@dumbcritic, this is super-exciting! We have waited for so many years for this! Without the proper formulation and carefully controlled trials in medical equipped facilities one would have never been able to properly analyze the power of 3-BP.
Yes, Cage pharma also appears to be approaching the starting line for their clinical trial which is another excitement. I think that the CD-3-BP mice trial that I reported above is the formulation that Cage intends to move into phase 1. I am not sure whether Ko Discovery intends to start with 3-BP TACE to the liver.
With a 3-BP product then we could have many powerful cotreatments that could synergize with it.
critic, what is your assessment of 3-BP?
Yes, Cage Pharma wants to move forward with the microencapsulated formulation (given systemically). Hopefully, they will be able to do this, but I remember the history of Dr. Geschwind and how Dr. Ko was forced out, so that leaves a bad taste in my mouth.
As for NewG Lab Pharma, using TACE would (for me) be the right way to start. Then, as time goes on (assuming all goes to plan) maybe move to treating patients with liver mets from certain unmet types, such as MSS CRC and pancreatic. Also, testing different combinations (to synergise with it), and maybe exploring using that delivery with approved anti-PD(L)-1's (for some indications, like NSCLC). The reason being is that it has been shown that the presence of liver mets correlates with poor outcomes to those treated with immunotherapy. Not only are there reductions in the objective response rate, but also reduced overall survival.
One company is working on first-in-class small molecules and this year should file an IND for its lead program which is a dual MCT1 and MCT4 inhibitor https://cancerres.aacrjournals.org/content/81/13_Supplement/1268 https://cancerres.aacrjournals.org/content/81/13_Supplement/1335
A combination that comes to mind https://ascopubs.org/doi/10.1200/JCO.2019.37.15_suppl.3014 https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.3590
Based on the data so far, those given Keytruda had a median overall survival of 14.6 months compared to 13 months for patients given placebo. The percentage of patients who were alive at two years was 34.3% for the former compared to 24.9% for the latter. Keytruda also improved progression-free survival and objective response rates.
At a cost of $10,268.72 per dose. And they know a thing or two about stacking the odds in their favor.
critic, do you think that it could even be possible that the 3-BP phase I/II could transform into a phase 3 trial? Does that happen? Can it? 3-BP is such a powerful treatment that there are scenarios that I could imagine where the evidence of efficacy were so overwhelming that it might seem reasonable to continue to research it.
3-BP has been out there in clinics and elsewhere for years now; there is not that much mystery that it is a very powerful treatment. Those who are very close to it might even be aware of many more patients that have received it. There is also the potential for patient selection which could mean that all patients were responders.
D, noted above his TLS page which I had been unaware of. What I found interesting was that apparently Newcastle virus is available for cancer patients in Germany (?). That is quite remarkable. I noted previously on this thread that Newcastle showed strong combination power with 2-DG and mannoheptulose.
It is impressive to think of how many combinations 3-BP could help to further potentiate. Viral therapy strikes me as a good one as it is cancer specific and it can also work down the energy supply of cancer cells. Viral therapy is another metabolic treatment! To be truly effective, though, they would need a topline treatment and 3-BP could be the one.
I've felt your enthusiasm years ago. Thing is, very few people share our enthusiasm. They really don't care. They are invested and identify with the prevalent story. They don't see, don't listen, don't hear anything outside that story. And yes, they will - in their unconscious state - sacrifice their children.
Antineoplastons, Phenylbutyrate, Butyrate, Citric acid, Artemisinin, 3BP, Oral Vitamin C, Curcumin, LD Naltrexone, etc. They just want to disprove.
The moment you identify with something, the intellect serves that identity always. - Sadghuru
@j Very much agree.
This is why very few can go beyond the limits of personal bias defined by own belief system, mainly influenced by own surroundings and these days fueled and amplified by search engine and social media algorithms.
Only crazy enough people, that do not see the information as a limit but as a reference point representing what we know (that may or may not be true, as we know very little), will be able to go beyond.
Interestingly, most geniuses were also considered crazy (not normal people in respect to the average people). But they are those who succeeded to go beyond normal, outside the noise created by this World, pickup the fruits of science and art, and get them back to us into this noisy World.
This is why, if we truly want to find a solution to cancer, we first have to live behind the bias created by those limited by information, and move in to the space where people use information to build new paradigms.
It is not easy to do that, as moving along this path of new paradigms, we will also meet a lot of misinformation. That is when, to clear up the air, we have to judge the new paradigms based on facts. Such an example in cancer seems to be dr burzynski with Antineoplastons, where facts seems to indicate this could be a valuable path. 3PB is the same, as it is Salinomycin.
The challenge is, that as we try to move to new paradigms, outside the typical belief system, we also need to fight the gatekeepers that are benefiting from the World as is. Fortunately, evolution and life always won.
Yes, and given for up to two years. I know Eli Lilly (and its partner, Innovent), wanted to disrupt the US anti-PD-1 market with sintilimab (starting in NSCLC) by offering it at a lower price, but Dr. Richard Pazdur, the FDA's oncology chief has said there would be significant hurdles in approving it based on data from a single foreign country (China) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00071-7/fulltext
On top of that, the agency seems to favour some companies over others https://www.fiercebiotech.com/biotech/agenus-withdraws-cervical-cancer-application-for-balstilimab-after-fda-fully-authorizes
I know another company is running a PhI/II testing a metabolic inhibitor (GAPDH, a-KGDH and NF-kB) in metastatic pancreatic, with standard-of-care gemcitabine. Once dose escalation (ongoing) is completed, they will run a dose expansion, and if all goes to plan will initiate a pivotal PhIII. So NewG Lab could take the same route. As for patient selection (assuming they do), that should help.
Yes, and given for up to two years. I know Eli Lilly (and its partner, Innovent), wanted to disrupt the US anti-PD-1 market with sintilimab (starting in NSCLC) by offering it at a lower price, but Dr. Richard Pazdur, the FDA's oncology chief has said there would be significant hurdles in approving it based on data from a single foreign country (China) https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(22)00071-7/fulltext
On top of that, the agency seems to favour some companies over others https://www.fiercebiotech.com/biotech/agenus-withdraws-cervical-cancer-application-for-balstilimab-after-fda-fully-authorizes
always nice to read of people who are making such an effort.
@critic, might you have an opinion on the FDA's approval of Aducanumab for Alzheimer's. I suppose you might have heard of the controversy surrounding it. It is too bad that such controversies do not happen more frequently in cancer as there might be faster progress if there were.
@johan, this is a very insightful idea that you have posted. The mind shapes our awareness in powerful ways; we align our perceptions to fit our beliefs. D is always trying to keep an objective framework in our efforts on thread, though it can be difficult, in order not to let our beliefs to become unrelated to external reality.
In our own way we can also fall into the trap of identifying with 3-BP and metabolics. This is what will happen naturally; you begin to feel that you must protect the idea that you must shape your thinking in such a way that 3-BP and metabolics must somehow be right. Yes, johan, it is important that we do not only see metabolics as the answer but also have time to see the truth that might be beyond what we see. Even still from everything that I understand metabolics does seem to be the right road.
The moment you identify with something, the intellect serves that identity always. - Sadghuru
I have avoided the traditional mainstream of cancer on purpose. I went online and I was about to buy a highly regarded cancer textbook. Yet, I looked inside the table of contents and there was barely a mention of metabolics. I could not understand this! I decided it was best not to buy this textbook. I was worried that I would become indoctrinated into a perception of the world that has simply been very very unsuccessful in helping people with cancer. Why learn the wrong answers? It is not easy to unlearn the wrong answers that you worked so hard to remember.
For me it is not so much that I need to be crazy enough to think in terms of metabolics, but instead that I do not know any other way to think about cancer. My perception has been shaped by our own discussions and my own reading. It is about writing your own textbook and forming your independent opinion. This takes much more effort than studying a textbook, though it is one strategy not to become embedded into the group mind.
From what I can see now we are on to something big. It is almost a surprise that we were able to find the right path when there were so many wrong turns that can be taken and it would seem so many people who want to point one in the wrong direction. It did seem at times an impossible challenge; that there would be an eternity of the same wrong ideas. Yet, we seem now to have reached through to the other side.
D recognized the way out of the seeming trap of the indifference of the world and the apparent impossibility of change: There is a longer-term evolution towards the truth that happens. When people continue to push and strive to go forward, then eventually the truth will win. It might take time; it might be difficult, but ideas win. Those who help guide others to this truth then can become powerful, wealthy and recognized (if they wish). Merely offering failure forever ultimately has minimal power associated with it.
If great ideas don't win, then what? Wrong ideas win? Anyone can have bad ideas, this is not a special gift. The powerful then lose legitimacy; they lose their ability to claim the high ground.
We can see this with 3-BP. The first results with 3-BP were introduced 20 years ago. We have seen how powerful it is; we have seen patient reports; we have seen clinics that have used it for many years. There are many other metabolic approaches that have also caught the public's attention. Through time people are able to understand how this could be applied to people, if only the scientific method is brought to bear. Finally we are starting to see this process begin! Yeah!
Lilly said it would price sintilimab similar to deeper discounted biosimilars, so about 40% off the wholesale acquisition cost, with the decision soon. But if Dr. Panzer's word reigns supreme, it is essentially already over.
Anyone have any ideas on how to get a small molecule into the brain? Intranasal? Carrier protein/molecule to move substance past the BBB?
What properties of a small molecule are needed for the intranasal route? What dose is tolerated?
Any suggestions or info would be appreciated.
Anyone have any ideas on how to get a small molecule into the brain? Intranasal? Carrier protein/molecule to move substance past the BBB?
What properties of a small molecule are needed for the intranasal route? What dose is tolerated?
Any suggestions or info would be appreciated.
here's an interesting, more recent view on the BBB
@johan, thank you. There is so much cancer research; it feels like it is almost infinite.The BBB is one of the many challenges present when thinking in terms of drug formulation.
I have been reading up on fluorine. It looks like this could be another one our list. We have known for quite some time that sodium fluoride is an inhibitor of enolase (and also OXPHOS). Yet, this never seemed all that helpful as fluoride can be quite toxic. How do you make this into a druggable idea?
One of the first potential chemical aspects of fluorine that could move us towards this objective is the observation that in acidic environments HF converts into H+ and F-. In such environments it is then difficult for the F- anion to make it into cells because of its negative charge. However, in environments closer to ~7 most of the fluorine would remain in its non-dissociated state of HF which has the ability to enter cells. This provides some insight into the challenges that would be present to directing fluorine to cancer cells. However, with a good formulation, (e.g. minicells) such challenges could be overcome.
We have talked a great deal about the important idea over the last many years of how the acid base context of the tumor environment shapes the entry potential of 3-BP and other treatments. The extracellular pH (epH) of the tumor cell is highly acidic and the intracellular pH (ipH) is somewhat basic. What I found of interest to day is that with metabolic treatment, the pH of the tumor could rapidly shift and this might introduce unique opportunities to throw acid-base logic into the mix for added anti-tumor effect.
The tumor's biology would dramatically change when e.g., the MCT-1 transporters were targeted with 3-BP. The beta-cyclodextrin 3-BP shown in a post demonstrated a fast evolution away from the MCT-1 cancer cells treated with B-cd-3BP. There had to be! The 3-BP had a free entry to cells with MCT-1 and this resulted in profound anti-cancer effects. This might be the first round of metabolic therapy. There are several additional rounds that are possible, though one possibility would be to amplify the stress caused by the change in pH levels. {One observation that might not be entirely helpful here is that when epH increases as with 3-BP treatment; there is an outflow of F- from the cell.}
Another question I would like to put out to the forum relates to potential fluorine toxicity to the liver. Could drugs (when taken in highish doses) that merely had fluorines in an aromatic ring or elsewhere, etc. be enough to cause toxicology problems (perhaps through ROS etc)? Any suggestions would be appreciated.
johan, I see from your other post that you have figured out how to upload figures. I think that you are using the "Browse" file approach. Another way of doing this is to find a figure on the internet and right click it. There should then be the choice of "copy image link", select it and then "paste" it into a forum post - the figure should automatically appear.
Preclinical data at AACR (the conference is next month)
Activity of 3 Bromopyruvate in human tumor primary culture 3-dimensional explants using ex vivo analysis of programmed cell death https://www.abstractsonline.com/pp8/#!/10517/presentation/15136
3-Bromopyruvate in combination with radiation inhibits pancreatic cancer growth by dismantling mitochondria and ATP generation in a preclinical mouse model https://www.abstractsonline.com/pp8/#!/10517/presentation/17530
I posted this idea to this thread about a year ago. This was originally posted to the cancer compass thread as it seemed intriguing to me at the time. The author came up with an approach to cancer based on urine and blood balance in the 1940s that appeared to have some success with patients.
One manifestation of the treatment involved dosing with glycerol and butanol.
https://chestofbooks.com/health/disease/cancer/Emanuel-Revici-Research-Physiopathology/Copper.html
Recently I have been extending out my knowledge of the metabolic pathways and I came across the link of glycerol to glycolysis. Glcyerol sheds an NADH to link up to glycolysis. I then reread an earlier comment about butanol and it apparently it is an LDH inhibitor! This got me thinking: Could the mechanism of action here be NADH overload?
In cancer there is a nice and neat balance of NADH: glucose ---> 2 NADH --> LDH --> LAD+. Everything is nice and stable. NAD+ cycles through NADH and back and there is no problem. What if LDH is shut down? What if you add in more NADH through glycerol? For whatever reason we have not focused that much on the LDH shunt to lactate and the NAD+ recycling.
This line of thinking might be erroneous as glycerol is mostly processed in the liver, though the book cited above included glycerol in cancer treatment based on a acid/base perspective which is highly congruent to how we often describe this more in terms of LDH and lactate output.
Importantly the glycerol and butanol treatment had rapid responses in cancer patients which suggests a metabolic mechanism. Another point to consider is that during the 1940s medical research was quite a bit less constricted than it is today. The doctors at that time apparently were give much more freedom to use their best judgment in providing care to their patients. This appears to have resulted in substantial responses to the glycerol and butanol treatment in terminal cancer even while using more of a folk medicine/non-pharmaceutical approach.
I would strongly encourage others on forum to carefully review the clinical results from the butanol and glycerol, etc. clinical applications and if you are interested to contact those with medical training to receive this treatment. Butanol can be dangerous, though the cited research claims that within the context of the treatment dose that it can be applied safely.
Very exciting! Very very exciting!
From time to time on forum we gain some insight that moves us forward; the above figure might just be one of those times.
What we see is the effect of ethyl pyruvate (EP) on ethyl lactate (EL) [yellow dots in teh middle of the figure] on glycolysis and on cell growth.
EP effects on glycolysis are particularly notable. EP blocks GLO1 and GLO2 and PK (pyruvate kinase). GLO1 and GLO2 are needed to process methylglyoxal (MGO) that arises as a consequence of the cancer cell's glycolytic overdrive. PK is an essential enzyme needed to complete glycolysis and derive energy from glucose. as seen in the figure EP can interconvert to EL which then blocks LDH. LDH is also a highly familiar enzyme to us as it is critically important for cancer cells to recycle NADH and then export lactate once the incomplete respiration of glucose has been accomplished in cancer cells.
What the above implies is that ethyl pyruvate would be another great one! It would be a great anti-metabolic approach against cancer. It would drain cancer cells of energy. This is exactly what the research has found -- through time cancer cells experience profound energy depletion when treated with EP.
Ethyl pyruvate is apparently considered generally recognized as safe (GRAS) by the FDA.
"FDA approved EP in cold beverages for human is ∼150 mg/kg, indicating that the doses of EP used in mice are achievable in human."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465275/
We have mentioned ethyl pyruvate before on thread, though the more recent research clearly highlights the potential of this treatment.
Very exciting! Very very exciting!
From time to time on forum we gain some insight that moves us forward; the above figure might just be one of those times.
What we see is the effect of ethyl pyruvate (EP) on ethyl lactate (EL) [yellow dots in teh middle of the figure] on glycolysis and on cell growth.
EP effects on glycolysis are particularly notable. EP blocks GLO1 and GLO2 and PK (pyruvate kinase). GLO1 and GLO2 are needed to process methylglyoxal (MGO) that arises as a consequence of the cancer cell's glycolytic overdrive. PK is an essential enzyme needed to complete glycolysis and derive energy from glucose. as seen in the figure EP can interconvert to EL which then blocks LDH. LDH is also a highly familiar enzyme to us as it is critically important for cancer cells to recycle NADH and then export lactate once the incomplete respiration of glucose has been accomplished in cancer cells.
What the above implies is that ethyl pyruvate would be another great one! It would be a great anti-metabolic approach against cancer. It would drain cancer cells of energy. This is exactly what the research has found -- through time cancer cells experience profound energy depletion when treated with EP.
Ethyl pyruvate is apparently considered generally recognized as safe (GRAS) by the FDA.
"FDA approved EP in cold beverages for human is ∼150 mg/kg, indicating that the doses of EP used in mice are achievable in human."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465275/
We have mentioned ethyl pyruvate before on thread, though the more recent research clearly highlights the potential of this treatment.
check out this
johan, thank you for the link!
I have read up further on ethyl pyruvate, it continues to look like a good one. We have a pretty good idea of what sort of qualities of a metabolic inhibitor we are looking for: very safe, effective ... it can take quite a bit of searching to find just the right one. Ethyl pyruvate has some of the good qualities.
A phase 2 clinical trial in post-cardiac surgery used IV doses of 7.5 grams every 6 hours for ~ 1 day. That is a truly massive dose! The FDA seemed to be saying that ~15 grams oral dosing was GRAS; all of sudden the clinical trial dosed at 60 grams over a day treatment period. In the cancer context 60 grams might be even more than what would be needed; 60 grams might move you into TLS. Apparently none of the patients after cardiac surgery had problems with such dosing.
As the figures above show, ethyl pyruvate would be expected to cause very large energy depletion, especially as the dosing moved towards complete energy shut down - in the cell experiments in some cell lines this occurred 10 mM. It is not clear to me what the human dosing reached with respect to molarity. Combining ethyl pyruvate perhaps with nanomethylglyoxal could amplify the effect. Alternatively, one could imagine that some other metronomic ATP depletor (e.g., metronomic vitamin C) might also intensify the effect of ethyl pyruvate.
Your link discussing EP and NAM was clearly of interest. It does suggest the possibility that a similar combination might apply in cancer.
A connection of microbes to prostate has been reported. This could have substantial clinical impact as this would seem to have a reasonably straight forward path to treatment. The anaerobic bacteria noted in the article also could help to explain the Warburg strategy used by cancer. Perhaps the advantage that cancer derives from an oxygen depleted environment is that it helps to provide an environment for bacteria to amplify oncogenic processes. Ironically there are also oncolytic anaerobic bacteria that thrive in the oxygen free environment that cancer has created.
https://euoncology.europeanurology.com/article/S2588-9311(22)00056-6/fulltext
D, I had not been sure about the microbe theory of cancer, though as noted above evidence suggests it has a role in prostate cancer. It is difficult to believe that this had not been appreciated before.
Here's another one that I have been wondering about for quite some time: metabolics and the circadian clock. Glycolysis should clearly follow the wake eat sleep cycle. Finding a way to treat cancer when it is the most vulnerable according to this cycle clearly is an approach worth pursuing. The above research did consider how resistance could be overcome in gastric cancer with metformin/2dg. More of these studies which also included 3-BP would be of great interest. Perhaps the success that we have seen with metronomic dosing (e.g., with hydrogen gas) relates to the idea that prolonged dosing stretches across circadian cycles and possibly then increases efficacy.
Ironically there are also oncolytic anaerobic bacteria that thrive in the oxygen free environment that cancer has created.
https://euoncology.europeanurology.com/article/S2588-9311(22)00056-6/fulltext
@jcancom I think the oxygen-deficient environment comes first, and in such an environment only certain species of bacteria, molds, and viruses can survive or even thrive.
Ironically there are also oncolytic anaerobic bacteria that thrive in the oxygen free environment that cancer has created.
https://euoncology.europeanurology.com/article/S2588-9311(22)00056-6/fulltext
@jcancom I think the oxygen-deficient environment comes first, and in such an environment only certain species of bacteria, molds, and viruses can survive or even thrive.
Here's an outrageous thought: cancer is putrefaction. "Putrefaction involves the decomposition of proteins, breakdown of the tissues, and liquefaction of the organs. The body is decomposed by the action of putrefying bacteria and fungi which releases certain gases that infiltrate and deteriorates the body tissues and organs. Putrefying bacteria play a major role in recycling nitrogen from the dead organism."
https://pubmed.ncbi.nlm.nih.gov/11533309/
"Cancer has been described as a nitrogen trap. The presence of a tumor produces great changes in host glutamine metabolism in such a way that host nitrogen metabolism is accommodated to the tumor-enhanced requirements of glutamine."
johan, thank you for calling me back to the forum! I greatly enjoy posting here and hopefully my posts are helpful for those in need when nothing else seems to be available to them.
I am not sure whether you will believe me or not, though I have read about a whole list of additional potential cancer therapies or updates on those we have encountered before.
One of the big update is with the potential use of a non-invasive sound therapy that liquifies the tumor mass and this appears to induce a potent immune response. This appears to be a highly promising approach.
Earlier in thread mito-honokiol and mito-lonidamine were mentioned. In just published researched they combined them and the results are even more impressive. https://www.researchgate.net/publication/360771195_Chemoprevention_of_Lung_Cancer_with_a_Combination_of_Mitochondria-Targeted_Compounds
There is also research for methyljasmonate. https://www.frontiersin.org/articles/10.3389/fphar.2022.828400/full What I find especially notable here is how MJ detaches HKII from VDAC which is quite specific to cancer cells. mito-MJ would be an interesting one to investigate.
There is also a new formulation for Fenbendazole. As seen in the article even monotherapy nano Fen is quite potent. https://pubmed.ncbi.nlm.nih.gov/35456716/ I am also impressed with the Fenbendazole combo with DCA or 2-DG. This has been noted elsewhere, though the synergy involved is extremely strong.
I had been unaware of how much clinical research had been conducted with Newcastle virus; this article found A LOT of such research. D noted that this virus is available in Germany, given how much clinical research has been done one might think that under Right to Try type legislation such a treatment would be broadly available to patients. Newcastle and other oncolytic viruses could be topped up onto a range of metabolic and other strategies. https://pubmed.ncbi.nlm.nih.gov/22131816/
So many exciting metabolic (and otherwise) treatments in development. Once we have at least one front line metabolic therapy (such as formulated 3-BP), there could then be very large responses.
Here's the url for the sound therapy.
