Anyone used 3bp (3-bromopyruvate)?

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

by dumbcritic on Thu Nov 29, 2018 05:39 PM

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The first patient with rGBM (all enrolled will have to have unresectable disease) has been treated with DNX-2440, an oncolytic virus expressing OX40L in a PhI. The company behind this has also entered into a strategic partnership to develop peptide-coated viruses as well.

Another (ONCR-177) will go into a PhI next year. This is injected locally and 'armed' with IL-12, FLT3L, anti-CCL4, anti-CTLA-4 and anti-PD-1.

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

by dumbcritic on Thu Nov 29, 2018 07:22 PM

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I've just come across SM-88. This utilizes a proprietary dysfunctional tyrosine derivative. After uptake, it interrupts the metabolic processes such as protein synthesis, which makes cancer cells vulnerable to oxidative stress and leads to apoptosis. Also, worth noting, the drug is comprised of three active non-tyrosine derivative components which are sirolimus, phenytoin and methoxsalen. Each of these is already FDA approved.

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

by dumbcritic on Sun Dec 02, 2018 08:12 PM

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On Nov 29, 2018 5:39 PM dumbcritic wrote:

The first patient with rGBM (all enrolled will have to have unresectable disease) has been treated with DNX-2440, an oncolytic virus expressing OX40L in a PhI. The company behind this has also entered into a strategic partnership to develop peptide-coated viruses as well.

Another (ONCR-177) will go into a PhI next year. This is injected locally and 'armed' with IL-12, FLT3L, anti-CCL4, anti-CTLA-4 and anti-PD-1.

Based on this [1] paper it would be nice to see a PhI testing Imlygic, Yervoy (+/- 2DG) in patients with PD-1 inhibitor refractory metastatic melanoma. In this setting Yervoy alone offers only a modest benefit (10%-13% ORR) and DOR isn't great either [2,3].

Refs:

1 http://cancerres.aacrjournals.org/content/early/2018/11/13/0

2 https://www.nature.com/articles/bjc2016107

3 https://www.ejcancer.com/article/S0959-8049(17)30500-2/abstract

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

by dumbcritic on Mon Dec 03, 2018 11:58 PM

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On Nov 24, 2018 6:01 PM Jcancom wrote:

Exciting 3-BP research brings everything together.Articl "" target="_blank" rel="nofollow">http://together.Articl " target="_blank" rel="nofollow">together.Articl e has the feeling that this is moving to the clinic.
PMID:30462852
Article mentions that 3-BP would combine well with hyperthermia. I would like to see this research. Metronomic 3-BP in vivo would also be of substantial interest. There has been a great shift in thinking on D's forum toward metronomic dosing. To this point only MTD dosing with 3-BP has been used. Metronomic dosing with 3-BP could have profound to the power of 3 anti-cancer effects. So, in vivo evidence would be highly appreciated.   

Hopefully something will be confirmed in the near future.

Rafael Pharmaceuticals has initiated the second PhIII trial in R/R AML and the first interim analysis could be completed as early as Q1 '20. With the other PhIII in pancreatic this could be the first to market. Behind them is CB-839 and a few other drugs.

VDA-1102 (IV) and VDA-1275 are two others. Preclinical data shows that metabolism targeting therapies should not only boost antitumour immunity while also inhibiting tumour growth [1,2].

Refs:

http://www.vidacpharma.com/images/Vidac_AACR_2018_poster_Abs

http://www.vidacpharma.com/images/press-releases/Publication

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

by Jcancom on Tue Dec 04, 2018 02:44 AM

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critic, thank you for posting about DNX-2440!

The company is DNAtrix. I was surprised when I looked at their pipeline to see the myoxma virus in preclinical development! D and I talked about that one years ago. It is so frustrating! Cancer products can take decades and decades to move forward nowadays. Widespread use of myoxma virus to control rabbit populations in Australia was first researched for years. This virus is understood to be non-toxic to humans, though it is thought to have anti-cancer effects. 

The prime source of energy for my posting to this thread over all these years is the mystery of why a potential anti-cancer treatment as powerful as 3-BP has not even started a clinical trial. While most other potential treatments are not in the same category as 3-BP, it still is a great mystery to me as to why these other treatments have also not gained enough traction to make it to the clinic.

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

by Jcancom on Thu Dec 06, 2018 03:55 AM

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Good one critic!

There is even more of an international 3-BP collaboration happening than I had realized. They talked of a private 3-BP conference in Brussels. Why wasn't the thread invited?

Yes, I had wondered about the Yeast article as well, what did they mean by a "wash". Sort of dab on it onto the melanoma? I would want a more thorough description as I am not entirely sure that dabbing would be safe. With a melanoma tumor I thought they meant it more as an IT injection. Do they really mean to just "wash" it onto the skin? The sequence of photos for that figure are quite impressive. I would also be interested in knowing more about this patient's experience.

This article has several points of note. 3-BP is positioned as an anticancer therapy that could control metastasis. The article proposes this as almost a unique property of 3-BP. I am greatly anxious to see how they might develop the idea that 3-BP "results in a dramatic increase" in apoptosis after prolonged exposure though not after only 4 hours. They also hinted at an article about P450 in preparation. Would be a great gift for the season!

The article quoted the 2012 WHO cancer statistics which noted mortality of 8.2 million. Shockingly the recent Globocan estimate for 2018 is a global cancer mortality of 9.6 million. We are within months of hitting an annual global cancer mortality level of 10 million! Something needs to be done!

This is what failure looks like! Hitting 8 figures should be telling us something: Specifically, we are doing something wrong. We need more innovation: We need a more flexible regulatory environment: We need patients that are more aware of the past results of therapies (e.g., chemotherapies) and explore other options: We need greater freedom of Right to Try for patients.

https://www.iarc.fr/featured-news/latest-global-cancer-data-

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

by dumbcritic on Wed Dec 12, 2018 10:22 PM

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SCLC data for the combination of pegzilarginase with keytruda (PhIb) will be out 4Q. Here are some slides [1,2]. Both AEB2109 (methionine) and AEB3103 (cysteine/cystine) are at the discovery stage.

Also, some more preclinical data for ADU-S100 [3].

Refs:

1 https://static.seekingalpha.com/uploads/sa_presentations/686

2 https://static2.seekingalpha.com/uploads/sa_presentations/68

3 https://www.cell.com/cell-reports/pdf/S2211-1247(18)31810-2.pdf

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

by dumbcritic on Wed Dec 12, 2018 11:37 PM

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A new paper on metfromin and syrosingopine https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31806-0 An older study was published back in 2016 http://advances.sciencemag.org/content/2/12/e1601756

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

by Jcancom on Sat Dec 15, 2018 01:55 AM

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critic, minicells are such a shockingly powerful cancer treatment. They are at the top of my list of all time most powerful anti-cancer treatments. They are magical! Nothing can compare to them. It is an extraordinary drug delivery vehicle.

I am anxiously waiting for minicells to be loaded up with metabolic medicines. I can only shake my head when I hear of gram scale drug dosing, even more so when this style of drug delivery is almost always non-targeted (meaning substantial risk of wide-ranging tocixity). With minicells, there is essentially no risk of such toxicity from the drug itself as the doses are usually so tiny. The only toxicity question relates to the minicells cells themselves, though this has been resolved in the latest research.   

Notice in the second citation below that they dosed with 500 NANOGRAMS paclitaxel and still 45% achieved stable disease. That is only 0·0015% of the usual dose and they exceeded the response expected from such a dose normally delivered with zero side effects associated with the paclitaxel. 

The first citation found a way to make the entire minicell process even simpler. With the current implementation there is a complication related to attaching the bi-specific antibodies to the minicell. With the newest version, there is an acid sensing peptide already attached to the minicell.

https://www.ncbi.nlm.nih.gov/pubmed/29556350

"Pharmacokinetic (PK) assessment of serum paclitaxel levels was not performed as it was determined that the maximum possible concentration of paclitaxel administered in a single dose ofEGFRminicellsPacwould be 4 orders of magnitude below (or 10,000-fold less than) technically feasible levels of detection

The dose of paclitaxel administered in 1x1010 EGFRminicellsPacequates to ~ 500 ng (0·0015% of 175 mg/m2), and a significant reduction in paclitaxel toxicity was observed."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699457/

The minicells currently used in clinical trials have issues related to LPS related toxicity. This is pushing the dosing just below what would be expected to be curative responses from the mouse dosing. Yet, the research below mentions using GRAS minicells. Would a GRAS product even be required to go through a regulatory process? GRAS minicells with homeopathic nanogram scale drug dosing is probably the best cancer treatment with the least potential for side effects that we might ever discover. Load up the minicells with anti-metabolics and watch what happens. Considering that 2 phase 1 trials have already been published, this might already fall broadly under the authority of Right To Try. Perhaps one could even argue that all minicell treatment especially with GRAS designations would be included under this legislation.    

"The aim of this study was to construct endotoxin-free
minicells from Corynebacterium glutamicum, which is a
gram-positive and non-spore-forming bacterium regarded
as a GRAS strain that has been extensively used in industry ..."

https://www.ncbi.nlm.nih.gov/pubmed/25341464

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

by Jcancom on Tue Dec 18, 2018 01:27 AM

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I want the readers of the thread to be aware that 3-BP now appears to be drifting toward finally starting a clinical trial. Bottom line this suggests to me that those interested in being treated with 3-BP should get on the first plane to Arizona and start treatment at Dayspring.

This is only based on my best guess, though everything seems to be lining up. For example, the Dayspring website has been undergoing substantial changes over the last few weeks. Before 3-BP was highly prominent in the tabs and throughout the webpages. Now, however, it is somewhat less prominent. On the new treatment page 3-BP is listed second after Vitamin C.

While they still have a very strong endorsement for 3-BP: "We believe 3BP may be the most effective alternative cancer treatment available today." , there is now a greatly reduced emphasis on its scientific background. One could consult the Wayback to confirm this.

It also caught my attention in one of the recent 3-BP articles that a considerable focus was placed upon what seemed to be highly practical comments related to 3-BP clinical treatment. It talked of 3-BP in connection with Vitamin C etc.

Along this line of practical implementation of 3-BP treatment, what is quite surprising to me is that no great emphasis has been placed on investigating the potential of using GSH/NAC as a possible rescue treatment, if 3-BP were to be misdosed or if side effects were to emerge in a clinical trial.

3-BP is the only cancer drug that I am aware of that has an antitode. For whatever reason in all of the media coverage about 3-BP this fact was conspicuously absent. If you have a problem with 3-BP, then promptly reversing the treatment could potentially be of considerable benefit. I am sure that many cancer patients would be quite comforted with this safety feature. They might ask their medical providers if such a safety feature is available for their current treatments. 

Patients in a clinical trial who felt that something was not quite right after being treated with 3-BP could dose themselves with GSH/NAC and reverse the effects of the treatment, and it would be their right to do so. I sincerely hope that a provision would be included in any 3-BP trial design that formally recognized the obligation of those running the trial to provide such an antitode if a request were made by a patient.

The big problem here is that I am not aware of an article that has been published that actually addresses using an antitode for 3-BP. It is an idea that has floated around, though I am quite fuzzy on the specifics. What dose would be needed? Would this treatment avoid organ pathology if given immediately? etc. etc. Conceptually shutting off glycolysis clearly is an extremely dangerous treatment approach. Before 3-BP, glycolytic inhibition likely seemed undruggable by pharmaceutical companies. With 3-BP's highly fortunate characteristics, glycolysis now appears to be within range. Nonetheless, adding in an extra layer of protection would still be welcomed.  

Yet, these are still very important questions that should have been answered about the safety feature, though apparently have been left unresolved. If research did in fact report that 3-BP  treatment could be so reversed, then there would be a great easing of safety concerns. 3-BP would then be in the highly unique position of being a cancer drug that had a built in safety net. It would set a new standard for safety amongst cancer drugs.

Corporate developments are also giving us signals that we are moving to a trial. Prescience was all set with an IND 5 years ago that was given authorization by the FDA to enroll patients, though the trial never started.

https://pipelinereview.com/index.php/2013072451613/Small-Mol

What appears to be the successor company to Prescience Labs, Cage Pharmaceutical is almost ready to file its own IND. From what I have read online, 30 days after official receipt by the FDA, companies can start dosing patients. 3-BP might be very close to finally arriving officially in clinics.

http://cagephar.ma/

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