May 03, 2017 05:48 PM
Quote | ReplyI do not understand your thinking re an inclusion being an outcome measure.  It is logical to propose that patients with certain characteristics could be potential responders to a newly proposed treatment.  If the treatment is for one type of illness, then you want people who do indeed have that illness.  There is nothing to be gained by testing for effectiveness in a patient population free of the disease, except to show that the well population is not HARMED by the treatment.

You do want to use some logic about who is likely to respond, which really goes to the reason for the proposed treatment in the first place.   The 'predetermined responder' does not really exist in scientific reviews, until you show that the presumed responder is indeed a responder.  That is what the trial would be attempting to do--using a biomarker or simply patient characteristics.

As to the question of finding the maximum tolerated dose, it is obvious that the researchers would make some very conservative guesses as to the dose in humans, based on previous animal studies, and will start at very low doses.  THere may be increasing doses, not really even looking for response as to the benefit of the treatment, but as to the side effects/adverse events, etc that could come with the disease.  When they encounter a patient who has an extreme side effect, and/or is hurt by the treatment--this does happen, and recently in trial in France--whether by the actual drug tested OR the delivery system--also needs to be designated--then the dose level would drop back.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by dumbcritic on Wed May 03, 2017 07:46 PM

Quote | Reply

On May 01, 2017 10:54 PM Jcancom wrote:

critic, I was just reading the 3-BP Stateside thread on Team Inspire and the last post mentioned a post that you made on our thread last August about Neonc and Perillyl Alcohol. Wow, you've known about that one for a year? It was not clear from the Inspire thread, though have they been talking about POH-3-BP for almost a year? I am not sure whether I remember this one before.

This thread is now completely unsearchable so I thought it would be easier to ask you directly.
I added a link to their site on this thread going back. It's only been in the last few months that they published some data on NEO218.

?NEO218 (3-Bromopyruvate POH)NEO218NEO218Quote | ReplyShare   Jcancom

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

by Jcancom on Wed May 03, 2017 07:58 PM
Quote | Replycritic, love to hear any thoughts that you might have about Neo218. The recent article talked of cell entry independent of MCT-1. That could be very awesome or not so good depending on how selective it was for cancer cells. Is NEO218 cancer cell selective?

I am also excited about POH itself. Some of the intranasal results brain results are impressive.They  also seem to indicate that this could be effective for secondary brain cancer. I wonder about the prevention potential.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Wed May 03, 2017 08:03 PM
Quote | Replycritic, about the inclusion question that we have been discussing. You have very insightful posts. Would the FDA allow it?

Inclusion: Body Wide total tumor MCT-1 positivity as evidenced by scanning

Secondary Outcome Measure: Metabolic tumor Response as evidenced by scanning

Randomized Trial: Patients with complete MCT-1 positive tumors will receive 3-BP or placebo.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Wed May 03, 2017 08:14 PM
Quote | ReplyFor the maximum tolerated dosing, I was disappointed that Prescience picked up on the same terminology that really does not apply to 3-BP. Every other cancer drug works on this idea that you find some response and then you keep dosing up until people get very sick. This is true even for the newest immunotherapy drugs. Some patients will have grade 3, 4, or higher adverse effects with many cancer drugs.

3-BP should be different. The published reports have not talked about substantial side effects that are a direct consequence of the treatment, though more from the massive TLS responses. Instead of maximum tolerated dosing, I think the more appropriate metric they should be investigating is effective therapeutic range. There is no need to max out anything with 3-BP as there is enough therapeutic index horsepower under the hood.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by dumbcritic on Wed May 03, 2017 08:22 PM

Quote | Reply

On May 03, 2017 9:35 PM Jcancom wrote:

Still thinking about whether an inclusion could also be turned into an outcome measure. Only allow predetermined responders into the trial?

This would be different from a similar use of genetic screens in that with a metabolic screen an exact predetermination of response is conceivable (it would be a quantitative measure). The genetic trials (e.g. BRAF mealnoma) have had strong results, though they were not able to select only the extreme responders.

The 3-BP trial could also be done in patients with very severe illness. Could this be filed as an orphan indication?
I'm hoping after a few more rounds of funding they will have raised enough for a few other phase I trials. Ideally they would test both PS-101 and 102. It seems the former is a specific systemic formulation but can also be delivered using regional delivery. The latter as we know is an oral version. Beyond their first IND for pancreatic cancer then I hope they test this in patients with HCC (via TACE) and in SCLC via IV.

After data from the phase I trials comes in then they could be granted fast track and orphan drug designations by both the EMA and FDA for these unmet indications. Another possibility is that the data shows a compelling median overall survival relative to historical controls and current SOC. Should this happen then they could meet with both the FDA and EMA for an end-of-phase 2 meeting which then allows them to go into a pivotal phase III.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Wed May 03, 2017 09:29 PM
Quote | ReplyI have seen enough bogus, fraudulent and unethical clinical trials to fear that we are probably going to be looking forward to decades of empty 3-BP trials that never show anything based on their poor design.

As soon as we see a pre-specification for response, then we should expect rapid development. There are other instances of cancer drugs that showed extreme response rates where the FDA quickly moved products to market.

Once this is IPOed with investors and daily trading we will have a much better idea of what the money thinks. Investors would never allow this to float for years and years if a biomarker could directly identify the immediate and total responders.

For the orphan indication, I was thinking something along the lines of MCT-1 responders. MCT-1 is the big biomarker, even more so than tumor location. So, start off with a basket phase 1 trial and pre-specifiy those who have large 3-BP potential response and then go with an orphan for that phenotype.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Wed May 03, 2017 09:39 PM
Quote | ReplyIt would be so cool if a fundraising effort could spring up that would find the extreme responders and directed them to the 3-BP trial. The company might do the easy thing and just open enrolment to the first 20 patients that showed up. That would likely not result in a successful trial.

However a crowdfunding campaign could raise the cash so that the patients in the trial were selected on the basis that they would have a large response. Technologies that might be suitable might include tumor or somatic genotyping, scans, liquid biopsies etc. .

There might be a fair amount of popular support for such an initiative because unlike most cancer research, such an idea would have a substantial chance of success.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Fri May 05, 2017 01:56 PM
Quote | ReplyVery startling!

PMID:28446878
Equations 1 and 2 are equations describing the growth of pancreatic cancer. Somehow they managed to reduce the entire complexity that is cancer into three main sets of variables: atp, glucose, glutamine.
3-BP helps out with atp and  http://www.calithera.com/publications/  helps out with glutamine. It would appear that if you then plug lambda (which should be driven to near zero with above treatments) back into equation 1 about all you are left with is the rate of change of cancer cell numbers as negative.Quote | ReplyShare    Jcancom

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

by Jcancom on Fri May 05, 2017 02:07 PM
Quote | ReplyThis was not an empty exercise in fitting the model to the numbers and then saying the model reflected the numbers. The simulations they used helped in providing validation.

This modeling approach as the article suggests could be used in other cancer and perhaps in vivo.

Having such an equation that was fully validated could be of considerable benefit in a 3-BP clinical trial. Perhaps it could give yet even more insight into how patients might respond to treatment (especially those who might be in more of the typical responder category).

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

by finder on Fri May 05, 2017 03:51 PM
Quote | ReplyDear Jcancom,

I think I will have to increase the confusion of doing a Phase I trial with 3BP. If we consider the possibility of TLS induced by 3BP in patients with responding tumors, what is the rationale of doing a Phase I? Giving 3BP to healthy people will lead to a maximum dose. If this dose is given to people with a responding tumor they are likely to be killed. As a tantalizing thought: why not give people a dose of 3Bp to find out whether they have a malicious tumor? As a diagnostic tool? Monitor blood chemistry and you will know.

kind regards, finder
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Fri May 05, 2017 05:21 PM
Quote | ReplyDear finder, I hadn't thought of that one: those who would be expected to be maximal responders could be put on the exclusion list. It might be too dangerous to treat them because of potential for TLS.

I had realized that seeking out the maximal responders could be dangerous as it is entirely possible that turning off the response once demonstrated with NAC etc. might not always be effective. I will be very interested to know how effective anti-TLS therapy can be in patients who are being carefully monitored for it.

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

by Jcancom on Fri May 05, 2017 05:28 PM
Quote | ReplyI would restate that maximum tolerated dose really should not apply to 3-BP. The problem is that every single cancer trial searches for a maximum tolerated dose and so Prescience thought well we should search for the MTD too.

This makes no sense for 3-BP. Maximum tolerated doses are only investigated because pharma wants their cancer drugs to have the best possible chance of hitting the p value. The more drug the more responders and also the more the side effects.

Considering the likely therapeutic index of 3-BP, there does not seem a convincing rationale to try to push right up to the line when severe side effects would occur. Once within the therapeutic dosing range in the strong responder subclass, I really cannot think of what marginal benefit would exist for dosing up.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Fri May 05, 2017 05:38 PM
Quote | ReplyThis discussion actually helps to clarify my confusion about the question of "Why bother?". The "Why bother?" was in relation to the idea if you can predetermine the maximal responders, then any randomized clinical among these maximal responders will find that 3-BP has a massive anti-tumor effect for them. Obviously.

From the current discussion, I can see that the question of interest in a preselected clinical trial with 3-BP is no longer did the patients respond or not (that has already been established), the more interesting question is how best to manage the anti-tumor trajectory of these patients through time. One would guess that the plan would be to have this response as nice and steady though not excessively aggressive.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by peggyznd on Fri May 05, 2017 05:38 PM
Quote | ReplyJcancom,

The value of the maximum tolerated dose issue is not to determine how high a dose might go with every patient, whether with a tumor or not, but what a safe dose would be without exceedingly high side effects.  No one would 'push to the line of severe side effects", as the tolerability of any drug is part of the study.  Whether or not there is indeed 'a strong responder subclass', that alone may not be the case, and it may not be the Phase I goal.  Until someone is able to read the entire trial protocol, these questions are pretty irrelevant.  Is there a trial proposal in the works right now or not?
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### RE: Anyone used 3bp (3-bromopyruvate)?

by finder on Fri May 05, 2017 05:41 PM
Quote | ReplyDear Jcancom,

I appreciate your deep thinking. But I am afraid that even you do not have a comprehensive understanding how 3BP works. In itself, it is an unhandable chemical, due to its instability. BUT IT WORKS. An it works because of the MCT-1 uptake, its ability to inactivate GAPD. When administered to a healthy person, it will only elicit mild kidney pain. However, when administered to a person with a responding tumor, things are likey to give dramaticaly different outcomes. TLS kicks in, ammonia levels might go through the roof, and the patient dies. Look at the graphs in the case report. Most of the lake fish massive deaths are due to ammonia. And I know, ammonia is not commonly associated with TLS. But these people would not recognize TLS when it were in their own body.

kind regards, finder
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Fri May 05, 2017 07:08 PM
Quote | ReplyIn order for 3-BP it needs to simple; yet in order for an enforcable patent it needs to be more complex.

I was unsure about that point: do 3-BrOP, dibromopyruvate not also enter through MCT-1?

There are a few others that are claiming enhanced effectiveness, though I am wary because they have only reported in vitro results. Without selective entry 3-BP is only a toxic molecule.

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

by Jcancom on Fri May 05, 2017 07:13 PM
Quote | ReplyOne of the big lifts for me over the last few days is realizing that an entire economy/ecosystem is developing for 3-BP. Developing a diagnostic to determine who would be a good 3-BP responder could become such a great product for cancer patients. Without this, there have been several friends of our thread who are no longer alive partially because they were not able to know if they would be a 3-BP responder or not. Several others who have posted on our thread while never being treated with 3-BP took crucial time weighing the value of treatment with it. Having a simple test that could clarify likihood of response would be such a benefit for patients.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by finder on Fri May 05, 2017 07:17 PM
Quote | ReplyDear Jcancom,

the solution is quite simple: use PET scans with 76Br-3BP to find out whether a tumor has the appropriate metabolism to be targeted with 3BP. It will light up as a lighthouse.

kind regards, finder
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Fri May 05, 2017 07:18 PM
Quote | ReplyI am also encouraged when thinking of all the cancer products that might now want to combine with 3-BP. 3-BP has such large anti-tumor potential that there is quite likely a range of drugs that would love to steer some of that therapeutic horsepower in their direction.

From what we can see now combining with anti-glutaminase drugs should make sense.

I am also interested in whether a T-Vec with a cancer cell specific SLC16A1 (MCT-1) might not be on the table now.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by nothingtolose on Fri May 05, 2017 07:21 PM
Quote | ReplyHi J,

I know individual tumor characteristics vary a lot in each cancer type but there is existing info on mct 1 expression of most cancers, thats a good starting point to decide if its worth trying.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Fri May 05, 2017 07:25 PM
Quote | ReplyDear Finder, yeah I thought so. I just did not want to get slammed again and there is no way that I could go through all of the back posts.

I was thinking that perhaps even better would be to something like radiolabled lactate or propionic acid. For the screening, all we need is something that can selectively enter MCT-1, preferably without actually having a therapeutic effect.

One of my big worries would be that the FDA would require exhaustive testing for such a screen, even if were similar to already existing and in use technologies. It would be amusing if the components were already in some way now in use.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by Jcancom on Fri May 05, 2017 07:38 PM
Quote | ReplyHey, ntl! Thanks for posting!

Yeah, I was looking at D's 3-BP page and there is a figure that shows the different tissue MCT-1 expression for normal and cancerous cells. It is probably based on small samples and best to be cautious, though it looks like the two best ones to consider based only on that info would be pancreas and kidney.

Though with the diagnostic scanner idea we have been discussing none of that might really matter. A scanner could give you a good picture of where resistance could be expected. Earlier on the thread I noted that we have heard of a 3-BP patient who had a good initial response but then resistance occurred. By having a better view of the overal response potential perhaps such temporary responders might not be thought of as good 3-BP candidates.

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

by Jcancom on Fri May 05, 2017 07:46 PM
Quote | ReplyWhat is also notable from the recent docking study was that they found that propionic acid also seems to have anti-cancer properties. We went through that on the thread a ways back and we found that anything that looks similar to lactate/3-BP probably is going to have anticancer properties. So no surprise there propionic acid looks similar to lactate and appears to have potential anti-cancer properties.

What I found even more interesting is that propionic acid is a widely used food additive. Makes me wonder whether adding this in with 3-BP might make sense. Perhaps lower the 3-BP dosing while taking advantage of the strong points of PA as shown in the docking article.
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### RE: Anyone used 3bp (3-bromopyruvate)?

by nothingtolose on Fri May 05, 2017 07:49 PM
Quote | ReplyHi J,

I agree the scanner solution is more reliable.

I think temporary response is awesome, the rest is pretty unpredictable with cancer but u r right.

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

by Jcancom on Fri May 05, 2017 07:57 PM
Quote | ReplyIf there a genotype that predicted extreme 3-BP response that could be picked up from a simple gene chip that would be super awesome! By going right for the extreme responders you might be able to answer that question fairly quickly. That would definitely change the ball game. Typical people could simply their genotypes to establish whether they or even others in the family would be likely responders.

I am not entirely sure though whether that actually makes sense. For example, if one were to have some weird variant in the SLC16A1 gene that massively cranked up MCT-1 expression, then how would this help 3-BP to enter cancer cells selectively? Nevertheless, it is not completely unreasonable to suppose that there might be such variants that would help in a response.
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