A New Approach to Improve Effectiveness of Cancer Therapies is Getting Ready to Begin Human Trials

Dear Friends,

Today is October 18th 2018. That is exactly two years since my dear wife became an angel and exactly one year since the incorporation of MCS Foundation for Life with the aim of helping advanced cancer patients to live a better and longer life.

I promised I am going to share with you some very exciting news regarding a new treatment approach that based on early and anecdotal reports, in my view, represents one of the most promising approaches to treat cancer.

I will use this special day to release these news:

The project

Lampidis Cancer FoundationUSA (website), together with MCS Foundation for Life, the Netherlands (website), are actively preparing to collaborate with clinics worldwide on implementing protocols using 2-DG for patients who have failed standard treatment. This is a massive step towards making 2-DG accessible to cancer patients worldwide.

The details of this project have been made available at the website of Lampidis Cancer Foundation here.

Essentially, this new project relates to a new method to deliver 2DG to cancer patients, in a metronomic manner, meant to improve or enable effectiveness of conventional therapies including but not limited to chemo- and radio-therapies.

2DG has been previously discussed on this website (Ref.) and has been already given to cancer patients both in the context of clinical trials performed years ago in USA, and in private clinics around the world including in German clinics. But the results were not as exciting as expected.

Today, based on the research findings of Prof. Lampidis, professor of cell biology at the Miller School of Medicine in Miami, we now understand that when 2DG was given to the patients in the past trials, because 2DG “looks” like glucose, there is a subsequent release of insulin in the human body, redirecting 2-DG to fat and muscle and away from the tumor site. As a result, when given all at once, 2-DG cannot reach the tumor tissue at the relevant amount and for a long enough time-frame required to have a negative impact on cancer cells, similar to that observed in laboratory. That is not what we want.

A new approach to get 2-DG into the tumors

In order to avoid the insulin release and get the 2DG to the tumor, Prof. Lampidis came up with a trick. Instead of giving the 2DG all at once as it is being given typically to patients around the world, Dr. Lampidis proposed to give that in a much lower dose and during long time, up to a few days, at a rate and concentration that is below the insulin-inducing dose. That is what we call metronomic delivery of 2-DG.

It is not a question but a certainty that 2DG will reach the tumor at a very low dose. Why? Because 2DG is the very same substance that is used in the solution given to the patients prior to PET-CT scan. In that scan, 2DG is connected to a radioactive substance. Because 2DG looks like glucose, and because we know very well by now that tumors like glucose, 2DG will be absorbed by the tumors while the radioactive substance will behave like the blinking light sending the signal outside the human body and indicating the location of 2DG. That is how PET-CT works. And so from PET-CT scans we know that the absorption of 2DG at low dose is very selective and mainly absorbed by the tumors.

Using the strength of 2-DG to help conventional therapies work

Once getting the 2DG to the tumor, this will put pressure on the tumor via various mechanisms, including the reduction of energy (ATP) production which is required by the multi drug resistance (MDR) pumps to push chemotherapy out of cancer cells and including the reduction of anti-oxidant production required by cancer cells to fight the pro-oxidant nature of chemo- and radio-therapy. Prof. Lampidis has identified other mechanisms that may be even more relevant than these two and will be further discussed as soon as I get further clarity on that line.

Now imagine that we can use such an approach to put pressure on cancer cells, and lower their capability to fight conventional therapies. Imagine that we can use this while or just after the conventional therapies are given to the patient. Imagine how more effective the conventional therapy may become. And that would be nearly independent on the cancer type since most of the tumors are relying on glucose for the short term need of resources. Actually, we do not even need to imagine how much the conventional therapy can be improved. Instead, read this post I wrote some years ago, when a substance working in a “similar” fashion could be used in a hospital in US to make advanced cancer patients respond again to conventional therapies. Actually, the dose of conventional therapies could even be reduced when supported by a substance “similar” to 2-DG.

Next to the very clear and extensive scientific evidence supporting 2-DG, the prior results mentioned at this post is what made me very enthusiast when I head about the findings of Prof. Lampidis on metronomic 2-DG. The great advantage of 2-DG is that is a substance already used in humans, in clinical trials and in PET-CT. It’s safety profile is relatively well known and with limited or no toxicity. It is accessible as it is produced at compounding Pharmacy in Germany ready for intravenous administration. And it’s cheap. Perfect combination of attributes: effective, safe at known doses, accessible & cheap.

Implementation

The implementation of this new approach to help enable and/or increase effectiveness of conventional therapies, is beeing done in 3 different steps:

  1. Implementation on a compassionate basis, by clinicians located in countries and institutions where this is allowed
    • Here, Lampidis Cancer Foundation & MCS Foundation for Life, informs the patients and clinicians, and supports clinicians with the implementation
  2. Implementation via limited number of clinics around the world that can receive the approval to do so in a structural manner (such as being done by DaySpringClinic in USA with other substances)
    • Here, Lampidis Cancer Foundation & MCS Foundation for Life, supports a few selected clinics with the documentation required for application for approval at the relevant boards
  3. Implementation of 2-DG as a widely available drug, which will require FDA approval and clinical trials before that

At this point, there is a treatment protocol in place that is shared by Lampidis Cancer Foundation & MCS Foundation for Life on compassionate basis with clinicians around the world, addressing point #1 above. At the same time, the two foundations and collaborators, are working on point #2 and #3 above.

Patients interested in learning more about this approach can contact us and will be glad to inform.

Medical doctors interested in learning more and implementing this approach can contact us and will be glad to inform and continue supporting with our knowledge during the implementation process.

Very encouraging anecdotal reports

Although the data is still at an anecdotal stage, it is encouraging to know that multiple patients across the world are reporting excellent tolerance with metronomic 2-DG treatment, when used immediately after chemotherapy.

While these patients are being co-treated with other agents as well, they all seem to experience positive outcome following the treatment approach that includes metronomic 2-DG, from just feeling better to reduction in the size of their respective tumor types and markers.

All of the patients are advanced cancer patients with no or limited treatment options. While we do not have the consensus to publish their data yet, I can at least shortly and anecdotally mention several cases:

  • Endometrial cancer
  • Colon cancer
    • 70+ women; colon cancer & liver metastasis; 18% marker reduction after one week treatment
  • Brain cancer
  • Pancreatic cancer
    • 70+ man; pancreatic cancer with liver metastasis; tumor markers exploding during the summer; Gemcitabine only stopped the growth of markers; implemented metronomic 2DG and several other treatments. 90% decline of tumor markers in the following two months (family of patient will create own website to share experience – I will share the link as soon as that is available)
  • Sarcoma
    • 30 yeas old lady; sarcoma with metastasis; combining IPT (low dose chemo) with 2DG metronomic and a few other treatments and reporting feeling better, and feeling regression of some palpable tumors
  • Ovarian cancer
    • 50+ women; ovarian tumor with mets at liver, spline, ascites fast evolving; started two months of IPT (low dose chemo) & metronomic 2-DG and a few other treatments; two months after no tumor visible on MRI and patient feeling well

So far, the results we hear back are along the line of our expectation, and I am veryy happy to be able to say that. It’s important to say that the reports from nearly 100% of the patinets I know using it are indicating improvements.

The international team behind the metronomic 2-DG project

Dr. Metin Kurtoglu holds an MD and Ph.D. in cell biology and is one of the world’s leading experts in the mechanisms by which 2-DG works as well as its clinical application. Dr. Metin Kurtoglu and Dr. Theodore J. Lampidis have worked closely together and have published extensively on 2-DG as an anti-cancer agent. Dr. Kurtoglu, based in Washington DC, is also developing a novel CAR T immunotherapy that is currently in Phase I clinical trials.

Dr. Daniel Stanciu, based in the Netherlands, holds a Ph.D. in physics and has become an expert in traditional as well as new cancer treatments since his beloved wife Mihaela, who recently passed away, was diagnosed with cancer in 2013. Daniel is now devoting his life and career to helping others suffering from this devastating disease, through the MCS Foundation for Life. He has attracted a following of more than one million views to his blog, where he presents scientific information consolidated around new or improved approaches to treat advanced cancer.

Dr. Theodore J. Lampidis, Ph.D. is a professor of cell biology at the Miller School of Medicine in Miami, trained at the Dana Farber Cancer Institute, Harvard Medical School, and whose lab is internationally known for its work on developing 2-DG as a universal treatment for numerous cancer types. Dr. Lampidis is a leading authority on exploiting cancer glucose metabolism with sugar analogs.

The role of the two Foundations:

Lampidis Cancer FoundationUSA (website), based on the extensive knowledge acquired from prior research and prior clinical trials on 2DG, is in the lead for the following:

  • establishing and sharing the metronomic treatment protocol with medical doctors interested
  • supports clinicians during the implementation process, when required
  • translates report results into potential next steps including documentation required for the required steps in clinical trials
  • publication of results in scientific papers, and communication with the academic and medical communities to enable next steps

Therefore, main focus and experience of Lampidis Cancer Foundation is around the implementation of metronomic 2DG.

MCS Foundation for Life, the Netherlands (website), based on the extensive knowledge acquired from prior research and application on cancer treatments, as well as constant contact with patients and clinicians across the world, is in the lead for the following:

  • contributes to the establishment and adaptation of the metronomic treatment protocol
  • informs and maintains contact with patient and medical communities
  • supports patients and their doctors with the integration of the metronomic protocol as part of larger treatment strategies
  • collects and consolidates reports on results, to inform communities and to be further translated into documentation

Therefore, main focus and experience of MCS Foundation for Life is around the integration of metronomic 2DG.

Another activity that is currently the focus of both of the foundations is finding ways to fund the next steps of this project, with the goal of helping as many patients as possible across the world.

All activities described here are going with the disclaimers presented on this website and at Lampidis Cancer Foundation http://lampidisfoundation.org/2-dg-cancer-treatment-begins-human-trials/

Acknowledgments:

The results of this work that we saw so far and will further experience, are not only due to the team and foundations mentioned above but also and more importantly due to the professional attitude of many people involved including medical doctors, patients and their families.

I would also like to thank you (the reader) in advance for sharing this post on social media platforms such as Facebook & Twiter, to create awareness. You may save a life with that.

Donations:

Donnations to support the progress and acceleration of this project can be done on this website (with the note “support 2DG project”) or at Lampidis Cancer Foundation (website).

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

Please read an extended version of the Disclaimer here: https://www.cancertreatmentsresearch.com/?page_id=1794

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36 thoughts on “A New Approach to Improve Effectiveness of Cancer Therapies is Getting Ready to Begin Human Trials

  1. Wow!
    Daniel this is very exciting!
    This is something that could roll-out in the near term to help cancer patients!

    To clarify, is the idea to give continuous low doses of 2-DG for days at a time?
    I found this duration dosing energy depleting treatment strategy using vitamin C to be a highly compelling.
    If this is what metronomic dosing is, then I would think that it could be highly effective.

    2-DG takes an ATP through phosphorylation by HK and then gives back 0 ATP.
    A treatment that generates negative ATP has to have serious anti-cancer potential.
    By continuing this treatment through time, cancer cells should become energy depleted.
    Of course with the enormous appetite for glucose that cancer cells have, there would be selectivity of 2-DG effect.
    2-DG is perhaps even better than 3-BP as an energy depletor because it is hard to imagine any cancer that would not have abundant glucose transporters. With 3-BP, some cancer cells are lacking in MCT-1 transporters.

    D, has any consideration been given to formulation of the 2-DG for the trial?
    Using chitosan 2-DG might be an idea. Delivering at least some of the 2-DG with this formulation would deliver the 2-DG directly to the cancer cells.

    The Miami website does note that some QT side effects would need to be monitored.
    Perhaps the metronomic dosing could be cycled with other ATP depletors (such as Vitamin C and others) to reduce such potential
    side effects.

    The fact that 2-DG is a widely used drug, it should allow for a much more rapid roll-out then would occur with a new drug entity.
    One might anticipate that with such obvious upfront value to patients, raising money to collectively develop this idea should not now be overly difficult.

    D, might you know which nations have approved 2-DG for clinical treatment? The clinical trials to date had not been seen as overly successful, so I was surprised that patients are being treated with it. Yet, given this new treatment rationale, several of those on our forum might be interested in this treatment approach. I will be very interested in seeing what co-treatments might be added in to enhance effectiveness.

    Great job D!

    1. Hi J,

      Yes, this is something that is so easy to roll-out and implement, given it’s accessibility, cost and safety profile!

      1. Yes, J, the idea of metronomic 2DG is to be given for days at a time – the details of the procedure can be made available (at no cost) to any medical doctor that is interested. If patients are interested, they just have to ask their medical doctor to contact us.

      2. Phlorizin (referenced above) was also given in a metronomic fashion next to chemo and the presented results were great. I now see we start to get the same on the metronomic 2DG route. Just that it is easier to implement.

      3. Other re-purposed drugs can be used to increase the effectiveness of the approach. For example combination with Metformin, that would both inhibit mitochondria (and up-regulate glycolisis) but also reduce the blood glucose levels so that 2DG will be absorbed even better by the tumors.

      4. The metronomic Vit C is something that is my mind as a interesting method to further investigate. But I had no chance to spend enough time think about that, yet. But now, stepping into metronomic space, asap I will look in to it.

      5. You brought into the discussion 3BP which is a very good point – that reminds me that in another post we should discuss potential combinations of bolus 2DG & metronomic 2DG with others.

      6. Regarding new formulations, and looking at a PET-CT, the selectivity of 2DG to tumors is high enough that we do not need at this point to look into new formulations. Actually, given that selectivity, you could think of using 2DG as a targeting substance and combine with other substances toxic to cancer cells.

      7. Very good point J: actually the ovarian cancer patinet mentioned above intercalated vit C between the cycles of IPT+chemo+2DG

      8. Would be great if we could find ways to raise money fast to advance this approach. Even large pharma companies should be interested since it helps their drugs be more effective. And we also know they are intensively looking for such solutions, as the society puts pressure on the industry to come up with more effective solutions to cancer.

      9. We are now looking at what countries have regulations in place to allow the use of substances such as 2DG. The great thing is that 2DG is well-known and has been used in humans, and has strong science behind, which is required for use on compassionate basis. Many countries allow doctors to apply such new treatments when the patient has no other options. One such example is Germany and there is a reason why the German pharmacies have 2DG solutions ready-made for intravenous administrations. But yes, we are looking into identifying countries where adoption and implementation is easier. That in part of implementation action #1 above. But in parallel to that we are working on the other two routes mentioned above. Of course, if anyone has ideas for other routes to implement ion, we are happy to consider those ideas.

      10. Yes, J, cotreatment approach is KEY towards maximizing the value of this approach. This is actually a global trend in the clinical trials. An example is what Marcos is doing in terms of cotreatment https://www.cancertreatmentsresearch.com/community/forum-to-discuss-treatment-protocols-and-drugsupplement-cocktail/treatment-protocol-from-endometrial-carcinoma-stage-4/
      Cholesterol depletion could help 2DG be more effective. I had so info on that but cannot find it now. I will anyway search for it because this may be a key aspect.

      Thanks again J!

      Kind regards,
      Daniel

    1. Dear Alex, thanks for your question. Thinking along your suggestion, a good idea could be to do IPT with chemo (even if chemo is low-dose) and 2-DG (bolus) followed by metronomic 2DG. This is a relatively similar approach used for the stage IV ovarian cancer patient who obtained complete remission after about two months involving several cycles of these combinations. The drawback of IPT+2DG alone would be that the exposure of the tumor to 2DG would be for too short time frame, while a lot of 2DG will be absorbed by the body due to the injected insulin, which is what the metronomic approach want’s to avoid.

      1. Thank you, Daniel for your answer.
        The point is that when you do IPT, you have a time interval (abot 5 minutes), just before the patient gets hypoglicemic, when the cancer cells are permeable and the normal ones not yet. The drugs (whatever they are – chemo, botanics etc) should be delivered in this interval and a big part of them go in the cancer cells. Thus, the quantity of drugs used is smaller then in normal therapy and in the same time the uptaken quantity in the cancer cells is higher. This is why it is effective with chemo and with much, much less side effects.
        So, I was thinking about the possiblilty of using also 2-DG this way – in smaller doses than the regular ones used, so that you just don’t get the normal cells affected. The metronomic administration via an elastomeric pump may be quite a burden for some patients, not because of some pain or physical discomphort, but rather phsychic.
        Meantime, after I wrote the first comment, I discussed with a doctor, firnd of mine, wh tried this, but he said he wouldn’t try again because of the side effects of bolus administering of 2-DG. Still, I didn’t discuss about the dosage and maybe this is the key.

        1. Thanks Alex. I understand the claims behind IPT and have a good feeling about it, specifically as a way to use lower dose chemo. The mechanism related to the permeability of the cell membrane it is still questionable from my point of view. I nee to dive deep into the literature to see how valid is this claim. The second mechanism behind IPT (that makes very much sense, but only for Chemo and not other substances), is related to the fast glucose absorption triggered by injected insulin. That in turn accelerates glycolisis and makes the cancer cell more susceptible to chemo as chemo will affect stronger the more active cancer cells. In that was a lower chemo dose could still work. This second mechanism is clear. But it’s only relevant to chemo and it may explain why IPT is used mainly with chemo.

          Using IPT+2DG sounds interesting but would be purely experimentally as there is not much knowledge on that line. I would indeed expect that injected insulin will trigger fast absorption of 2DG, but that would not be so much different compared to teh results from clinical trials, I think. This is because the issue is exactly that: insulin release following 2DG bolus will trigger its absorption “everywhere” in the body. The permeability possibly induced by IPT is not needed for 2DG because the cells already have many glucose transporters ready to receive that.

          Beyond that, I would say that “Changing the winning team” makes sense only to try improving the current “metronomic 2DG” at the point when this approach doesn’t show results to a specific patient. Otherwise, I would stay with the treatment approach used so far as it appears to show good results.

          I do not know what could be the side effects of the approach you mentioned (IPT+2DG) but what I know is that 2DG bolus at a dose of e.g. 500mg in one hour given as IV does not show any special side effects (typically). However, I can imagine that could lead to side effects if the medical doctor accelerates the absorption of that with prior admin of insulin.

    1. Its difficult to make a statement o that, since the patient would not be able to take it continuously and since before getting in to the blood there may be different dynamics in different patients when taken via oral route. But it could be better than nothing to support conventional therapies.

  2. D, the Lampidis Foundation website mentioned research with lab models that established the effectiveness of the metronomic metabolic depletion approach. Might you know of any references for this? I would love to see the comparison between metronomic and standard treatment for 2-DG, 3-BP , vitamin C etc.

    Here are some of the exciting articles that I have read recently:

    PMID: 24158437 In pancreatic cells which are glycolytic, 3-BP treatment lead to permanent Calcium overload.
    Apparently, the ATP supply for the PMCA (calcium pumps) is sequestered either with the
    glcolysis path or the OXPHOS path. This might partially explain why cancer cells are so
    glycolytic: They need the glycolytic ATP to pump out the calcium! Actually, cells appear to
    use a fair amount of their ATP to pump out calcium, Na, K etc. Overloading the cell with calcium
    and at the same time depleting ATP might be a good combo.

    PMID: 26294767 In this follow up article they looked what would happen when the glycolytic cancer cells were transformed into
    oxidative cancer cells. What was fairly surprising was that they were able to do this by simply “supplementing
    with α-ketoisocaproate or galactose”. Notably, transforming the cancer cells in this way reduced their
    “proliferative rate” (see below). This has been something that I have been unsure about for quite some time.
    If you simply move cancer cells into an OXPHOs state from glycolysis, then how is this helpful? As the article
    finds, OXPHOS is a less virulent cancer state and as you have noted, there is then the opportunity to shut off
    the cancer cells OXPHOS energy. Notably, 3-BP can shut off glycolysis and OXPHOS selectively through MCT-1.

    “The highly glycolytic phenotype of these cells was first reversed by depriving MIA PaCa-2 and PANC-1 cells of
    glucose and supplementing with α-ketoisocaproate or galactose. These culture conditions resulted in a
    significant decrease in both glycolytic flux and proliferation rate, and conferred resistance to ATP depletion by
    glycolytic inhibition while sensitizing cells to mitochondrial inhibition. ”

    PMID: 24166504 This was another exciting one! Glucose deprivation can upregulated MCT-1.

    “While this posttranslational induction could be recapitulated using glycolysis inhibition, hypoxia, oxidative
    phosphorylation (OXPHOS) inhibitor rotenone or hydrogen peroxide” Hydrogen Peroxide! This had me thinking
    about vitamin C treatment. If you could upregulate MCT-1 with vitamin C due to the hydrogen peroxide,
    glycolysis inhibition, and ROS generation (see note 1 below), then you could cycle back with 3-BP once the
    MCT-1 is activated.

    “That ROS can stimulate MCT1 and CD147 protein expression was established by showing a B 2-fold increase in
    the expression of both proteins 24 h after treatment with 0.8 m M H 2O2” PMID: 24166504 (Open Access)

    PMID: 26708213 Sodium Citrate! Look at Figure 5A. High dose Sodium Citrate massively reduces ATP. For some reason tehy do
    not show the ATP out at 24 and 48 hours, though in Figure 5B the lactate levels at 48 hours of the cells treated
    with sodium citrate are extremely reduced. Has metronomic sodium citrate been shown safe in humans? Is
    anyone aware of research that looks at metronomic metabolic depletion?

    Look at Figure 4A, high dose 3-BP massively reduces HK activity! Especially look at 48 hours; it’s almost 0! At
    those levels of ATP production cancer cells would simply no longer be viable. Cancer cells need a minimum of
    10-20% of normal ATP production to maintain viability. Look at Figure 4B, sodium citrate almost stops PFK-1
    activity at 48 hours. One would certainly wonder what would happen with a 3-BP and sodium citrate combo.

    Figure 1D. I have been wondering about cancer cell cycles with respect to metabolic applications for quite a
    while now. If you could synchronize cancer cells into a high ATP part of the cell cycle ( S phase?) and then treat
    with an ATP depleting treatment, then this could be even more effective. Figure 1D shows how the different
    treatments can manipulate cells into different parts of the cell cycle. Cancer cells move through the cell cycle
    more rapidly than other cells, so this should selectively stress the cancer cells with a metronomic dosing
    approach. Great part with metronomic dosing is that with prolonged dosing you will automatically be able to
    benefit from this effect. Yet, with traditional short term dosing schedules this would not automatically occur.

    Figure 1B shows how 100% cell inhibition rates occur with 3-BP and sodium citrate after only 2 days of in vitro
    dosing. Would be great to see this in vivo.

    D, metronomic metabolic treatment is superexciting! The focus of research until now has been almost entirely focused on the idea of giving people the maximum possible dose. Using a maximum dose strategy meant that patients would need time to recover after
    intense treatment with often substantial side effects. In the context of cancer, maximum dosing is an extremely misguided approach. All that you are doing is selecting the most malignant cells. Sure you can obstensibly have large responses, though now when relapse occurs the treatment will no longer be effective. Metronomic metabolics would to a large extent avoid this. If the treatment can be tolerated essentially indefinitely, then there is no longer a time for a super resistant cancer line to emerge. In fact, what happens is that you are pushing the cancer cells to evolve towards OXPHOS which is a less aggressive cancer phenotype. Of course knowing that the cancer cells have been moved in the OXPHOS direction then gives you the opportunity to treat with OXPHOS inhibitors.

    I am not aware of this approach ever being tried before. The research to date almost always stops after 5-48 hours. Depleting ATP or even just stressing metabolic pathways in other ways ( though ATP depletion would be the most direct) for days at a time should lead to very extreme responses. I found this approach which I referred to as duration dosing on the Vitamin C thread to be highly compelling (https://www.cancertreatmentsresearch.com/high-dose-vitamin-c-cancer/ see my post on April 13, 2017).

    If we can all move toward a common protocol, then we could leverage the group knowledge and perhaps find an effective and safe cancer treatment. There might be dangers using various variants of the metronomic approach, though many of these treatments have been used safely already in many patients for many years using the maximum tolerated dosing appraoch.

    1. Hi J,

      Answering shortly to each point due to time constrains:
      – I will need to look back for the reference, if I forger please remind me
      – ATP is indeed essential for many processes required to support fast division -> no ATP, no fast division
      – The above applies indeed to the switch from fermentation to respiration inside the cell, as mentioned in the ref you sent – but we still need to address those cells that a developing slower based on respiration – that is why, for me 2DG like substances are essential but they need to be part of a larger approach that would also attack the pure oxidative cells (such as chemo, etc.)
      – Indeed it makes sense that MCT1s will be upregulated when too low glucose is available as the cell will try to switch on alternative supplies to generate ATP in the mito. Actually some of the patients using 2DG metronomic have also used the substance you are thinking of now 🙂
      – Regarding your question: “”Has metronomic sodium citrate been shown safe in humans? Is anyone aware of research that looks at metronomic metabolic depletion?” The first one I do not know. The second I need to check, but the best answer is to look at the patients that used Phlorizin, and the success in that.
      – You stated “D, metronomic metabolic treatment is superexciting!” – I so much agree with this. This is why I liked the Vitamin C idea as well, just that Vit C can only have the fermentation inhibition activity in high dose. Using Vit C in high dose for long time is not sustainable. And in addition, we do not know if Vit C will always get to the tumor.
      In contrast to that, what PET CT scan tells us is that 2DG virtually always get’s to the tumor. It’s as simple as that. The fact that PET-Ct works and is used world wide for all cancer patients, tells us about the relevance of 2DG and how easy is to get that to the tumor even in very low doses. 🙂
      – most of the people I know who used 2DG metro, have also used OXPHOS inhibitors according to many of ours discussions and understandings, including about the right timing of those when integrated around chemo.
      Kind regards,
      Daniel

        1. Hi J, you better contact Prof. Lampidis at Lampidis Foundation (link above) and ask him if he could share something with you on that line as I am not sure if he published the findings yet. It would help me if you do that, so I can focus on other points. Thanks.

  3. Hi Daniel,

    I am thinking adding a statin to decrease cholesterol uptake and improve 2 DG……

    I think that an alternative to less aggressive sodium phenylbutyrate to inhibit glutamine may be to add iodine L2 and green tea to partially inhibit GDH glutamate enzymes.

    What do you think about?

    1. Hi Manuel,
      I do find statin drugs as good tools to address intracellular cholesterol production in cancer cells. Of course there are more ways for them to have access to that and this is why I developed this strategy https://www.cancertreatmentsresearch.com/reduce-cholesterol-in-cancer-cells-to-fight-cancer/
      I like Green tea as well, but I think a more effective approach to address glutamine is by addressing the mitocondria with mito inhibitors as we previously discussed https://www.cancertreatmentsresearch.com/a-list-of-mitochondria-inhibitors/
      As we also discussed in another post, phenylbutyrate may have other actions as well against cancer that may be more relevant compared to its impact on glutamine.
      Kind regards,
      Daniel

  4. Hola Daniel!! Felicitaciones por tu trabajo y dedicación. Tu ultima publicación nos ha renovado la esperanza en poder ayudar a nuestra sobrina que padece astrocitoma difuso. Vivimos en Argentina, en la ciudad de buenos aires. Podrías recomendarnos profesionales o instituciones que se adhieran a este ensayo. El.oncólogo que asiste a nuestra sobrina es reticente a cualquier terapia que no sea tradicional. Agradeceré toda la información que puedas aportarnos. Saludos cordiales. Carina

    Google translation:

    Hello Daniel!! Congratulations for your work and dedication. Your last publication has renewed our hope in being able to help our niece suffering from diffuse astrocytoma. We live in Argentina, in the city of Buenos Aires. You could recommend professionals or institutions that adhere to this essay. The oncologist who assists our niece is reluctant to any therapy that is not traditional. I will appreciate all the information you can give us. Best regards. Carina

    1. Dear Carina,
      Thank you. We are now working on finding ways to implement this approach in such a way that we will be able to answer questions like yours, and help the patients find trained centers on 2DG implementation. However, until that point, it can be used on compassionate basis by your current doctor, or a medical doctor that you find by yourself. Therefore, the best is for you to find a doctor in your area that is willing and is allowed to implement metronomic 2DG next to conventional therapies. Once you find him, you let us/me know, and from that point on things can move fast.
      Kind regards,
      Daniel

  5. This is super exciting! Metronomic is the way of the future … or continuous as it were. I don’t know if you were aware of this, but we developed a “Linear Elastomeric Pump” to make continuous IV more convenient (for example, places a long skinny pump along the same limb where the needle is inserted for a wholly self-contained solution). Additionally we have been developing some novel needle technologies for subcutaneous and extravisceral (tumor adjacent) infusions of chemo agents like this. Stay tuned. Sounds like a match made in heaven. Also recent studies demonstrating these therapies are concentrated locally using ultrasound and TENS therapy directed at the tumor site. The machines to do this are quite reasonably priced, especially on a rental basis. Best of luck! Expect to hear good outcomes from this.

    1. Thanks! You can add the links to the pumps and needs here. I will not consider them as advertisement.
      Can you please explain what do you mean by:
      “Also recent studies demonstrating these therapies are concentrated locally using ultrasound and TENS therapy directed at the tumor site. The machines to do this are quite reasonably priced, especially on a rental basis. Best of luck! Expect to hear good outcomes from this.”?

      1. Hi Daniel –

        Our pumps are not yet available but that shouldn’t stop people from doing the treatment. For elastomeric pumps the halyard homepump is the industry workhorse. A number of sources can be found online with a quick websearch: https://www.google.com/search?q=halyard+homepump&tbm=shop
        When purchased in quantity of 24 the can be had for just around $13 each, and even less in quantities of 48

        As for the ultrasound and TENS tech, I have an ultrasound that I’ve purchased cheap for evaluation. Here’s about 20 articles on the subject: https://drive.google.com/drive/folders/1iUOR21sBHBJ9kIwBIG3o98GGHQxlCSPw?usp=sharing

        One study (the one on gliomas) demonstrated a 6-8 fold increase in the absorption of nanoparticles by the tumor when subjected to ultrasound.

    2. lullabyman, you are so right this is SUPEREXCITING!!!

      It is such a simple idea that it almost has to work!

      It would be super awesome if this thread and much of the rest of the cancer treatment infrastructure could converge on this idea.
      If we could lock in on an cancer effective treatment, then we could finally remove much of the noise that people need to work through and send them directly to something that will be effective for them. Perhaps D might consider reorganizing this site so that people are channeled through the Metronomic Treatment idea on page landing. This will be especially important as more positive patient reports emerge.

      Shutting off energy supply to cancer cells and doing this over a prolonged period of time should have very very potent anti-cancer effects. There are a range of cancer treatments that could be used for this purpose including Vitamin C, 2-DG, methylglyoxal etc..
      While 3-BP could be highly effective in such an approach, it might be perhaps best to stay with the others as they might be safer.

      lullabyman, do you have any articles that show Vitamin C ATP depletion through time? I would be especially interested in those that used metronomic dosing. Has metronomic iv vitamin dosing been done in vivo? Might you be aware of clinical results or at least patient reports of metronomic iv vitamin C dosing? I believe I did encounter an anecdotal example of prolonged vitamin C dosing online with a large response. Has metronomic iv vitamin C dosing been shown to be safe in humans?

      Here is the posting from the Vitamin C thread when we discussed this idea last year.
      As soon as you explained how the Scottish Vitamin C results were likely a result of the duration schedules used, a bunch of light bulbs went off for me. It was then fairly clear to me that a duration dosing strategy should be a highly effective anti-cancer strategy. Knowing that this is officially called “metronomic dosing” can let us access the existing research literature.

      https://www.cancertreatmentsresearch.com/high-dose-vitamin-c-cancer/

      Jcancom
      April 13, 2017

      “… In terms of treatment duration [in relation to iv Vitamin C], has there been reports where they could maintain within the mM range over extended periods of time (perhaps even days?).”

      lullabyman
      October 10, 2017

      “Good question. … A dozen studies now demonstrate that the main cancer killing mechanism is by NAD depletion, or in other words cancer is starved to death. This explains how Pauling was able to get such great results: when starving something to death the critical parameter is not dose but time. … It is also important to note that the tumor response with his low-rate but long duration protocol was so pronounced that a number of patients experienced tumor lysis ( sadly resulting in death). Although sad, it dos demonstrate once again that dose is not the critical factor. .. [A large iv vitamin C cancer centre] have never seen a tumor lysis in the history of the centre [perhaps due to non-duration dosing?]. It means that with patients with heavy tumor load will probably not be candidates for our pump, not until the bulk of them are removed, and then administration rate wold be especially slow to start with.”

      Then it seemed to take me about a month to fully process lullabyman’s comment:

      Jcancom
      November 14,2017
      “Oh MY!!
      …. ARGGH!”

      This is extraordinarily important!
      Even simply stopping glycolytic cancer cell overdrive with metronomic ATP depletion (without addressing OXPHOS concurrently) would be of substantial help. Pushing cancer cells to OXPHOS, to a certain extent normalizes them. Add in OXPHOS inhibition and things are even better!

      Look at Figure 1b, 2c and D, and 3 in below article! Even 48 hours of dosing can result in very large reductions in viability, ATP, lactate, HK II etc. PMID: 27163639

      Others now are also thinking in terms of metronomic metabolic treatment.
      Here is a methylglyoxal metronomic dosing study!
      Look at Figure 1a, and B. This one goes out to 120 hours. Simply using 0.2 mM MG over 5 days nearly gives you 50% reduction in cell viability.

      It was somewhat disappointing though that when they went in vivo MG metronomic was not enough! (Figure 10A).
      Seems somewhat surprising to me. It could just be there setup. I would have guessed that merely consistently pressing ATP depletion would have done it. Yet, D does note that you need more of a stress ( with OXPHOS inhibition etc.). When they added in chemo, they stopped cancer growth! PMID: 30170097

      I wonder why they did not instead use their existing MG treatment plan which includes oral Vitamin C etc. Also would be very interested to see what might happen if one were to replace MG with nanoMG!

      1. lullabyman,

        what would your dream implementation of metabolic metronomic dosing look like?

        There are a range of ATP lowering agents available; it might be best to rotate through some of them to see
        which of them were most effective. This would also reduce potential for side effects.

        Any suggestions for formulations? Delivering the agents directly to the cancer cells with chitosan etc. would
        be an elegant way to enhance effectiveness and lower risk.

        I am very interested in hearing your suggestions for combos for metronomic vitamin C. Also would like to know what you meant by ultrasound add-on. What would be your ideal metronomic protocol?

          1. lullabyman, your blog comment is right on the mark!
            I am super excited and I hope that others of the forum also see the potential.

            Thank you for taking the time to consider my question in such a formal and thoughtful manner. The internet age has allowed people the opportunity to bang away on their keyboards and often transmit their unprocessed thoughts to a global audience. It is always gratifying when someone steps back and writes a considered reply.

            The entire concept of metronomic dosing (and more particularly metabolic metronomic dosing) is finally starting to congeal for me and hopefully for others on forum. It is simply beyond my comprehension how the words “metronomic” and “metabolic” have until now somehow not been put side by side before or possibly hardly even imagined at all. When I lurked around pubmed, I found a paucity of related literature. Is it really conceivable that the greatest threat to our greatest threat was someone asking “What if…?” ?

            When will patients finally realize that if they do not ask such questions and allow themselves to be treated with protocols that are entirely lacking in basic common sense that the result will be yet more TailorXs? The follow-on question for me obviously is: If chemo were ineffective in 85% of early stage breast cancer patients, then how could it be expected to be effective in later stages? What about all the other hundreds of thousands of other early stage patients who are likely on the same treatment plan? Is there even research underway that is addressing this question?

            The conversations that we have had about the power of duration dosing (metronomic) are still as eye opening for me now, as when you first revealed the concept. Right away– the first time you filled in the blanks for me– the sky opened up for me and transcendent truth was before me!

            These powerful folk wisdoms are self-apparently credible and very likely correct. For example (roughly), “when starving cancer cells it is not dose that is important but instead duration”. This statement should to most of those on our thread almost be read as a tautological truth. It is true because it could almost not be not true.

            The quote below is eerily and profoundly true. The mistake of thinking in terms of maximum tolerated dosing is almost hardwired into deep human psychology. Often real breakthroughs and real genius only occurs when people finally ask the question: What if it isn’t what we have always thought it had to be?: What if it’s the opposite? People want to see the big hit against cancer, when what you likely need is an ongoing continuous force that knocks it down through a prolonged time.

            This one revealed itself to me when looking at Don’s chart. The real power of his treatment program was with the ongoing effect of his diet program than with a large single hit. It is quite startling to realize that MTD approaches might only give you on the order of an hour per day of therapeutic effect. The real question people should ask themselves is: How could such a dosing approach possibly be successful, even if the treatment is known to be effective? It is known that cells (including cancer cells) have a range of short term responses that are on constant standby to counteract almost any threat (pulse threats). These pulse threats are everywhere! How likely is it that in our evolutionary history that long term threats would be as prevalent (press threats) and of more importance that mechanisms would have evolved to defend against them {ironically, the big example of a press counter-response that springs to mind is ketogenic diet which is unsurprisingly a long term survival strategy that has significant anti-cancer potential}?

            “When cancer wins it happens in between the cancer-killing treatments. Always. It’s that simple. The battle against cancer is decided in the spaces between conventional treatments, not during conventional treatments themselves.”

            As a first approximation of a basic mathematical formulation of the effect of metronomic dosing perhaps:
            Effect = Dose * [e ^^ Duration] would suffice. To add more realism, we could add in the dual effect of OXPHOS and glycolysis: Effect = Dose(ox) * [e ^^ Duration(ox)] * Dose(gly) * [e ^^ Duration(gly)]

            From the conversation on the vitamin C thread, I can see the connections for:
            https://www.ncbi.nlm.nih.gov/pubmed/?term=30170097 and
            https://www.cancertreatmentsresearch.com/a-new-approach-to-improve-effectiveness-of-cancer-therapies-is-getting-ready-to-begin-human-trials/#comment-7838 (this thread)

            In Press-Pulse, if you replace “Press” with “metronomic” the approach moves into much greater focus for me
            https://www.ncbi.nlm.nih.gov/pubmed/?term=28250801

            E260 could finally conclusively demonstrate the effectiveness of metabolic medicine and more particularly how effectiveness could be amplified by glycolytic metronomic stress. What happens when the effect of this treatment is a constant raised to the power of the duration? I will leave this as an exercise to the readers to contemplate. Selectively and effectively stopping OXPHOS and glycolysis in cancer cells should mean a profoundly profound metabolic hit. The entire cupboard of metabolic treatments that we have discussed on the forum would then have greatly enhanced potency.The trial is expected to start roughly next April. Patients might need to be told that optimizing with glycolytic knock down could rapidly lead to TLS.
            https://www.nature.com/articles/s41467-017-00832-w#Sec61

            A promise was made to our friends on this forum and the compass that through our combined efforts we will discover and help to manifest a treatment that will help others who are now on their own cancer journey. Considering the intractability and, yes, the seeming eternal persistence of metastatic cancer, such a wish might have been regarded as hopelessly optimistic not so long ago. However, the metronomic metabolic approach is so intuitively logical and potentially powerful that this idea could discharge the obligation: A promise made will be a promise kept. The results that D is already tentatively disclosing suggest that the promise will be kept.

            1. What is interesting is that this strategy, and it’s efficacy has been known for quite some time. Michael Retsky, who is on my SteadyPivot team, cured himself of cancer using this strategy some 20 odd years ago using cheap (out of patent) chemotherapeutics. He simply used a TPN pump with a PICC line, and a bag that he filled himself. Now, it did take him over a year to do this, but he was able to lead a fairly normal life at this time. He has since become an advocate for a number of low-cost cancer therapies with the goal of $1/day to cure cancer, and earlier this year was highly instrumental in getting the FDA to finally approve the recommended treatment to put cancer patients and survivors on daily low dose anti-inflammatories which has consistently demonstrated a 20%-30% increase in life expectancy.

              A group of French doctors (most not oncologists, unsurprisingly), headed up by Nicolas Andre’, have been advocating for a metronomic approach in 3rd world countries for years now due to the high value / low cost / but this approach has met with little acceptance. You can read more about their efforts at metronomics.org. Here’s a good video he did: https://www.youtube.com/watch?v=d9VLJ_fGLMI

              He is focused mainly on doing it orally, which is great if you can get it to work, but current chemo agents aren’t quite there yet. Maybe we’ll get lucky though and can make that happen, but I’m afraid that right now oral metronomics dances on the edge of marginally better that it’s not really going to revolutionize cancer treatment.

              Andre’ talks about an interesting concept about cancer, and it’s one that Dr. Hunninghake at Riordan Clinic, a partner of mine, has a sympathetic ear, and that is that cancer is a part of life, and the “cure” if there is to be such a thing, needs to be respectful of that fact. In that way cancer is not a thing to be destroyed, but controlled and minimized, and the patient empowered to keep it at bay, which they’ve likely been doing all their life until it got out of control. Cancer, in that way, is more of a verb than a noun. And metronomics or continuous treatment is a more suitable strategy within that paradigm. If you kill off all cancer, and cancer keeps the body’s resistance vigilant, then does that resistance get lazy until recurrence metastatically happens all at once, everywhere? Seems to. In truth, we probably have DNA mutations all the time from birth … many of the time resulting in uncontrolled growth (cancer), but in our youth we efficiently keep it in check. So it only becomes a problem when the burden on our systems is overwhelming and it’s allowed to go haywire. Immunology oncology seems dependent on this principle.

              I think conventional oncology may be scared of metronomics because it can, in fact should be, done mostly at home … and expensive chemo is no better than cheap out-of-patent chemo, so fewer visits? Fewer expensive treatments? And if it works well enough then there may be fear that other profitable treatments will be found superfluous. Personally I’m certain that won’t happen … cancer is a beast, and what we know of metronomic therapy targeting metabolics is that for aggressive cancers it is not enough. You have to at least have something that directly attacks cancer too, target angiogenesis (IVC does this, incidently), strengthen’s immunity, etc. Much of that can be done metronomically though. This is what Andre’ calls Metronomics 2.0. Doing it for maintenance is Metronomics 3.0.

  6. Daniel,
    I could not be prouder to read this news. Congratulations – this is just reward for your tirelessly good, and humble, work in this field. I’m so looking forward to hearing news of the trial as it progresses. We know that it’s so easy to get carried away with potential treatments, but with each trial we learn more (even if it’s just ‘well, that didn’t work’) You are contributing so much to this field.
    I recently came across another case whereby the marker for scans (in this case for my own cancer, prostate, has had remarkable effect. You can see them in this image, which I believe has won an award for best cancer image of the year: http://www.snmmi.org/NewsPublications/NewsDetail.aspx?ItemNumber=29483

    I really have to make time to do that interview with you before the year ends!

    Congratulations, Daniel – Mihaela would be so proud.

    1. Dear David,

      So nice to hear from you again and thank you so much for your words and thoughts of appreciation.

      I very much think and feel the credit goes to the many other people involved during the past years in one way or another: The patients and their caregivers doing more than the average. The medical doctors and related clinics or hospitals doing much more than the average. The academics (such as Prof. Lampidis and dr. Metin, and many others) doing much more than the average. The contributors on this website not only thinking but also sharing their thoughts to help others. And of course those supporting the existence of website and related activities like this with their kind donations – and with that I like to thank you again as you were the first to support this website! 🙂

      Yes, most of those like the visitors of this website and like us, searching for solutions and going beyond the “limits” of what is generally known and accepted, we have the tendency to keep searching even after we may have found good solutions. We need to put a lot of energy and momentum in taking this approach, and due to inertia is more difficult to stop when we find relevant solutions. I think that until we have better solutions, metronomic 2DG is a unique tool that should be considered as part of nearly all treatment strategies. This is why I decided to make a stop here and help bring it under the spot light. And the nice thing is that there is now more and more evidence/facts supporting this view.

      What is important for all of us to understand is that until we do not completely understand the origin of cancer (or various forms of cancer), we should build strategies involving multiple tools to attack the major weak spots of cancer cells. This is where the industry also moves now, and that is reflected by so many combo studies emerging during the past years. And this is where metronomic 2DG contributes as it is addressing an essential soft spot of cancer cells related to their need for high amounts of glucose during the fast division and during the fight with conventional therapies. I actually think that the industry should see the opportunity here, as such approaches can help make the pharma drugs work again.

      I will check the link and it is always a pleasure to speak with you, David!

      Kind regards,
      Daniel

        1. Thanks J. I’ve seen the paper when that was published and I like it.

          The advantage of restricted-KD is indeed two fold:
          1. higher 2DG dose can be applied while possibly reducing side effects
          2. lowering the blood glucose levels, the tumor will be more avid for glucose and thus will absorb 2DG better.

          The challenges related to this idea:
          1. restricted-KD is difficult to achieve for most patients
          2. to maximize this concept we would still need to address the challenge related to the high insulin release following high dose 2DG admin … unless we would also use another drug to reduce the insulin release or inhibit insulin receptors prior to and during the application of high dose 2DG.
          3. hormonal cancers or dose relying more on respiration would not do well on KD
          4. side effects of higher dose 2DG, higher than used so far, it is unknown at this point

          Therefore, to avoid some of the above risks and benefit from this concept, what we can do in my view is one or a combination of the following:
          1. use restricted-KD when possible with the current metronomic-2DG aproach (and not with a higher 2DG dose)
          2. to further enhance this or alternatively to reduce blood glucose levels, use Metformin (which also adds value from the mito inhibition point of view).

          Note that Marco’s wife was (and I think she is still using that) on KD while also using 2DG and others treatments and while obtaining continuous positive results. Nevertheless, other patients with positive results were not on restricted-KD (but most used Metformin at the RIGHT timing according to own treatment schedule). Therefore, while metronomic-DG seems to help effectiveness of chemo regardless if the patient is on restricted-KD or not, restricted-KD could further add value to this concept. Finally, it’s about what the patient feels it works the best for him/her, but the low sugar/carbs should anyway be a basis in any treatment strategy.

          What do you think?

      1. Please do not thank me for being the first to support the website – I considered it a great opportunity to help in a field (people powered innovation) that I passionately believe in.

        More when we meet in person!

  7. Estimado Daniel,

    Gracias por tu pronta respuesta. Uno de los problemas que enfrentamos es la dificultad de encontrar algún profesional dispuesto a aplicar cualquier tipo de terapia o tratamiento que no sea el tradicional. Que hacer? Hemos hecho consultas sin resultado alguno . En buenos aires habra algun centro o profesional que estudie esta enfermedad? Gracias nuevamente por tu tiempo.

    Google translate:

    Dear Daniel,

    Thanks for your prompt response. One of the problems we face is the difficulty of finding a professional willing to apply any type of therapy or treatment that is not traditional. What to do? We have consulted without any results. In buenos aires will there be a center or professional who studies this disease? Thanks again for your time.

    1. Dear,

      Very interesting coincidence:
      last evening I was speaking with a man who informed me about a clinic in Argentina that is giving 2DG to their patients. Here is the clinic https://terapiametabolica.com and here is one of their paper http://www.clinicsinoncology.com/pdfs_folder/cio-v3-id1512.pdf
      So the great news is that you can have access to 2DG in your country and given in a professional environment (as it seems from the website of the clinic and published articles).

      However, please note that to my knowledge, when they use 2DG they do not use it in metronomic way (which is the way it should be used) but it is used in the old approach (bolus).

      So what I think you could do if you want to start using 2DG metronomic is the following:

      1. contact the clinic in Argentina and ask if they have a medical doctor willing to give you 2DG metronomic
      2. If they agree, you let me know and I will give you the e-mail of Prof Lampidis
      3. Next, the Medical Doctor in Argentina is contacting Prof Lampidis for treatment protocol of metronomic 2DG
      4. After they receive that, I can speak with your doctors on best practices regarding the implementation of the protocol within a larger treatment strategy (that will include also some re-purposed drugs)

      Please let me know if this is clear or you need anything else.

      Kind regards,
      Daniel

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