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Jcancom
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15/09/2020 4:32 am  

Recently I have posted about Newcastle virus and 2-DG. This result did not seem to be as strong as it could have been. There are many many possible metabolic combinations that could be tried and it was disappointing that only 2-DG appeared to have been studied. Perhaps they could do a full screen of all metabolics? Perhaps also could try and triple combo as the virus is highly specific to the cancer cells.

The update is that the research team has now published a new combination with Newcastle: This time mannoheptulose. I searched the site and apparently I posted about mannoheptulose a year or two ago. It is quite interesting. Mannoheptulose is a monosaccaride heptose. It is a naturally occurring sugar that confuses cancer cells by having a chemistry very similar to that of glucose. One concern (especially for diabetics) with mannoheptulose is that it has been described as being able to induce "instant diabetes". By inhibiting glucose uptake it can increase blood glucose levels, though cancer is highly dependent upon glucose.

One of the main glycolytic enzymes associated with cancer that we endlessly post about is HK2. HK2 is centrally involved with cancer. Mannoheptulose inhibits HK. What this new article brings to our attention once again is the importance of GK (glucokinase) (see the second reference). Glucokinase is active in the liver and pancreatic beta cells and also apparently in tumor cells. It gives tumor cells more glucose phosphorylating ability.

What would happen if GK were knocked down? It appears to have a significant impact on tumor growth. Mannoheptulose has been found to be a specific inhibitor of GK. What food contains significant amounts of mannoheptuolose? Avocado. Surprisingly, 10% of the dry weight of avocado is mannoheptulose. Mannoheptulose could be another good metabolic cancer lever.

 

https://pubmed.ncbi.nlm.nih.gov/32874134/

https://pubmed.ncbi.nlm.nih.gov/7614462/

 

 

 

 

 


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Jcancom
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16/09/2020 2:28 am  

This is another mito formulation; this time lonidamine. Once again a strong result even with a large dose reduction and good safety profile.

 

https://pubmed.ncbi.nlm.nih.gov/31101821/

 


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Jcancom
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16/09/2020 11:44 pm  

Some probably find my constant posting about metabolics as perhaps somewhat misplaced: There has to be more than cancer than metabolism. This is true though it truly is quite surprising how constantly metabolics pops up.

Here's a great example.

After patients were treated with all the current top line (and expensive) melanoma therapies, the (inevitably) resulting resistant cells turn out to be "hypermetabolic". Basically after CTLA-4 and PD-1 blockade, patients had turbocharged glycolysis and OXPHOS. It is surprising that this is the latest science and it involves the most advanced treatment approaches from the world's premier cancer hospital and what we wind up with is that we have chased melanoma... back to the metabolic highway. This is what I mentioned a few posts ago. Almost no matter where you start, no matter what side alley you run down, you almost always seem to wind up back on the metabolic main drag. It was disappointing in the article that they then applied some weakish metabolic treatments (non-metronomic 2-DG, metformin). It would not be that surprising that if you put in some effort with a "hypermetabolic" cancer that you could wind up with treatments that might support my hyperbolic statements. Targeting OXPHOS with a specific cancer treatment should be highly doable.

One problem here is that probably many of the melanoma patients are never made aware of the follow-on treatments that could then be very helpful for them: i.e., metabolic approaches. One of these quasi- metabolic approaches which might then be a good next line of treatment could include T-Vec as this would follow the logic I posted above about oncolytic viruses being metabolic in nature. 

{If I remember correctly I think BRAF melanoma also showed a metabolic response with 3-BP.} 

https://pubmed.ncbi.nlm.nih.gov/32917656/


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Jcancom
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18/09/2020 2:14 am  

Good one kimster!

It is always amazing how they publish the initial with doxycycline etc. and then they find a better combination and then they find a better chemical here Doxy-Myr and then I suppose the next ante is to find a better formulation.

I am going to re-post the finding here as it is yet another good metabolic treatment. 

 

https://www.frontiersin.org/articles/10.3389/fonc.2020.01528/full

 

 


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Jcancom
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19/09/2020 5:08 am  

Ihave liked this article as a prototypical metabolic approach for quite some time. It is basically starve the tumor. They give the background on how this basic idea has probably been behind thousands of cancer remissions. This is a highly basic form of the idea.

https://arxiv.org/pdf/1407.7622.pdf

Starvation of Cancer via Induced Ketogenesis and Severe Hypoglycemia  arXiv:1407.7622v2 [q-bio.OT] 8 Dec 2014

This idea was recently updated to a hypothetical protocol. It starts to become increasingly plausible as the protocol that they have described uses standard medical procedures and medicines, though they have yet to be applied in a cancer setting. This pure metabolic approach would essentially take away glucose from cancer cells; reasonably this would have a substantial effect on cancer. The question that needs to be considered is to what extent will other critical areas in the body continue to receive their glucose supply.

 

https://pubmed.ncbi.nlm.nih.gov/30037608/

 

 


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Jcancom
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19/09/2020 5:19 am  

Other researchers are thinking along these lines. This article considers ExtraCorporeal Membrane Oxygenation (ECMO) and selective glucose perfusion of the carotid vessels to maintain severe hypoglycemia without causing cardiac or brain damage. These are fairly conceptually simple metabolic approaches and yet the underlying logic is compelling: shutting down glucose supply to cancer would reasonably have substantial anti-cancer effects. It would not be overly difficult to imagine co-metabolic treatments that would reasonably be able to amplify such an effect.

 

https://pubmed.ncbi.nlm.nih.gov/31383320/

 

 

 

 

 


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Jcancom
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20/09/2020 5:57 am  

Another metabolic approach. D mentioned quite some time ago gluconate, though it is well worth reposting here. Gluconate can block citrate uptake in cancer cells by interfering with the ctrate transporter; this has anti-cancer effects. We have also seen that high dose citrate can have an anti-cancer effect. This is one where it can go either way.

Follow-on research cited below has found that inhibiting gluconate kinase (gene name IDNK) which is involved in the Pentose Phosphate Pathway and phosphorylates gluconate inside of the cell also has anti-cancer effects.

There truly are a great many of these metabolic approaches: I hope others find it as helpful as I do to have all of these treatments concentrated here with these very helpful figures. One can certainly try to contemplate how combination approaches might help to increase the effectiveness of gluconate etc..

 

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593216/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049873/pdf/ott-13-1767.pdf

 

gluconic acid


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Jcancom
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21/09/2020 3:57 am  

Cancer is this never ending unfolding of metabolic relationships. Here we now have glucosamine. What is quite startling here is that in the reference below mice treated for 40 hours with glucosamine experienced a near complete necrotic response in their tumors. Metronomic dosing profoundly changed the metabolic cancer environment. Glucosamine runs somewhat parallel to glucose, though it very near to the main metabolic path of glycolysis. It is fairly remarkable how almost all of these mainline metabolic pathways typically wind up having substantial basic research support for the treatment of cancer. Often it is more that it would be surprising if a cancer treatment effect were not reported.

 

https://cancerres.aacrjournals.org/content/canres/32/4/756.full.pdf

 

 

 


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Jcancom
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22/09/2020 2:08 am  

Whoa! D reported on the G47delta virus last year when there were some strong results in GBM. What is interesting now is the extent to which these results appear to be globalizing in other cancer. The article below speaks of gastric cancer. This virus has also reported a human clinical trial in prostate cancer etc..

This is exciting! Once approval were obtained in a first indication, then perhaps it could be used off-label. It is also exciting from the perspective that then combinations could be considered (e.g., perhaps metabolically based?). Research has already found that combination G47delta and fasting significantly enhances the anti-cancer effect of the virus.

The lack of first line metabolic treatments has substantially hindered its development. It is actually quite surprising how few metabolic treatments have been approved. I am not sure whether I can immediately think of any nominally designated metabolic therapies that advanced through clinical trials and was approved. However, once this does occur it will dramatically reduce the difficulty of seeing large anti-cancer effects. It is critically important to have that strong first round treatment and then others can amplify the effect. 

One other observation from D's write up that is of interest is that apparently  the Newcastle oncolytic virus might already be available in Germany. That would be extraordinary. There have been a few posts on this thread about Newcastle virus and how its anti-cancer effects could be enhanced with metabolic treatment. If Newcastle could truly be obtained then these insights might be of value. One also starts to wonder how effective a cocktail of oncolytic viruses and metabolic therapies might be.

https://www.cell.com/molecular-therapy-family/oncolytics/fulltext/S2372-7705(20)30047-4


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Jcancom
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22/09/2020 2:18 am  

There are not that many metabolic treatments that I am aware that have been FDA approved, though CPI-613 now appears to be well into phase IIIs with a reported end date of October 2021 for one of these trials. As we can see from the figure, CPI-613 targets two of the cancer pathways that we have discussed endlessly on forum. The PDH/PDK pathway is related to pyruvate entry into mitochondria and is the mechanism of action for DCA and KGDH is related to glutamate entry into the TCA cycle. CPI-613 apparently can inhibit both of these enzymes. One could certainly anticipate that such dual metabolic targeting would have anti-cancer effects. Of course, here again once this product were available many add-ons would then be able to amplify the effect. Perhaps an oncolytic virus? and others. Having these initial metabolic approaches will allow for effective cancer therapies to finally emerge.   

 

https://rafaelpharma.com/research-and-development/cancer-metabolism


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Manuone
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22/09/2020 10:23 pm  

Hi friend J! I've been very busy lately! but do not doubt that I always read your publications! I am sure that very soon we will be able to propose a solid therapy against cancer and I am sure that in it the main approach will be metabolic


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Daniel
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23/09/2020 1:31 am  

@jcancom Hey J, very nice to hear from you. There are multiple types of viruses that are used in Germany as an anti-cancer treatment!


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Jcancom
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23/09/2020 3:43 am  

D, it is so exciting how we continue to make progress in our understanding of cancer.Emerging from this thread has been a deeper appreciation of the role that oncolytic viruses can play within a metabolic strategy. What is especially encouraging is that these viruses might begin to be seen as a safe platform that could have some base genome which could then be changed to add in additional genes. Once specific replication in cancer cells could be conclusively shown then this might not be unexpected. This would allow for a numerous genetic modifications: a gene for a mir that blocked HK2, or upregulated/blocked MCT-1, ... . The possibilities are endless! I have begun to see oncolytic viruses as a central part of any anti-cancer strategy.

Some ideas that I have thought of that could modify these viruses include: a strategy in which instead of attempting lysis the virus is programmed such that it continually produces a moderate number of new viral particles that can then leave the cancer cell. (This way instead of destroying the cancer cell through lysis one could have constant production). Another idea is that perhaps the viral particles could be formulated in liposomes or chitosan. The viruses could be delivered directly to the tumor environment largely avoiding the attacks from the immune system. 

I am very encouraged by your confirmation about viral treatment in Germany. I see engineered oncolytic viruses popping up in a great many nations, so the technology to genetically modify them would seem not to be too onerous. This could be a great driver of cancer treatment innovation. One could well imagine that multiple rounds of various oncolytic virus treatment could precisely target a wide range of metabolic targets. This could be a highly effective strategy as we know that the problem with typical "natural" or even conventional cancer treatments is that there can be so many targets for even a single treatment that adding in more than 2 or 3 treatments at any given time can lead to a wide range of interactions (perhaps nullifying treatment effectiveness). However, with oncolytic viruses the precision involved could be so exact that one might be able to keep taking shots on goal without the problem of cascading side effects.

I am glad that you were able to confirm this idea of German viral availability as oftentimes there is a problem that patients are not able to link up with the treatments that will help them. They just do not know where to go or who to ask. Oncolytic viruses are a good treatment to be aware of. Perhaps the German clinics might be able to create a chitosan formulation for the particles as well.

D, your mention of the Starve Cancer book finally induced me to purchase a Kindle copy. I am glad that I did. The book describes the journey taken by the author as she sought out (mostly metabolic) treatment for her stage IV cancer. What stands out for me about this book are the many prototypical mistakes that patients will make as they embark upon the cancer learning process. The book would be of great value for those who want to avoid trying to reinvent the wheel of alternative cancer treatment. When we work collectively we can all learn from each other.

The book also underlined for me the near universal resistance that we have seen from mainstream medicine. You noted in one of your posts that it did not seem reasonable that basic metabolic ideas such as pre-treatment fasting, anti-metastatic treatment etc. have not been incorporated into standard oncological protocols. Yet, the book mentions many of these same observations. A certain collective consciousness is emerging as it becomes more widely recognized that these reactions appear to have become deeply ingrained into medical culture.

There was mention of 2-DG, 3-BP and metformin as a particularly strong combination. D, I think you mentioned that you had also heard about strong results from this combo. Is there a particular clinic that has been using this? The book does not elaborate on this point.

  


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Jcancom
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23/09/2020 3:50 am  

Manuone, it's good to hear from you again! I did not want to bother you, though there are just so many interesting treatment ideas that keep popping up and I am eager to start up. I would really like to see us finally synthesize a chitosan formulation.

Clearly, as a patient, there is never reason to say that there is nothing left: There is! It is almost infinite the number of potential treatments. The more you read the more you find. We have only been searching in Western medical sources, though probably every small human population have made their own observations about treatments. Even after all of these years it still feels that we are in the discovery phase of our efforts.

Best Wishes, J 


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Jcancom
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24/09/2020 3:19 am  

Another metabolic approach methionine restriction (MR). This one starts to become somewhat complicated as the pathways involved broaden out into serine, glutathione, glycolysis, ketogenesis etc.. Even still it appears to be another method of integrating a controlled diet into cancer management. Surprisingly, simply using diet restriction strategy produced substantial methiomine reductions in humans over the span of a day or two. Also of interest is that while methionine is considered an "essential" amino acid, it does not actually seem to be truly essentially; how can 1 of the 8 essential aas not be essential? Mention is made in the literature that normal cells can convert homocysteine to methionine while cancer cells often are unable to make this conversion.

One of the articles described MR along with cycloleucin as an effective combination in cancer.

 

https://pubmed.ncbi.nlm.nih.gov/30712196/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631235/

https://www.naturalmedicinejournal.com/journal/2015-12/role-methionine-cancer-growth-and-control

 

There is a fair amount of information to process with methionine biology.

In the figure below an alternative view of methionine is given. Here the T cells

are shown to be competing with cancer cells for methionine (and losing).

Cancer cells can extract methionine with the transporter SLC43A2 which

is unavailable to the T cells. This research lead to the interesting counter-conclusion

that supplementing with methionine could also be an effective anti-cancer approach.

This is one of those topics that D has mentioned where there is so much going on that

this should only be thought of as a pointer to an entire literature to research. However, given the

totality of evidence it does appear that a therapeutic approach can be derived from this research.  

 

https://onlinelibrary.wiley.com/doi/full/10.1111/imcb.12385

 


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Jcancom
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24/09/2020 3:56 am  

Starving Cancer has got me thinking. On the level of the treatment proposed what is most striking for me is that almost all of the treatments mentioned are so familiar.

We might be reaching a point in which there is a list of perhaps 100 to 200 treatments that will become the recognized universe of metabolic therapy. Such a consolidation would be a significant step forward. As it is now there is considerable confusion as everyone tries out there own combinations without much commonality.

Yet, what we have seen with chemotherapy is that combinations are magnetically drawn to include a chemo drug even when these drugs can often not be that impressive as monotherpies. Once you have a standard everyone wants to combine off that standard. This same sort of standardization process might arise in metabolics. Once a treatment is approved then everyone will want to combine off the standard. It might no longer be the goto strategy of including a chemo drug.

One other aspect of interest with this potential consolidation is that the unity of the metabolic conception of cancer could be made more clear. As it is now there are a great many metabolic flavors being discussed: fenben, 3-BP, DCA, ... there are a great many perhaps 100 or 200 on this website. From what I understand all of the "natural" cancer cures are metabolically based. The immune based breakthrough drugs are heavily engineered. I am not aware of any pure immune treatment that could be included in "natural medicine." At some point the strong commonality linking these various metabolic approaches will lead to a more united effort. Possibly even a comprehensive combination of many of these treatments into a highly effective protocol. By creating a logical map that systemcially probed the many metabolic vulnerabilities of cancer one would clearly expect that a powerful anti-cancer treatment would result.     

Notably, though from the book is that author use more of a strategy of throwing everything at the wall and waited to see what stuck. Many people might dismiss such an approach. However, it should be remembered that achieving a long-term remission from stage IV cancer is still something we are striving for. The author's results have been impressive and this could be a lesson we can learn from the book: with cancer typically people will undertreat the problem and not overtreat it.

I know myself that over the last many years I have not taken any medications. This has been true for years and years. I can not even recall over many years whether I have even taken an aspirin. The problem can be that when people who lack any medication history are confronted with cancer, they might think that medications are bad. We have seen this on many occasions on the compass thread and even here on forum. Some patients with very serious illness never receive the treatments that might help them because they need to analyze everything. Typically this is a good idea; yet with cancer thinking more in terms of intensive almost continuous treatment might be a more helpful model. The author spoke of buying long lists of items from the supplement store. This is somewhat of a haphazard approach, nonetheless it produced impressive treatment results. The lesson here might be to think of the day as divided into roughly 5 treatment windows (or how many might be reasonable based upon the half life of the treatments). One could then rotate various strategies during the day. Given that the author was successful (of course this involves a strong selection bias), these ideas might guide others to more successful outcomes.


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Jcancom
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25/09/2020 12:03 am  

Whoa! This thread is gold! I am trying to pack as much value into a small space as possible (using the figures helps in this quest for idea density). This next one could take us up to another level. This could be one of the biggest ideas so far posted to the forum (right up there with metronomic dosing): genetic prediction!

Yeah! This is BIG!!! Below are some details about. The table show some genes, some variants, some treatments, some effects in different cancers. This starts to unlock the potential of all the posts that I have made on this thread. The big question many people would have after looking through all this ideas is: Which one is right for me? Until now it was not entirely obvious how might one go about making such a determination (aside from trial and error). With the genetic insights below one starts to see the potential of objectively choosing among the many options the one choice that had maximal genetic advantage.

Posters on thread might want to consider genotyping, genome sequencing (somatic/tumor) nuclear DNA mitochondrial DNA and work through some of these pathways. Admittedly this likely will be a daunting challenge. The neat and simple answers have not been published yet. This is mostly going to be off road. There will probably be some software tools out there that will make it easier, though there are a great many unknowns involved. One might have to make a guess on which way it might go. Such guesses can often be wrong; it is strange how there can be a counter-intuitive logic in the universe. 

Even an exome scan could have ~100,000 variants (somatic). A tumor genome might have an enormous number of variants, though possibly the more deranged the tumor genome the more opportunity to target its metabolic weaknesses. However, there might be ~300 variants that were particularly notable. For example, stop gains stop losses, important frameshifts etc. that could be immediately recognizable. Just imagine if a tumor genome had a de novo stop gain in HK2 or in fact any major glycolytic gene! The great thing here is we do not have only one shot on goal. If we had to hit a stop gain in HK2 for the win it would be hopeless. It would be about 1 in a million. Yet, all we need is a stop gain etc. in any of the many genes. That starts to become almost realistic. We could then use one of the many metabolic figures posted to this thread.  

I hope posters carefully think about the potential of this approach. It is very powerful. Instead of saying here are a whole bunch of treatments, though we do not know what will work for you. It should be possible with genetic knowledge to select the treatment that will work.   

Below in the table specific genes are considered. Here again the potential to precisely select a treatment based upon a defined genotype becomes possible.

How would this apply in real world cancer care? First, it should be recognized that this is no longer  prohibitively expensive. Over the last few months it was announced that full genome sequencing was going to move down to ~$100. the article focused on germline genome variants though other research focuses on the somatic genome. With the somatic genome one could sequence it once for ~~$100. The germline (that is, mutatable cells in e.g., the cancer) might have to sequenced from time to time as it changed with treatment. However, this would provide valuable insights into treatment options. For example, if the base clonal cell had a variant in a metabolic gene (as would seem almost certain given the vast number of metabolic genes), then  this could provide a powerful treatment insight.

 

This will also be of considerable relevance in the development of metabolic therapies such as 3-BP. If we could objectively and prospectively determine who will be a 3-BP responder, then something close to a riot might break out. If we could look at the genome of (for example, the 3-BP melanoma patient) and say "This patient will experience a >99% reduction in LDH with 2 combination treatment of 3-BP and paracetamol (as happened with this patient)" then further discussion about the need to conduct clinical trials would essentially be over. It would no longer be realistic that 3-BP could be withheld from such patients under those conditions. Doing so could very likely constitute a crime under international human rights legislation.

Until now this has not been as clear because the genetic tools were lacking: given current technology it is would seem highly plausible that such predictive ability is now possible.

Patients should now (within the constraint of their budgets) start genotyping and genome sequencing. This will not exactly be easy. There are over 3 billion base pairs in the human genome and there is an extreme amount of research that needs to be done, though we need to start to build up the database. We should insist that this information is included in clinical research trials and even more particularly in anecdotal reports. Indeed such genetic information should be considered a requirement for drug approval by the FDA.

When the FDA says this treatment is effective, the assumption that the treatment will be effective for any specific patient should not be made. All that is being claimed is that for a group of patients with the condition on average treatment did better than the control. However, it is widely understood that there often will be a responder genotype and a non-responder genotype. Clinical trials have not always made this distinction transparent. In the genomic age, FDA approval should only be given for the subgroups who have been proven to have benefited. Anything less means that approved medicines cannot claim the moral high ground by falsely suggesting that their legitimacy is based on a scientifically validated foundation.

The patients who have gained recognition for their individual responses could upload their genome sequences to the web (as much as they felt comfortable with) in order to clarify whether unique genetic features to their cancer might have been a driver for their successes.     

 

Table 1

Summary of the most common enzymes/transport systems, the genes that code for them, metabolised drugs and expected therapy outcomes

Enzyme/ Transporter Gene Variant alleles Drug molecule Effect Neoplasm Reference
Dihydropyramidine dehydrogenase DPYD DYPD*13, DPYD*8, DPYD*7, DPYD*12, DPYD*3, DYPD*4, DPYD*2A, DPYD*9A Fluoropyramidines – 5-fluorouracil, capecitabine, tegafur Efficacy/Resistance/Toxicity colorectal carcinoma, breast cancer [4]
head-neck cancer [5]
Thymidylate synthetase TYMS TSER*2, TSER*3 5-fluorouracil, capecitabine Efficacy/Toxicity colorectal, bladder, gastric carcinoma [4]
Methylene tetrahydrofolate reductase MTHFR 667 C > T, 1298A > C, 5-fluorouracil, methotrexate Efficacy/Toxicity colorectal carcinoma, ovarian cancer, gastric cancer [4]
Thiopurine S-methyltransferase TPMT TPMT*2–24 (TPMT*1, TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C, TPMT*4) azathioprine, mercaptopirune, thioguanine Dosage/Toxicity/ADR acute lymphatic leukemia [4]
ovarian cancer [6]
breast cancer [7]
Uridine diphosphate glucuronosyl transferase UGT1A1 UGT1A1*27, UGT1A1*28, UGT1A1*6 irinotecan Toxicity/ADR colorectal carcinoma [4]
Glutathione S-transferases GST GSTM1, GSTP1 platinum compounds - cyclofosfamide, carboplatin, doxorubicin, cisplatin, oxaliplatin Efficacy/Toxicity/ADR colorectal cancer [5]
bladder, head and neck, lung, ovarian and testicular cancer [7]
Excision repair cross complementing group 1 ERCC1 496 C > T, 8092 C > A, 19007 T > C platinum containing anti-cancer drugs Efficacy/Toxicity non-small cell lung carcinoma, bladder cancer [4]
colorectal carcinoma [8]
Excision repair cross complementing group 2 ERCC2 965 G > A, 225 A > C platinum containing anticancer drugs - oxaliplatin Efficacy/Toxicity colorectal cancer [4, 8]
ovarian cancer [9]
non-small cell lung carcinoma [10]
ATP binding cassettes ABCB1, ABCC2, ABCG2 1236 C > T, 3435 C > T, 2677 G > T, 421 C > A, ABCC2*2 irinotecan Efficacy/Toxicity/Resistance ovarian cancer [10]
X-ray cross complementing group 1 XRCC1 1301 G > A platinum anti-cancer drugs, 5-fluorouracil Efficacy/Toxicity colorectal, gastric and non-small cell lung carcinoma [4]
Cytochrome P450 2D6 CYP2D6 about 80 CYP2D6 variant alleles; most common ones - CYP2D6*4, CYP2D6*3, CYP2D6*5 and CYP2D6*6 tamoxifen Efficacy/Toxicity breast cancer [4]
 
Here are specific writeups for MTHFR and GSTs.

"The MTHFR 677C > T variant was first discovered by Frosst et al., as being the causal variant for the thermolabile MTHFR protein. The thermolabile MTHFR protein is associated with 50% lower activity in vitro. It was also the first genetic risk factor identified for spina bifida. There is a huge body of work on this variant, in association with a variety of drugs, phenotypes and diseases, and much of it is contradictory. It has been examined in a myriad of diseases including cardiovascular diseases, cancers, disorders of pregnancy and development and in the context of drugs such as methotrexate (both as chemotherapy and for inflammation).   .... Furthermore, studies have found that the T allele is associated with higher total homocysteine than the C allele particularly in individuals with lower plasma folate. In studies of methotrexate-treated pediatric acute lymphoblastic leukemia patients, the T allele was associated with a lower probability of event free survival but was not a risk factor for toxicity or seizures.  ... In one study of 43 patients with ovarian cancer, treated with MTX, grade 3–4 toxicity was observed in 77% of those who were homozygous for the TT genotype, 6% in the heterozygous ones and 8% for the individuals with CC homozygous genotype [4]. The levels of homocysteine in those patients who were homozygous for the TT genotype were higher and were associated with increased toxicity. Furthermore, patients with TT genotype showed better outcome when treated with 5-FU. In a clinical trial of 43 people with colorectal carcinoma who took 5-FU, the homozygous for TT genotype presented with better response and overall survival [4, 13]. "

 

"Glutathione S-transferases gene polymorphism and platinum compounds

Glutathione S-transferases (GSTs) comprise a family of enzymes responsible for the detoxification of xenobiotics including platinum compounds. There are several classes of GSTs, each of which is encoded by a different gene or gene family. Polymorphisms in the genes are supposed to result in an altered effect or toxicity manifestation when oncology patients are treated with drugs such as cyclofosfamide, carboplatin, doxorubicin, cisplatin.

GST is encoded by GSTP1. The most frequent polymorphism in this gene, which is associated with a better therapeutic outcome from treatment with oxaliplatin, is the non-synonymous SNP in exon 5 (313 A > G). It is detected in about 40–45% of the Caucasian population and in 27% of the Asian population [4]. One study of 107 patients with advanced CRC who were treated with 5-FU/oxaliplatin showed significant difference between individuals with the variant genotype and those with the wild genotype: the first group had a median survival of 24.9 months, while he second one – 7.9 months [4]. In a group of 64 patients with gastrointestinal cancer, who received oxaliplatin based therapy, the reduced activity of GST was associated with increased toxicity [4, 25]. Severe (grade 3) neuropathy has more often been seen in patients who are with the wild type genotype.

A published meta-analysis on glutathione S-transferase gene polymorphisms in patients with non-small cell lung cancer (NSCLC) revealed that both the null GSTM1 and the GG genotype of GSTP1 Ile105Val gene were associated with better clinical outcome and therapeutic response to cisplatin-based chemotherapy. The GSTP1 Ile105Val gene polymorphisms were more frequent in the East-Asian patients with NSCLC rather than the Caucasian ones. Chinese individuals with NSCLC showed better therapy response, which was associated with the fact that they were carriers of the null GSTM1 polymorphism. ..."

https://pubmed.ncbi.nlm.nih.gov/32821392/


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Jcancom
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25/09/2020 12:46 am  

Whoa. This url gives more than 4,000 different genotype pharmacological pairings.

There are some fairly familiar drugs included here: acetominophen, berberine ...

This list is only a start though it is still a helpful resource.

https://www.pharmgkb.org/downloads

https://pharmgkb.org


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Jcancom
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Posts: 510
25/09/2020 5:43 am  

Enough emphasis on cancer stem cells has probably not been stressed on forum. Below are some of the findings from this line of research. One prominent research effort is the use of mitochondrial targeted therapies including doxycycline, azithromycin, d-TPP, some mito drugs ... . Cancer stem cells are thought to be the driving force behind cancer progression, the overwhelming proportion of cancer cells in this theory are dismissed as merely part of the bulk tumor mass. Yet, typically the bulk tumor mass is what patient follow in order to determine their response to treatments. This might be a somewhat misguided way of understanding response. I am not sure whether there is a biomarker available that could also give a readout on the level of cancer stem cells present; this would be a very helpful measure of true cancer extent.

The first figure below illustrates this modern take on cancer therapy. Cancer stem cells occupy a much more prominent role in this conception of cancer. 

The next figure is from D's 3549 reference  from https://www.cancertreatmentsresearch.com/community/breast-cancer/ampk-activation-via-metformin-enhances-survival-of-clinically-dormant-residual-er-breast-tomor-cells/#post-3970   . This is one of many variants that has emerged from this research group. In this variant they combined doxy, vitamin C and fatty acid catabolism inhibition.

The next iteration went to dual mitochondrial protein translation inhibition doxy and azithro and used vitamin C to induce mild ROS stress --> mito biogenesis. Quite smart! Invoking mito biogenesis and then shutting off mito protein synthesis leaves mito without OXPHOS! That is cells with rho zero mitochondria (non-functional). These cells are then non-viable. Perhaps other mitogenesis approaches could also be used perhaps using induced fission/fusion treatments that can be achieved by diet modification.

The next few figures elaborate upon this idea.

Last one shows Dodecyl-TPP (d-TPP) as a treatment for cancer stem cells.

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Anti-mitochondrial therapy. Vitamin C can act as a pro-oxidant, via the production of free radicals. The ascorbate radical is normally very stable, but becomes highly reactive in the presence of metal ions, including iron (Fe). As mitochondria are rich in iron, they could become a key target of the pro-oxidant effects of Vitamin C, sequentially driving first mitochondrial oxidative stress and then mitochondrial biogenesis. However, the use of inhibitors of mitochondrial protein translation, together with Vitamin C, would ultimately prevent CSC mitochondria from fully recovering, leading instead to CSC eradication. Additional experimentation will be required to further test this hypothesis.

 

 

 

 

Summary diagram highlighting the mechanism(s) of action related to the triple combination of Azithromycin, Doxycycline and Vitamin C. This approach effectively results in the synergistic eradication of CSCs, using vanishingly small quantities of antibiotics. It is important to note Doxycycline and Azithromycin are not direct OXPHOS inhibitors, but instead are inhibitors of mitochondrial protein translation. The 2 metabolic targets are the large mito-ribosome and the small mito-ribosome. Azithromycin inhibits the large mitochondrial ribosome as an off-target side-effect. In addition, Doxycycline inhibits the small mitochondrial ribosome as an off-target side-effect. Vitamin C acts as a mild pro-oxidant and can stimulate the production of free radicals, driving mitochondrial biogenesis, secondary to mitochondrial oxidative stress and the anti-oxidant response. Vitamin C is also thought to act as an inhibitor of the glycolytic enzyme GAPDH (Glyceraldehyde 3-phosphate dehydrogenase). However, here, we did not observe any inhibition of glycolysis, when Vitamin C was tested alone.

 

 

 

 

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Dodecyl-TPP (d-TPP)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692486/

 

Hmm, this is somewhat amusing; apparently cancer stem cells can be thought of as being of metabolically derived origin.

 

 

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"Interestingly, a combined analysis of biological, biochemical, pharmacological, and genetic studies has recently revealed that CSCs may rise from metabolic events occurring in non-CSCs. Certain early and late metabolic hits are thought to affect chromatin organization and activate epigenetic program involved in the metabolic-driven reprogramming of CSCs."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941316/

 

Salinomycin has also been found to have a substantial effect on cancer stem cells. Sali has an effect on the drug effluxers. Possibly combining (perhaps best for safety in sequence) the mitoprotein synthesis blockers with sali could be a powerful combo

https://www.hindawi.com/journals/bmri/2012/950658/

 

This is an exciting development in cscs research with additional follow-on likely to emerge. One wonders how other features of mitochondrial biology might be able to integrate into this research. Foe example, fission/fusion, aspects of mitochondrial agglomerating etc...

I had not been aware of the logic behind this research before probing more carefully. It had seemed to me that this was largely just another idea related to targeting OXPHOs and then perhaps glycolysis. however, when you look carefully at the diagrams you can see that much more than plan A is happening here. Using doxi and/or azithro to stop mito protein synthesis greatly changes the biological implications. Would like to know how doxi/azithro can be so cancer selective. Also would like to see some better formulations (perhaps chitosan doxi etc.)     

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022456/pdf/biomolecules-10-00079.pdf

https://pubmed.ncbi.nlm.nih.gov/31947879/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022456/

https://www.aging-us.com/article/101905/text

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593549/


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Jcancom
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Posts: 510
25/09/2020 5:48 am  

This is  a nice article looking at the metabolic properties of Fenbendazole and other azoles.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458798/#S1

 

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Jcancom
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27/09/2020 5:37 am  

Very startling! Mitochondrial transplantation.This technology could be very powerful therapy across a wide range of illnesses.

In the below study, roughly purify and inject mitochondria into tumors and then add in radiation. For such a minimal intervention the result below was fairly large. Tumor weight was 1.31 g in control, 0.31 in combination. Clearly we will want to see more metabolic research applied here. Also would like to see some (genetic and otherwise) engineering of the mitochondria. The ability of possibly converting cancer cells back to normal by redesigning their mitochondria could offer a very powerful strategy.   

 

Theranostics Image

https://www.thno.org/v09p3595.htm

 

There are a great many of practical applications of this technology for example in improving fertility treatments etc., so there is substantial research interest in advancing this science. Research into the natural mitochondrial transfer in a cancer environment can help explain mysteries such as how rho 0 cancer cells can actually survive (they can receive healthy mitochondria from nearby cells). 

There is also a considerable amount of other mitochondrial biology that could be of importance in cancer. Some of the links below explore fission and fusion in a cancer context. The cell's cytoskeleton plays an important coordinating role in various aspect of the remodeling of mitochondria. This has me wondering whether perhaps fenbendazole (with its cytoskeletal effects) might make a good combination.

 

https://pubmed.ncbi.nlm.nih.gov/28342934/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121133/pdf/fonc-08-00344.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278520/pdf/ces-04-114.pdf


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Jcancom
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Posts: 510
28/09/2020 1:17 am  

kimster, wow ... it's like Christmas! This is another exciting potential metabolic treatment! Thank you for posting this one, it is very inspiring. The treatment effect appears to be quite substantial.

https://www3.ntu.edu.sg/CorpComms2/Research%20Papers/Amino%20Acids%20Mimicking%20Porous%20Nanotherapeutics.pdf

I appreciate that they included all of the essential amino acids, so we had a comparison. Combinations? I would have also liked to have seen the non-essential amino acids. Perhaps also they could include analogs (e.g., for serine, glycine etc.) that might block their uptake.  

It is quite surprising that an essential amino acid would have this effect (I would not have guessed this would be true).

The figure does not want to display; url is below. Basically, more Lat-1 on the cancer cells which allows more of the amino acid in with a tumor response. Cancer cells only upregulate Lat-1 by ~2 fold as per the article, and this is the effect? I was reading recently about mitochondrial proteins that are upregulated over 100 fold!

https://www3.ntu.edu.sg/CorpComms2/Research%20Papers/Amino%20Acids%20Mimicking%20Porous%20Nanotherapeutics.pdf


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Jcancom
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19/10/2020 3:12 am  

I will just plagiarizing kimster because there are just so many solid metabolic posts. It truly is amazes me; is there no point in the metabolic pathway that does not offer a therapeutic effect. I have tried to keep up with all of the metabolic targets, but it is so overwhelming. 

This time we have SUCLA2 which is upstream from succinate in the Krebs cycle; when cancer loses RB1 it typically also loses SUCLA2 which is nearby on the chromosome; leads to mitochondrial respiratory deficits in SUCLA2 negative cells. Article found that thymoquinone selectively targeted SUCLA2 knockout cells. 

It is almost too much. There must be thousands and thousands of metabolic targets.We would need an entire team dedicated to finding all of these. It is a little too much for any one of us, so if you see another one of metabolic treatments please post it.

https://pubmed.ncbi.nlm.nih.gov/32694611/

 

Amazing this finding might have broader relevance to cancer

https://www.mycancergenome.org/content/gene/rb1/

@Manuone

Wanted to let you know about this one, though the importance seems more related to SUCLA2 deletion than merely mutation in RB1.

"RB1 is altered in 8.19% of glioblastoma patients [3]."


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Jcancom
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31/10/2020 7:24 pm  

It is so striking how central glycolysis (metabolic features) is for human disease. Here an article describes how Alzheimer's APOE epsilon 4 (the main risk factor for dementia) results in high lactate/low energy brain state with glycolysis dysregulation. I wonder how this might be applied to cancer. It would seem that those with epsilon 4 would be resistant to brain cancer.

https://www.biorxiv.org/content/10.1101/2020.10.19.345991v2.full.pdf+html


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Jcancom
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Posts: 510
01/11/2020 1:08 am  

Sorry, everyone I am going to repost this one to the metabolic thread here. There are just so many amazing metabolic articles out there that I want to concentrate in one place. This one is a non-MCT-1 formulation for 3-BP: which means 3-BP has almost unlimited access to cancer cells (no need for MCT-1). 

 

Kimster, I am very glad that you have taken the metabolic ball and are running with it. After all of the years that we have been posting about metabolic cancer strategies, I do not believe that there is any longer anything even worth arguing about: Metabolic cancer when (if?) it finally arrives will provide a curative option. The one confusing part for many of us is to cope with the oceans of high quality metabolic research that is available.

 

Here is ANOTHER!!  3-BP formulation with considerable potential potency. It uses the folic acid receptor so it does not even need MCT-1 (Whoa!). There are so many of these formulations now it is stunning. The preparation method that they describe below appears so simple. The high pressure homogenizer might be somewhat tricky to arrange, yet everything else seems very basic. 

Not having to be limited by MCT-1 certainly begins to offer the potential of an amplified version of 3-BP. Nevertheless, I would like to see one of these formulations that took it to the next step and added another layer of protection; make it into a 2 or 3 stage formulation. For instance, perhaps they could coat the cubosome in chitosan or turn it into a prodrug. I am not aware of a 3-BP prodrug formulation yet. Adding in another level of safety would be comforting. We know that 3-BP will attack virtually everything inside the cell; we just want to be very sure that it is attacking exclusively cancer cells. Some of these formulations actually seem to have shown this in vivo, however, even more safety (if possible) would be appreciated. 

 

 

https://pubmed.ncbi.nlm.nih.gov/32956335/bh

 

 


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