@jcancom thank you, all very interesting! Histotripsy looks very promising indeed.
johan, yes, the histotripsy article was quite startling. I had heard of lithotripsy, HIFU etc., though this approach of a partial ablation that then acted as an in place tumor vaccine was new to me. As the article showed it was highly effective in creating long lasting responses in almost all of the mice. One reason that I have been so focused on the metabolic approach is that there are almost endless examples of natural products that interfere with glycolysis etc.. I had not been aware of many treatments that are ~natural and accessible that could have such a powerful anti-tumor effect. This type of sound therapy appears highly effective.
We also now have a long list of metabolics with strong combinations and good formulations that are giving us an increasing level of control over potential tumor escape. I am developing cautious optimism; we have seen too many times in the past, though how tumors have been able to bypass such containment.
johan, yes, the histotripsy article was quite startling. I had heard of lithotripsy, HIFU etc., though this approach of a partial ablation that then acted as an in place tumor vaccine was new to me. As the article showed it was highly effective in creating long lasting responses in almost all of the mice. One reason that I have been so focused on the metabolic approach is that there are almost endless examples of natural products that interfere with glycolysis etc.. I had not been aware of many treatments that are ~natural and accessible that could have such a powerful anti-tumor effect. This type of sound therapy appears highly effective.
We also now have a long list of metabolics with strong combinations and good formulations that are giving us an increasing level of control over potential tumor escape. I am developing cautious optimism; we have seen too many times in the past, though how tumors have been able to bypass such containment.
I share your cautious optimism. The view I hold at present is that cancer starts when cells adapt to changes in their environment, mainly to oxygen. When the cell senses that the requirements for normal cellular respiration can no longer be sustained it switches to anaerobic respiration. It is a survival mechanism. If such a condition is not resolved some cells don't initiate apoptosis and over time these cells start accumulating. A well-working immune system can, to some extent, control cell overgrowth. If "cancer" cells start escaping such protective systems, tumors, lymphomas or leukemias ensue. Symptoms appear and cancer is diagnosed. Although current treatments are sometimes highly effective at eradicating much of the overgrowth, those same treatments often make the underlying condition - the lack of oxygen and, progressively, carbon dioxide - worse. This creates a vicious cycle, and more places in the body now become vulnerable to the switch from regular cellular respiration to anaerobic respiration. This is called metastasis and such a condition becomes untreatable eventually. Treatments that eradicate fermenting cells, stop those cells from fermenting and limit the consequences of aerobic fermentation (glucose conversion into lactic acid instead of carbon dioxide), and simultaneously help restore the oxygen and carbon dioxide deprivation, not worsen it, should prevent metastasis from occurring or exacerbating.
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."
"comparison of the putrefaction pathways in the gut microbiomes of healthy, carcinoma and adenoma datasets indicate higher abundances of putrefying bacteria in the carcinoma stage of CRC."
https://www.frontiersin.org/articles/10.3389/fmicb.2017.02166/full
Sorry, I have been unresponsive and only posting sporadically. There are other duties to attend to at the present though in the medium term I hope to back posting with gusto.
I had to post this one, though.
This is a startling result recently published in NEJM. A phase 2 clinical trial in repair mismatch rectal cancer had 100% 6 month complete response with monotherapy PDL-1 without any supporting therapy. For example, patients who did not completely respond were scheduled to have chemotherapy, radiation and resection of the rectum? With this treatment no one required such additional treatment. The treatment power involved is stunning. Simple monotherapy without resorting to primitive style cancer treatments |( such as chemo, radiation, or surgery resulted in 100% long-lasting responses? Yeah!
I have been highly focused on metabolic approaches which I still believe have considerable treatment potential, however this newest result suggests that the end of cancer could be on the horizon with an immunological treatment approach. Either way metabolic or immunologic, effective treatment for cancer appears to be approaching.
https://www.nejm.org/doi/full/10.1056/NEJMoa2201445
@jcancom HI J. Thank you. While most of the time you were the first to share news, this time you are behind Johan and Pouya who already shared these results. 😊
It's important to clarify here that this is not a new drug type. It has been used for about 8 years now with limited success so far, and it comes with side effects that can be lethal in some cases. Therefore, it's important to bring the context around these news, as taken out of the context makes it look like the solution to cancer.
On a positive note, life has been added to those patients and that is a fact, most valuable. Regarding the science, this demonstrates the concept can work in specific conditions. This study moves the knowledge regarding the application of anti PD1/PDL1 drugs one step further, helping to define one group of people that are highly likely to respond.
Clearly, a metabolic approach is not the only way to fight cancer. I think that is what we tried to discuss on this website over the years, as we also discussed virotheraphy, immunotherapy, hormonal therapy, etc. However, the metabolic perspective is the one that has an outstanding strength: there is strong knowledge + it can be potentially manipulated by "tools" (drugs and supplements) that are accessible (example is Metformin, that can slow down tumor development). We can not say the same about e.g. immunotherapy. There is still a large gap in knowledge about how the immune system works, and the tools available to manipulate that are more limited.
However, as we move forward, we can expect fast development of knowledge on the immune system activity since that is where the most money of the pharma industry is invested at this point, both in oncology and beyond.
Kind regards,
Daniel
@j Exactly Johan. That is my point. This in my view was marketing. The investment was too high and the results to limit next to the side effects. This is why there are so many studies on combo of these immuno therapies with chemo, to try to find more working points. So probably oncologists went back to chemo as there were not many results (to put it nicely because they often accelerate growth) with anti PD1/PDL1 but many side effects. Now the industry needs to create some excitement again and give a push to sales.
Look at this:
"A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose–positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported."
This looks like the perfect solution to cancer: 100% complete response, and no side effects.
I actually don't believe it, knowing these drugs.
In fact this drug is already approved for endometrial cancer with microsatellite instability,and it worked quite well,but not to that extent.in fact the trial is with stage 2 and 3 patients,and in addition they had never received chemotherapy cycles,so it is assumed that their immune system was not yet deteriorated,which may explain the success of the drug in anal cancer,the thing changes when there is distant metastasis and they have received several cycles of chemotherapy. In addition, keytruda was also tested in patients with anal cancer and microsatellite instability, but without discriminating according to stage and having received previous cycles of chemotherapy and was not as successful.
In fact this drug is already approved for endometrial cancer with microsatellite instability,and it worked quite well,but not to that extent.in fact the trial is with stage 2 and 3 patients,and in addition they had never received chemotherapy cycles,so it is assumed that their immune system was not yet deteriorated,which may explain the success of the drug in anal cancer,the thing changes when there is distant metastasis and they have received several cycles of chemotherapy. In addition, keytruda was also tested in patients with anal cancer and microsatellite instability, but without discriminating according to stage and having received previous cycles of chemotherapy and was not as successful.
Agreed, they carefully selected the group of patients. They sure have succeeded with this marketing effort. A complete response for 6 to 24 months in stage 2 cancer doesn't say much.
Complete Responses (CR) and improved Progression-Free Survival (PFS) are encouraging results in any study, but IMO the only result that really matters is Overall Survival (OS). So many studies report improvements in CR and PFS with little or no increase in OS.
@j yes Johan, and that even after large companies are in the best position to design the study, collect and analyze the data such that the reported outcome is maximized.
D, thank you for clarifying! Yes I was aware of the clickbaity quality of the story: stage 2-3 mismatch repair rectal cancer with a drug class that has been around now for ~ a decade. When people are coping with cancer there is always a naive optimism that the cure is somehow just around the corner, yet we have seen how often this has not been true. Breakthroughs in cancer, more often than not are highly specific and usually only potentially effective over the longer term in the pre-metastatic setting.
One aspect of the story that stood out for me was the extent to which genetic mutations would be present in a mismatch repair tumor. I have read the background involved over the last few years related to neoantigens. What they found was cancer such as melanoma and mismatch repair etc. have so many genetic errors that it winds up changing the neoantigens on the tumor surface. It is an interesting idea. All of the large number of mutants with these cancer can then make them visible to the immune system. Adding in PD-1/PDL1 then has a logic to it. However, many other tumors would not be targetable in the same way.
What I have found so attractive with the metabolic approach is how generic it seems to be (versus the immune approach). Metabolic features of cancer are broadly shared across type and across stage.
I recently read your article about GSH's role in the local tumor environment and interaction with the immune cells. We have seen a fair amount of research published along this line of the metaboimmune response to cancer.
All of the large number of mutants with these cancer can then make them visible to the immune system. Adding in PD-1/PDL1 then has a logic to it. However, many other tumors would not be targetable in the same way.
That's why I think this type of treatment has limited use and only in early-stage cancer, once there's metastasis you get a variety of other mutations. Still, good news for the stage and type of cancer mentioned in the study.
Very impressive! Metabolics has just stepped up to the potential challenge from the immune system approach as noted above.
https://pubs.rsc.org/en/content/articlelanding/2022/sc/d2sc02297d
I realize that I am supposed to be off thread at this time, though I found the time to find this gem in my spare time. They added 3-BP and siRNA for the gene SLC7A11? That is a startlingly powerful idea! This should now open up the entire field of siRNA to be incorporated in similar formulations! I have thought about this application before ... I thought wow wouldn't it be so powerful if you could do the lab in vitro siRNA trick and then do it in vivo. If you can specifically shut down specific genes the cancer cell is enormously vulnerable. For example, shut down FerT or perhaps PK M2 and then combine it with 3-BP etc. -- this should be massively powerful. The in vivo results for 3-BP + siRNA SLC7A11 were massive, the tumors shrank. It is not difficult to imagine with continued development that even better results could be reported!
(Sorry no graphical abstract to post; graphical abstract for article is attached. I will post the below more for eye candy than for direct relevance to the article. )
So much exciting research! It truly is hard to keep up with it all.
Let's see we have a new 3-BP article that has found that it disrupts the cytoskeleton and so much more!
Out of it all one that especially caught my attention was a recent genetic modiificaion of the oncolytic Newcastle virus. The image (or perhaps only the url) below is particularly exciting because they used monotherapy oncolytic virus with genetic modification (angiogenic inhibition) that nearly stopped tumor growth! That is impressive.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8982889/
For whatever reason I had not been as impressed by an earlier Newcastle virus article, though as I review the figure below it too is highly impressive; they essentially achieved 100% tumor growth inhibition? https://pubmed.ncbi.nlm.nih.gov/31612140/ The same group then also combined NDV with D-mannoheptulose.
Here's another one in liver cancer. https://pubmed.ncbi.nlm.nih.gov/35528990/
Oncolytic cancer therapy clearly is a promising approach. Having the ability to rearm with almost any DNA and specifically target cancer cells makes oncolytics are a powerful cancer approach that we should pay more attention to. It is quite remarkable that now even monotherapy can achieve strong results; one of the few questions I have is whether these results are confined to intratumoral injection models.
3-BP with New Lab in South Korea might already be in clinical trials; it's not easy to decipher what is happening. Yeah!
Hmm, that's actually sort of funny ... guess what the first combo that Ko Discovery has decided upon for 3-BP?? Keytruda (i.e., PD-1)? Scroll down to the 2022.03.18 article in the url below. They are doing the preclinical research and they are talking about synergistic effects of 3-BP + Key! Wow, that could be fairly powerful. What is also of note is that Keytruda is now widely approved in many indications. Latching onto a main line of treatment could mean that 3-BP could rapidly become standard of care across most of cancer!
What this is also telling me is that the big pharma want to link up with an emerging winner. There are a lot of cancer treatments that have little or no benefit for patients; often about all they do is cause side-effects. Yet, if you can match up with a breakthrough treatment such as 3-BP then anything else in the combo looks good by association. It appears that big pharma are already lining up to partner with 3-BP. It would not be that surprising if we were to see some very large responses with these combos. Would also like to see a metabolic combo trial. Those would very likely be synergistic: e.g. 3-BP citrate, or Fen or ....
Sorry I have been absent of late.
3-BP brought me back! This is a paper which considered 3-BP as a HK-2 inhibitor in Alzheimer's. I believe that I had heard that there might be some interest in the clinical use of 3-BP in AD. Anyone hear of this?
https://pubmed.ncbi.nlm.nih.gov/36203054/
Best Wishes, Jcancom
I have just been looking on the net and it appears that 3-BP has now finally entered clinical trials !!!!!!
I am unable to extract the full url; here is the best that I can do. This is awesome! We have waited so long for this! If anyone can find out more details please post!
The post is from September 1,2022. The headline is "New G Lab pharma pays attention to global phase 1 clinical trial of KAT, an Metabolic Cancer drug"
"KAT has entered the ?US FDA phase 1/2a clinical trial.
... "In Korea after the IRB we started recruiting patients in August of this year. "Phase 1/2a clinical trial take about 1 year and 6 months and the goal is to finish by the end of 2023."
partial url
https://news-mt-co-kr.translate.goog/mtview.php?.no=2022090108574055633&type=1 ...
Here it is everyone !!! Yeah! We have waited so long for this! This could help millions and millions of cancer patients! It appears that they want to move this through trials post haste.
https://news.mt.co.kr/mtview.php?no=2022090108574055633
This is the google translation of the website:
"KAT has entered the U.S. Food and Drug Administration's Phase 1/2a clinical trial." Pharma first received US FDA (Food and Drug Administration) Phase 1/2a IND (clinical trial plan) approval for liver cancer last year," he explained.
... "In Korea, after the IRB (Clinical Research Review Board) review, we started recruiting patients in August of this year. "Phase 1 clinical trial will take about 1 year and 6 months, and the goal is to finish it by the end of 2023."
Here it is everyone !!! Yeah! We have waited so long for this! This could help millions and millions of cancer patients! It appears that they want to move this through trials post haste.
https://news.mt.co.kr/mtview.php?no=2022090108574055633
This is the google translation of the website:
"KAT has entered the U.S. Food and Drug Administration's Phase 1/2a clinical trial." Pharma first received US FDA (Food and Drug Administration) Phase 1/2a IND (clinical trial plan) approval for liver cancer last year," he explained.
... "In Korea, after the IRB (Clinical Research Review Board) review, we started recruiting patients in August of this year. "Phase 1 clinical trial will take about 1 year and 6 months, and the goal is to finish it by the end of 2023."
thanks for the update, J
johan, thank you for your reply!
This is fantastic news! We have waited and waited and waited so many years for this. It has been so difficult when we have tried to help people and yet we did not have the exacting science that is applied in a clinical trial environment. Science can provide the answers that we have not been able to find for ourselves.
We know that 3-BP has large treatment power when the MCT-1 pathway is open. In this context, 3-BP can almost immediately shut down the tumors energy supply.
Yet, there is a subset of patients that are natural superresponders. They do not need combinations; all they need is 3-BP and they will have large responses. I will be very interested to see what percentage of non-selected patients are such superresponders. In a careful clinical trial setting, such patients can be identified using FDG PET and then treated with caution.
Some advanced 3-BP patients have had large responses. If the clinical trial achieved such results, then it might mean that the clinical trial program would need to be rapidly accelerated.
I already feel better knowing that the 3-BP clinical trial process has started. I sleep better knowing that a very powerful cancer treatment is approaching.
johan, thank you for your reply!
This is fantastic news! We have waited and waited and waited so many years for this. It has been so difficult when we have tried to help people and yet we did not have the exacting science that is applied in a clinical trial environment. Science can provide the answers that we have not been able to find for ourselves.
We know that 3-BP has large treatment power when the MCT-1 pathway is open. In this context, 3-BP can almost immediately shut down the tumors energy supply.
Yet, there is a subset of patients that are natural superresponders. They do not need combinations; all they need is 3-BP and they will have large responses. I will be very interested to see what percentage of non-selected patients are such superresponders. In a careful clinical trial setting, such patients can be identified using FDG PET and then treated with caution.
Some advanced 3-BP patients have had large responses. If the clinical trial achieved such results, then it might mean that the clinical trial program would need to be rapidly accelerated.
I already feel better knowing that the 3-BP clinical trial process has started. I sleep better knowing that a very powerful cancer treatment is approaching.
Looking forward to the result, I hope it will be a good outcome!
@jcancom I found this, and it may be of interest to you.
"Decreased serum cortisol levels have also been suggested as a factor in the pathogenesis of nocturnal airway obstruction in adult asthma (10-12). Cortisol, a glucocorticoid produced by adrenal glands, shows a circadian rhythm with its peak at about 0800 h and its nadir at about midnight. These low cortisol levels at night precede the nocturnal fall in FEV1 and may result in less suppression of airway inflammation with subsequent increased airflow limitation "
From what I've read it sounds like you had (or have) long-covid. One of the main markers of LC is lower cortisol. LC can occur in asymptomatic disease.
johan, thank you for your post about cortisol. Interesting! That will be an avenue that I will pursue. I will look into whether they have cortisol monitors as I thought these monitors exist for those with flight or fight type stress reactions.
I actually now have a stack that I am using including: vitamin C, forskolin, black cumin. etc.. Clinical trials have shown that even some of these as single agents had clinical benefits over the course of 2-3 months. I think one of the great blessing with typical non-cancer illnesses is that if you find a treatment that is effective then it will continue to be effective (i.e., no resistance usually develops).
Exciting news!!! 3-Bromopyruvate is now on clinicaltrialsgov!!! Yeah!
After all of these years and after so many of our friends have tried 3-BP (with varying levels of success), there is finally an officially posted trial. The actual names used for the treatments are KAT101 (oral) and KAT201 (IT) and it is being conducted out of South Korea through NewG Lab Pharma.
phase 1/2 148 patients non-randomized oral and IT dosing in Hepatocellular & Fibrolamellar Carcinoma
https://clinicaltrials.gov/ct2/show/NCT05603572?term=NCT05603572&draw=2&rank=1
NCT05603572
It is such a feeling of relief that after over 20 years of pre-clinical research 3-BP can finally go through proper clinical evaluation. It is also a great feeling that such a powerful treatment is now in motion and could be available to help the millions of cancer patients who would benefit from it in the years ahead,
@jcancom that's great news about 3bP.
I believe a saliva cortisol test is a good option.
