Case Report Stage IV Pancreatic Cancer: Good News from Jess

During this summer, on August 10, 2018, Jess was informing us (here) regarding the fact that her dad, dealing with Pancreatic Cancer Stage IV, will start a similar treatment approach as that successfully used by Marcos, and shortly discussed on this website (here).

Jess and I have exchanged a large amount of e-mails this year and consequently also became friends. She is extremely clever, and everything she does is carefully and extensively addressed leading to high quality work. Not only that her quality approach to what she is doing is impressive, but also her care for others is outstanding. Jess dose so much for helping her dad but she doesn’t stop there. And so recently, she did something very impressive: One of our good friends and visitors of this website needed some specific help for her dad, and Jess decided to fly to another continent for a day just to help our friend that she never met before. How impressive is that?

Status before the treatment, before August 2018:
– Jess’s dad was diagnosed with Stage IV pancreatic adenocarcinoma on Oct 3, 2017, with a primary tumor in the tail of the pancreas and several liver lesions. His CA 19-9 marker was 47.000 at diagnosis
– performed FOLFIRINOX until April 17th, 2018, and his CA 19-9 was 3.440
– removed oxaliplatin due to toxicity and continued with FOLFIRI but markers started to go fast up during the summer of 2018 (see graph below)
– during August 2018 decided to start low-dose Gemcitabine supported by many treatment approaches discussed on this website, and latter also introduced Abraxane

Results reported on October 2018:
CA 19-9 dropped by almost 95% over 2 months of treatment. Not only was the CA 19-9 response to this combined therapy much more rapid than the response to his first-line chemotherapy, in fact the CA 19-9 fell more rapidly than it rose during the two month “rest” period. Finally, a PET scan from Oct 10th, compared to one from July 25, showed decrease in intensity of the primary tumor and most importantly, “significant decrease in FDG uptake [from 8.1 to 4] within the large liver tumor, with mainly large photopenic region in the center of the lesion and a moderately FDG avid rim.” This result is consistent with necrosis in the body of the tumor.

The treatment:
Next to the chemotherapy, the treatment schedule included a few other substances expected to exert a strong pressure on the cancer cells including glycolisis inhibitors such as 2DG intravenous, Salinomycin, 3BP, Photo Dynamic Therapy (PDT), thyroid protocol but also diet approaches such as fasting, and various supplements and drugs.

As it can be seen from the graph kindly provided by Jess, the initial (low-dose) Gemcitabine dose could only slightly reduce the markers. Only after the introduction of the supportive therapies, the markers started to strongly decline. These impressive results clearly indicate the importance of the supportive therapies when dealing with advanced cancers.

In order to share her experience and help others, Jess started up a website. Please visit Jess’s website in order to get more details regarding the treatment schedule employed in treating her dad, as well as the related dose of chemotherapy and the supportive therapies used. In addition to that, Jess will continue to share on her website information regarding new treatment approaches she is researching and considering, so it would be a good idea to check her website from time to time for new content.

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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77 thoughts on “Case Report Stage IV Pancreatic Cancer: Good News from Jess

  1. Great news!!!

    This demonstrates once again the efficacy of the adjuvant metabolic approach to chemotherapeutic treatments.

    We use a similar protocol perhaps more aggressive in number of drugs fighting a glioblastoma.

      Best wishes

  2. Great news!

    D, I am seeing a pattern here! It is amazing! This has almost emerged out of nowhere. All of sudden everything seems to be clicking. There is this emergent property where you have a lot of energy and a set of variables and people can work through the combinations and before you know everything falls into place. Extremely exciting.

    I will be anxious to hear of any updates that you might post.

    D, Jess is doing a fantastic job!
    I know in the past you have suggested that people stick with success, I agree, though having something on the backshelf
    also seems to be a good idea to me.

    Thus, nanoMG if possible might be a good choice.
    Easy synth, selectively toxic to cancer cell OXPHOS subunit 1.
    nanoMG is much more cancer specific than MG, enhanced with combo with vitamin C.

    https://www.ncbi.nlm.nih.gov/pubmed/?term=30170097
    https://www.ncbi.nlm.nih.gov/pubmed/?term=25999714

    Best Wishes D, for a job well done!

    1. Hi J –

      Thanks for the support and the suggestions. I have been perusing the recent conversations and have my finger on the `buy` button for regular methylglyoxal, but have not yet found the breadcrumbs pointing towards obtaining or manufacturing nanoMG. Can you elaborate on the `easy synth?`

      I am also acquiring stiripentol and am going to give a try at Rafael pharmaceuticals to see if they will provide some CPI-613. I’ll be updating on my dad shortly … (who is doing well).

      By the way I was reading about continuous vitamin C (Manuone, Daniel, Lullabyman, you) and somewhat serendipitously this morning my mom was concerned about a shortage of IV sets as she was preparing an IV vit C. We have plenty of 270 mL, 27 hour elastomeric infusion pumps (so 10 mL/hr with saline). So we are putting 100 mL (50 g) of vitamin C in the pump and we will see if we also get the 5 mL/hr rate. If yes, this will turn into 2.5 grams an hour over 20 hours for 50 grams. Note that typically my dad does 100 grams via saline over 2 hours.

      1. Jess, stepping up to synthesis can dramatically change the therapeutic index.
        Minicells were found to have large therapeutic effects on mice with nanogram scale dosing.
        It is magical.

        There are so many synths and most of them follow largely the same plan. Learning the basic drill makes a great deal of sense.
        Almost anything can be added in, e.g. paracetamol etc etc. Being able to almost deliver the treatment directly to the tumor
        should enhance safety and efficacy, though it would be best to approach this cautiously.

        At the least, learning the skill set would give you the comfort of having multiple last lines of defence. Often people can be completely unprepared for progression and are then in the position of having no fall back position. There are so many many
        very strong nanoformulation fall backs: mito-HK was highly impressive! (Even when dosed 20 fold lower than a safe dose). …

        The trial that is expected in the not too distant future with 3-BP, could be the cyclo-dextran formulation that was used for pancreatic cancer https://www.ncbi.nlm.nih.gov/pubmed/25326230 .This was found to be safer and more effective in mice than straight 3-BP. NanoMG was found to have comparable effects in mice at doses almost 100 fold less than straight methylglyoxal.

        Of particular interest, MG is a SPECIFIC OXPHOS inhibitor. It should not be a great surprise that encouraging results have been reported in the clinic when combining Vitamin C, Methylglyoxal, and creatine (creatine added to prevent cardiac side-effects).
        This would block glycolysis and OXPHOS! It might be best to develop a comfort level first and then work up to the full potential that this treatment has to offer. For example, the vitamin C that was used in the original clinical work was 400 mg oral Vitamin C which clearly seems inadequate. lullabyman noted that these gummy bear type vitamin C are known to oxidize, so there might have been little actual vitamin C provided. Could work up to metronomic iv vitamin C and add in straight MG (plus creatine), and then move to alternating metronomic C (plus creatine) and metronomic methyglyoxal, then dual Vitamin C and MG metronomic, and then possibly NanoMG, though marcos mentioned that he had reasons to steer clear of NanoMG. It would be good to contact him to uncover what he meant by this. Would also be a good idea to contact the Indian researchers for their comments.

        Other MG combinations also have potential (e.g. curcumin is a strong GLO1 inhibitor) so it could combine well with MG. MG is an easy one to buy and have on your shelf when needed. The nanoformulation is somewhat off-road, though chitosan is considered GRAS and it has the potential to essentially deliver the MG almost directly to the tumor.
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435252/

        The big problem is that there are a large range of these nanoformulations and they look exceptionally impressive in mice, though for whatever reason, none of them have ever appeared to move to people. mito-DCA was reported to be 1000 times more potent than DCA!

        The basic idea of moving to complexify your plan by adding in other metabolic inhibitors metronomically such as MG with combinations makes a great deal of sense to me. In time, yet others could be added such as tocotrienols etc.

        Here is the synthesis recipe.
        I am not completely which of the many similar products are correct for the synth, though this would give a rough idea (This method was given in the most recent article noted below).
        Basically: sonicate, stir, stir, stir, stir, filter and strain.

        Synthesis of nanoparticles

        MG (40% aqueous solution, w/v),
        low-molecular-weight chitosan,
        3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT),
        Sephadex G-50,
        trypan blue,
        cell culture media, and
        fetal bovine serum were purchased from Sigma Aldrich Co. (St Louis, MO, USA).

        Nano-MG were prepared by the method described previously, 21 with some modifications. In brief, initially

        1. a 100 mL solution of 0.3% low-molecular-weight chitosan (~40 kD) in dilute acetic acid (34.8 mM) was prepared by sonication for 45 minutes at 37°C.
        448869-50G Only 6 left in stock (more on the way) – FROM 72.30

        2. To the above solution, 1 mL of MG was added under stirring condition followed by addition of 1 mL Tween 80 after 1 hour of stirring.

        Methylglyoxal
        M0252-25ML Only 5 left in stock (more on the way) – FROM 101.00
        67028-100ML Available to ship on 12/09/18 – FROM 277.00
        Tween 80 8221870050 Estimated to ship on 12/24/18 25.70

        3. Stirring was continued for another hour before adding 0.4 mL of 20% sodium sulfate solution dropwise.
        sodium sulfate
        239313-500G Available to ship on 12/09/18 – FROM
        This SKU is also available as ACS grade in our Exclusive Redi-Dri™ free-flowing product line.
        67.40

        4. To crosslink the nanoparticles, 10 µL of 25% glutaraldehyde solution was added, with stirring for another 30 minutes.
        glutaraldehyde solution
        G5882-10X1ML Only 4 left in stock (more on the way) – FROM 157.00

        5. Finally, 1 mL of 10% sodium metabisulfite was added and the solution was stirred for another 30 minutes and kept overnight at room temperature.
        S9000-500G Only 5 left in stock (more on the way) – FROM 37.50

        6. The Nano-MG solution was passed through a Sephadex G-50 column (20×1 cm) to eliminate small molecules using normal saline as eluent.

        7. The solution was strained through 0.2 µm-pore-size filter paper and preserved at room temperature for further characterization and therapeutic studies.

        The same protocol was repeated with the chitosan molecules to prepare void chitosan nanoparticles (without MG) without sodium sulfate (to avoid precipitation of nanoparticles). This was designated as Nano-Chitosan.

        The synthesis of NanoMG was published in these two articles, though the more recent one apparently had better results.
        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4435252/
        https://www.ncbi.nlm.nih.gov/pubmed/?term=24368179

        https://www.ncbi.nlm.nih.gov/pubmed/28903386

        Be careful with the stiripentol!
        It appears to interact with everything! https://reference.medscape.com/drug/diacomit-stripentol-1000287#3

        I have been waiting anxiously for an update!
        Might you offer us the latest CA 19-9 number as a preview?

        This is great to see innovation on metronomic dosing with vitamin C! You have 2-DG and fasting as metronomic metabolic treatments: adding in Vitamin C, methylglyoxal and perhaps others seems very sensible. {I would think though it would be best to stay away from metronomic 3-BP and salinomycin}.

        Duration is more potent than dose. Cutting off the energy supply to the cancer cells for 2-4 hours might not be long enough. Yet, with prolonged energy deprivation the cancer cells might be pushed below their critical energy levels. Adding in MG could target those cells that are just able to survive the glycolytic stress of Vitamin C, but might not be able to cope with MG’s reduction in their OXPHOS ATP supply. Glycolysis and OSPHOS is such a strong combo.

        This approach will need to be explored, as for whatever reason the Scottish lead was never embraced by others.
        From what we understand they were using possibly 1 gram/hour over most of the day(?). Even this point is not overly clear.
        There are a range of variations that could be tried for example, perhaps start off with 100 grams over 3 hours and then maintain with 2 grams per hour from there. I think it would be helpful to do the dosing calculation with the formula that I posted somewhere on the forum. It is quite neat that such a simple formula appears to give a reasonably good idea of the blood levels of vitamin C. Might also try out the glucometer approach. By keeping an eye on these measurements it is possible that one could develop a sense of what vitamin C levels were required to be effective.

        Note in the recent article that I cited on this thread that pancreatic cancer was found to be a highly hypoxic cancer. This sent up a large signal to me to think about the metabolic treatment potential that this would imply. If it is highly hypoxic, then it wold only have glycolysis available (and perhaps on the margins OXPHOS). It is reasonable to suspect given this that stressing its metabolism would result in significant anti-cancer effects.

  3. Speaking from my experience of FOLFIRINOX and Gemcitabine + Abraxane combinations used for a loved one for a Pancreatic Adenocarcinoma diagnosis.

    Both these chemo regimen are first line/second line treatment for Pancreatic Adenocarcinoma and shows excellent results (in terms of activity on the tumours and reduction in CA 19-9 markers) on people who respond to these drugs till the resistance kicks in. So in this case the drastic fall in the CA 19-9 markers after introducing Abraxane with Gemcitabine is typically seen in a lot of people who respond to Chemo drugs and addition of Abraxane is very likely the key here.

    One other thing is for people responding to these drugs FOLFIRINOX and Gemcitabine + Abraxane can be used in sequence i.e. when one of these regimen fails; the other combination can be started; like it has been used here.

    1. Thanks. As an abstract level, fair comment. I would think the same but the “details” make the difference:

      1. we could make it sound very easy but the reality is the opposite – let’s not forget this is one of the most aggressive cancers – little number of patients can influence so nicely the tumor and this is why the overall survival is extremely short when following the conventional treatments only; increasing the chance to be one of the responding patients is extremely valuable
      2. here the patient was using lower dose chemo, and lower frequency:
      – typically Gem+Abraxane is given at Gem 1000mg/m2 and Abraxane at 125mg/m2 every week (Ref.)
      – the patient here used only Gem first at 800mg/m2 and when Abraxane was introduced at 80mg/m2, Gem has been further lowered to 500mg/m2
      – as it can be seen in the graph above, when Gem (800mg/m2) is introduced first there was not a major response – as the 2DG metronomic dose has been increased and PDT & 3BP introduced the marker started to decline faster while Abraxane was not yet added. Next, Gem dose has been further reduced to half while adding lower than normal dose Abraxane and latter Salinomycin. The markers continued declining.
      3. indeed, the doctor following the patient stated that the response is faster and better vs. what she has seen in patients before
      4. most treatments that have been used here have strong scientific base (not B17 or similar) and are indeed expected to do what we see here
      5. this is not a single case – it is part of a larger number of patients with different cancers using similar approaches and experiencing response to conventional therapies while all are in a difficult stage IV

      Therefore, what we have here is a patient using low dose chemo and responding nicely to that in one of the most difficult to treat cancers.

      1. thanks Daniel for the details and clarifying it. It makes perfect sense to me now.

        If you can upload the other graph (from 8/12/2018 onwards) which zooms-in to the specific area of the drastic fall of the CA 19-9 markers to this blog post itself; it will be great and i think it will keep the complete context in one place for future too.

        About your point #4; I have NO doubt on the detailed analysis (of scientific nature) that goes into each treatment option mentioned here. This website is the ONLY of its kind and is really making a difference in the lives of patients especially stage-IV who are left with limited or no options from conventional therapies and you and (others helping out) cannot be thanked enough for making this happen; so thanks again for all the efforts that you are putting in here.

        About FOLFIRINOX; Jess mentioned that the oncologist removed oxaliplatin (and continued with FOLFIRI) out of concern for “potential” future nerve damage. I could not make out from her description if the neuropathy was actually there or not when the decision was made; because the drug-resistance kicked in immediately after dropping oxaliplatin. Basically from the options available currently in the conventional therapy for Stage IV Pancreatic Adenocarcinoma the only instances of long term remissions that i have read about (a couple of them only though) are with FOLFIRINOX only where people continued (who could tolerate) on maintenance FOLFIRINOX for really long. So if someone is responding to FOLFIRINOX and tolerating fine; then I think they can try to talk to their oncologist to go ahead with a full combination of this regimen as long as it responding.

        And I sincerely hope that the other supportive therapies being administered are able to remove drug-resistance of the tumour for FOLFIRINOX here and they can revisit this regimen at a later point in time if required and if the fitness levels allow.

        Regards,

  4. D, finally we seem to have turned the corner.
    It is almost 4 years since I entered the conversation and we have lost dear friends and you your soul mate.

    It has been so tough moving through this abyss with no idea when we would finally arrive at the journey’s end.
    Yet, here we are and we are starting to see some very startling responses.
    These responses are happening right now!
    Typically published research is YEARS distant from patient outcomes even when it is freshly published.

    One speculation that I will put forward is that if the metabolic response is truly happening for these patients so far,
    then we would likely see the response continue. With metabolics there are very few escape routes, cancer cells have
    to produce energy somehow and 2-DG is entering via a glucose pathway. I would find it difficult to believe that a cancer
    cell could find an effective means of avoiding glucose uptake. With glycolysis under stress it might switch to OXPHOS,
    though MG would be there to block out that escape route as well.

    D, if more evidence for this accumulates there could be a wave of patients reaching out to you on your site. I think the basic protocol might be tightened up somewhat, though the core idea of metronomic metabolic dosing seems very solid.

    Best Wishes, J

    1. HI J,

      Thank u for your nice comment. It becomes clear to me that metabolic treatments alone are not enough since we will never be able to fully shut down cancer cells using that approach without shutting down the normal cells as well. However, metabolic treatments represent amazing tools to put cancer cells under pressure while being attacked by conventional therapies.
      There is more evidence accumulating that suggests that.
      But that means that in order to have effective treatment strategy, you need not only an effective metabolic tool (such as 2DG metronomic) but also an effective conventional tool. If the conventional tool (such as chemo) is not able to kill cancer cells not even when they are under pressure, the conventional treatment needs to be switched. So far it looks like just adding 2DG metro to chemo is enough to produce effectiveness (implying results from slowing down cancer growth, to stopping growth and even killing totally the tumors).
      But there is more to understand in order to maximize even more the outcome. For example, in some cases, the treatment may not be effective in reducing tumor below a certain size. In that case the remaining type of cells are not responsive to the therapy. When that happens, the reason for that could be either the remaining cells are of oxidative nature (slower and thus not responding to chemo and glyco inhibitors), or have acquired resistance to the specific chemo and that needs to be change to another regime. Another option could also be e.g. the physical barriers for the treatment to reach the tumor. However, I think the first (oxidative slower cancer cells) is the most relevant. Therefore we need to think of solutions against oxidative cancer cells for cases when resistance may be reached. One approach could be a more intensive use of mito inhibitors and/or fibroblast inhibitors (feeding the oxidative cells) and/or ion dynamics modulators. Actually I now realize that angiogenesis inhibitors should also work very well for these type of cells. Any idea is very welcome. We need to innovate together 🙂

      Kind regards,
      Daniel

  5. I have to improve the therapy ….. glioblastoma seems much more resistant. It has advanced much slower than expected but has advanced.
    I need to incorporate other iv in addition to 2 dg metronomic, vitamin c and salinomycin.
    Jcancon MG is methylglyoxal? Methylglyoxal crosses the BBB? If so, I can try to find a nano or chitosan formulation ….
    I need a game changer for gbm

    Dear Daniel I am waiting for your answer when you are less busy

    Best whises for everyone

    1. Manuone, I am so excited by this recent development!
      It has been years and years and it looks like we have finally found something!
      Before, we might see a short term response, yet then there would be progression.
      Ongoing responses now appear to be occurring!
      We should not over-assume, though this looks very promising.

      This could be our first major step forward.

      My understanding is that this is related to the metronomic metabolic approach (specifically 2-DG).
      When you look at the list of the treatments that are being used the one notable difference is the metronomic dosing.
      All the other treatments are mostly well recognized by those on the forum.

      It should not be assumed that step 2 will be any easier to achieve than step 1, though we can start to think about what we
      could modify next. I will let D show leadership on this, yet for me the obvious next amp up would be to go combo metronomic metabolic. From what I see only 2-DG is dosed metronomically now. Trying combo 2-DG and MG metronomically could be a very
      powerful combo. Instead of shutting down glycolysis over time you would be shutting down both glycolysis and OXPHOS over time.

      I have been suggesting NanoMG for some time now, though posters of the thread have not been able to do this synth. The url below shows how very powerful this nanoformulation could be. The synth presented appears very straightforward. It was only recently that I discovered that MG is a quite selective OXPHOS inhibitor (it is suggested thought that creatine be given to protect against cardiac toxicity). The suggestion was to use low doses of vitamin C in combination when using the non-nano form of MG.
      I am currently wondering how effective combo metronomic NanoMG and vitamin C would be. On paper it should be quite a powerful combo. Some might even start with the easier to obtain though less effective approach of simply metronomic iv MG and iv vitamin C. There is a great deal of excitement and I am looking forward to how D feels about the various options available.
      https://www.ncbi.nlm.nih.gov/pubmed/?term=25999714

      It surprises me how many cancers now appear to be metabolically vulnerable, including GBM.
      https://www.ncbi.nlm.nih.gov/pubmed/30138705
      “Glioblastoma (GBM) is the most common brain tumor; however, no effective treatment for it is available yet. Monocarboxylate transporters, which are highly expressed in GBM, play a role in transporting antitumor agents, such as 3-bromopyruvate (3-BrPA).”

      On a first run through, yes chitosan does appear to be bbb penetrable.
      http://www.ijpsonline.com/articles/discerning-the-potential-of-chitosan-extracted-from-bio-resources-as-a-competent-brain-drug-carrier-to-cross-the-blood-brain-barri.html?view=mobile

      Another idea that I picked up from a url given by lullabyman on the metronomic 2-DG blog page was the idea of chaotic cancer treatment. An oncologist proposed that creating a treatment model in which cancer is constantly exposed to unexpected stresses
      could give a treatment boost. As real world evidence of this effect he showed successful cancer regimens that did have to some extent a chaotic treatment schedule. How would this chaotic treatment approach work with metronomic 2-DG? One could cycle through different metronomic treatment combinations such as vitamin C, MG, 2-DG, DCA and others (though I would tend to steer clear of dosing 3-BP metronomically). The strategy would be to destabilize the ability of cancer to effectively respond to the stresses involved. Simply giving the same treatment with the same dose over the same time interval gives cancer the advantage of
      being able to create a possible counter-strategy. A chaotic might counter the counter-strategy.

      I realize that this must be a very difficult time for you.
      I wish that the efforts of those on the forum will be able to help you.

      Best Wishes, Jcancom

    2. I’d start hitting the damned thing with a different chemo, and a combo of supplements:
      Vitamin D3
      Liposomal Curcumin + Berberine
      Honokiol + Magnolol
      Luteolin
      Betulinic acid + Delphinidin
      Citric acid
      Sodium selenite
      Resolvins(EPA, DHA and DPA)
      Royal Jelly(has Phenylbutyrate) + Melatonin

      Drugs: phenylbutyrate, Tamoxifen

      Take care

    1. J, I was away these days – this is why a little delay in my response.

      For metronomic 2DG, I think its best to take a different approach compared to other treatments discussed here. The approach could be one of the following two options:

      1. the patient finds a doctor willing to help him/her with implementation -> the patient contacts Lampidis Foundation or myself -> receives the e-mail address and his medical doctor requests the treatment protocol from the academic team -> the medical doctors receives treatment protocol as a document & continuous support in discussions during the implementation
      The medical doctors sends feedback back to the academic team regarding treatment results.
      2. if the patient really cannot find a medical doctor but wants to consider 2DG, which is not the recommended route, I (as a blogger) can have an informal discussion (via private communications) with the patient where I can share what I know.

      However the best route is the first one, because there is a doctor assistance, there is an assistance from the US academic team, and the protocol (including the dose, time & additional drugs used) may be adapted on the way as a result of the learning following the consolidation of information we receive from various medical doctors using 2DG. Potential side effects can also be addressed much better on the first route. All this will not be available to the patient if patients chose to do the treatments by own means.

      I agree to share information with the patient even if he doesn’t find a medical doctor, as the purpose is to help people. But I do that via private communications in order to keep the process clean and coherent. Only through clean and coherent processes we can learn and be able to use that to help even more people, as opposed to the more chaotic implementation of e.g. 3BP. The goal is to keep things clean while accessible to anyone.
      If u like to discuss dose of 2DG etc., we can have a Skype call and discuss about this. It would be a pleasure anyway to finally talk to the man known as “Jcancom” 🙂

      If u have ideas about improving the process described above, please let me know and will be glad to consider improving our current approach on this treatment route.

      Kind regards,
      Daniel

  6. Hi guys,
    I am considering applying vitamin c iv metronomically. Similar to 2dg metronomical:
    -I have vitamin c vials of 50g in 100ml
    -I have elastomeric pumps from 100ml to 2ml / h

    An option of 10 gr per day would be to use 20ml of the 100ml vial, this would be 10gr administered in 2ml / h would be equivalent to 10 hours of metronomic infusion / day.
    Any ideas? suggestion?….
    It is difficult to measure interactions with the rest of the cocktail: temozolamide low dose, sodium phenylbutyrate 3 gr, tamoxifen 40mg, metformin 1700mg, naproxen 550mg, quetiapine 20mg, simvastatin, ecetrol, tetrandine liposomal ….

    Best whises

    1. Hi Manuel,

      lullabyman seems to have good knowledge on metronomic Vit C. Maybe a god idea is to write your questions related to this as a reply to one of his comments, so he can receive e-mail notification on this. Regarding the interactions, I do not see any major issues but this is difficult to estimate as there is no literature on that.

      Kind regards,
      Daniel

      1. Thanks Daniel!

        I will ask lullabyman for the metronomic administration of vitamin c ….. jcancom seemed interested in this administration of vitamin c
        What did you think of my treatment plan?

        kind regards

    2. Hi Manuona

      Have you looked at Berberine?

      – enhances anti-tumoir activity of tomoxifen (PMID: 27432642)
      – potent anti-tumor effect against glioblastoma (PMID: 25504754, PMID: 27557493)
      – Berberine protects against metformin-associated lactic acidosis PMID: 28656086

  7. Dear Manuone, yes I am very interested in this approach. What I find so compelling is that there is a range of metronomic options that could be applied (perhaps even in combination). The combo potential of metronomic vitamin C and metronomic methyglyoxal (metronomic 2-DG) seems especially powerful.

    There are many ideas that could be tried. With these metronomic approaches you have a wide range of combos that are open to you and you could continue to change the dosing rates and days of treatment etc. in order to attempt to capture the chaotic effect that is mentioned by an oncologist in a link supplied by lullabyman. I will wait anxiously for his response. He has a very good understanding of the vitamin C protocols and how to boost up their effectiveness.

    D and I talked about myxoma virus on this forum previously. The same company that is developing this oncolytic myxoma virus is also developing an oncolytic virus for GBM (Tasadenoturev). I wish that these viruses can finally be approved so that they could help patients like you!
    https://www.dnatrix.com/pipeline/

    Best Wishes, J

    1. Hi Jcancom,
      Thanks for your words.
      I’m not going to stop looking for all the options ….. you do not doubt this!
      It has caused me sadness about Dnx unfortunately the reality is not like that.
      My mother was not chosen for dnx 2440 … they considered that their karnofsky index was not appropriate to participate … they decide continuously for the lives of others as if they were gods.

      kind regards

  8. Hi Manuone,
    That’s an impressive cocktail, I truly hope it’ll knock out the gbm.

    Have you looked at Berberine?
    It could enhance tamoxifen (PMID: 27432642)
    Potent anti-tumor effect against GBM (PMID: 25504754, PMID: 27557493)
    Berberine/Metformin synergy (PMID: 28656086)

    Regards,

  9. Some suggestions for Jess:

    – Perhaps tocotrienols are worth a look. In a clinical trial with pancreatic cancer patients doses of around 1 gram per day appeared to have some efficacy.
    26844278

    If possible moving to nano multilammelar vessicle alpha-tocotrienol might help a great deal to amplify the effect. A fair portion of the mice dosed with only 10 microgram had complete responses. In Figure 6 the mice treated with tocotrienol in these vessicles showed potent tumor suppression.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=27993600

    It should be noted that gamma tocotrienol was found to powerfully reduce MCT-1 expression. So, tocotrienols and 3-BP would not be expected to mix well. Figure 2 shows that tocotrienol greatly reduced glucose consumption and ATP levels. It also greatly reduced MCT-1, HK-2 and LDH-A levels (Figure 3).
    https://www.ncbi.nlm.nih.gov/pubmed/?term=26328490

    – Combining Salinomycin with DCA might also make sense. One wants to find combinations that the research has shown to be additive or better yet synergistic. Sal and DCA appear to be a good match.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=30531808

    However, the research above used combinations of 15 milliM DCA and 0.25 microM Salinomycin. As can be seen in the article, there is strong synergy especially as the dosing of DCA and Sal increase from there. Yet, human dosing of DCA is more on the order of 0.4 milli M and Sal is perhaps 0.2 micro M.

    DCA and Omeprazole also looks like a good combo, especially as Omeprazole appears to be quite well tolerated.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=22740984

  10. Hi everybody. So great to see all this amazing commentary! As a preview to the writeup that is coming, my dad’s CA 19-9 on 10/2/2018 (end of the reported period above) was 2804 U/mL, according to Labcorp measurements from Wisconsin. The latest measurement he had was on 12/11/2018 when it was 989 U/mL.

    More soon….

    Jess

      1. johan, do think that a citrate increasing/ lowering strategy would fit in well for the protocol that Jess has developed?

        Here are 2 patient reports using a plain citrate increasing approach.
        https://wwjournals.com/index.php/ijar/article/view/7111
        https://www.worldwidejournals.com/indian-journal-of-applied-research-(IJAR)/recent_issues_pdf/2015/December/December_2015_1450703927__126.pdf

        A more advanced version of citrate therapy might be applied after first applying the above basic protocol.
        https://www.ncbi.nlm.nih.gov/pubmed/27912843
        What is actually interesting is that in the latest treatment protocol Jess already has ALA, DCA and hyroxycitrate!

        Citrate could complete the combo, though I suppose it is best to just ease into things and feel more comfortable gradually.
        As the article above notes in the abstract, the Warburg effect leads to low intracellular citrate which promotes glycolysis and intracellular acidity. It even proposes that citrate levels could be monitored as a biomarker of tumor response. If it is believed to be this important than why not simply manipulate citrate levels as proposed in the article? (See Figure 2). Metronomically would be best. There already exist FDA citrate products on the market which dose up to 8 grams or perhaps higher. Inone of the many articles by the author of the first two articles cited above doses somewhat higher were used in a more recent publication.
        It should be clearly recognized, confirmed by the research evidence, that citrate is an impressive and powerful anti-glycoslysis agent. I have been impressed by it for quite some time as in some of the 3-BP articles, citrate when given head to head with 3-BP actually often seemed to do better. The combination of citrate and 3-BP was especially powerful.

        Citrate is an especially important biochemical branch point; hydroxycitrate could block off ACLY ( Figure 2).

        As we noted on the citrate thread one could also decrease citrate as an anti-cancer strategy. The article below actually got it wrong: disulfiram had no anti-cancer effect, it was the zinc gluconate! One could hit it either with citrate or zinc gluconate or perhaps treat with citrate and or the full citrate increasing protocol for a week or two and then move to zinc gluconate. This would be the floor it and then full brake approach. One consideration though is that zinc gluconate is an irreversible inhibitor of pmCIC. One might actually want to keep the doorway open for increasing citrate as it has the positive effects noted above. (Always good to have a range of options!). http://mct.aacrjournals.org/content/3/9/1049.long

        What is perhaps even more exciting is another finding with gluconic acid, the acid form of the gluconate anion from zinc gluconate. https://www.ncbi.nlm.nih.gov/pubmed/?term=29633614 This one is best described as shockingly powerful!
        The article describes creating a “motor” that can be imported into cancer cells that takes in glucose, oxygen, and water and converts them to gluconic acid and hydrogen peroxide; and in another reaction takes Manganese oxide, water and protons and creates oxygen Manganese ions and water.

        Glucose + O2 + H2O —> gluconic acid + H2O2
        MnO2 + H2O + 2H+ –> O2 + Mn2+ + H2O

        The net result of all of this is that glucose –> gluconic acid reduces glucose levels.
        The stoichiometry is not entirely obvious though apparently net oxygen is also produced, which can lead to normoxia of cancer cells and this leads to reduced GLUT 1 levels (Scheme 1 of the article). Funnily enough the gluconic acid if it were to then leave the cell might then decrease pmCIC levels ( or it might also chelate other metals in the cell and form e.g. zinc gluconate!).

        This is quite extraordinary! What we actually have here could best be described as a Warburg Motor! This decreases glucose, increases oxygen, and downregulates GLUT1. These are the treatments that we have been talking endlessly about for years and years at the macro scale with ideas such as hyperbaric oxygen, glucose lowering strategies etc. ! Yet this treatment is at the cellular level! All the arguments would end if such a precise treatment could be shown effective in vivo. This is a precision treatment according to the Warburg perspective. Was Warburg right?

        Yes!!! When they went in vivo with this tumors stopped growing (Figure 6)! They only went 14 days, though they seemed to actually be shrinking! It would be even better still if they could have had a single net product such as reduced glucose but constant oxygen or vice versa, though this is a very very powerful confirmation of Warburg’s theory of cancer.

        It will be exciting to see this one further developed for human use.

  11. J is for Jess!
    J is for Jess!
    I will need to cede to the new J on the forum!

    It was so bleak for so many years here as we were unable to find the key.
    Yet, now everything seems to be fitting in place.

    What I believe that I am seeing here is that a highly hypoxic type of cancer (pancreatic) is being exposed to truly massive
    metronomic metabolic stress along with the low dose chemo. The central part of the tumor (mostly hypoxic) was reported earlier to have turned necrotic which would be consistent with this interpretation. This inside part of the tumor would be low oxygen, low nutrient, and high acid (i.e. highly glycolytic). Step 1 of the plan to debulk this main part of the tumor and the corresponding regions in any mets has been an overwhelming success. The update has provided us with the great news that a very substantial portion of this glycolytic tumor mass has been deactivated. We now have the opportunity to witness how a mostly non-glycolytic cancer behaves (I have been wondered about this for quite some time).

    What will be eventually left is a more oxidative remnant tumor residue, that might be more diffuse, less acidicly concentrated, and potentially somewhat normalized cells: It will be perhaps best described as a Warburg Effect cancer. Being ready with oxidative metronomic metabolics (such as methylglyoxal) would be the next obvious strategy. It is truly impressive, though, how far the biomarker has already fallen. The question certainly arises of how much of the oxidative tumor has already been eliminated with the current treatment. Jess, have you measured the LDH numbers through time?

    {Hmm, that was surprising! I just looked up CA 19-9. Anyone know what CA 19-9 is? Astonishingly, “It is a tetrasaccharide with the sequence Neu5Acα2-3Galβ1-3[Fucα1-4]GlcNAcβ.” wiki This makes me think that perhaps CA 19-9 could be used as a vehicle to bring treatments to cancer cells.}

    {This is also interesting. https://jamanetwork.com/journals/jama/fullarticle/1817797
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996199/pdf/fphys-09-00685.pdf
    There would seem to be substantial potential for this to be incorporated into treatment (e.g. therapeutic miRs, or perhaps using the miRs as a biomarker for the evolution of the tumor and identifying treatments (in particular metabolic treatments) that would synergize best within a given miR readout.}

    Yeah, Jess!

    1. I noticed that the glucose reading in the lab reports was 95. I had been wondering about what the glucose might be. It was surprising that it was so high after all that fasting, though when I went online and watched a video about this by ketogenic experts even after prolonged fasting of up to 20 days, glucose levels were still over 90. Interestingly, the experts called this state with a GK Index of 0.87 phase 1 of their plan. Phase 2 of the plan was to … bring down glucose levels. They said that this would dramatically enhance the anti-cancer effectiveness. They spoke for example of using insulin to massively reduce glucose perhaps as low as 9 mg/dL. This was also noted in the article that D just quoted me on from the Mitochondrial inhibitor thread page. In that study, very obese subjects were fasted for about 1-2 months and then in a state of deep ketosis, their glucose levels were greatly reduced. Even at 9 mg/dL there was no apparent effect on cognition. This is quite surprising as people who were not in ketosis could go into coma if their glucose readings were even in the 40-45 mg/dL range.

      The interview went on to speak about how some had water fasted for 30 days and this had caused large metabolic stress on tumors, though of course this would be an extreme measure that would need to be considered carefully.

      Link

      They also speak about using DON as a glutamine blocker, though they are unclear about the human safety of this treatment.

      This video and the insights it provides could intensify the current program being pursued by Jess.
      Adding in a glucose reducer and possibly trying a prolonged (up to 30 day water fast) might be worth considering.

        1. finnan, thank you for posting to the forum!
          Always great to have more perspectives on cancer.

          We are making progress!
          The point that glucose needs to be lowered has been largely completely overlooked on our forum!
          The articles below show how extremely important glucose lowering is.
          This should be obvious to all of us cancer cells NEED glucose.

          This article speaks of possibly over 1000 cancer remissions based upon a largely uncoordinated glucose lowering strategy.
          https://arxiv.org/pdf/1407.7622.pdf

          This more recent update of the basic glucose lowering idea finally gives an approach that seems to be a highly translatable protocol.
          As noted in the paper all of these treatments have been used in humans before, and the protocol was actually already used in peole without cancer.
          It would seem to be within the Right to Try legislation.

          This link is behind a paywall
          https://www.sciencedirect.com/science/article/pii/S0306987718303840
          D has a link for this here
          https://www.cancertreatmentsresearch.com/wp-content/uploads/wpforo/default_attachments/1547388186-2018-A-hypothetical-method-for-controlling-highly-glycolytic-cancers.pdf

          I think that we should fall into line with the thought leaders of the Metabolic approach.
          They have done a large amount of research and have alredy worked out the main pathways involved.
          After all their research, they have distilled cancer treatment down to glucose and glutamine inhibition, with
          press and pulse metabolic stressors. They have left open the question of which glutamine inhibitor might be the best
          and are somewhat ambivalnet about dosing/ scheduling.

          We somewhat independently finally understood the idea of press which we have called (metronomic dosing/duration dosing etc)
          Strangely, with us we have added metronomic glycolysis stress on top of the ketosis Press, whereas the recommended idea from the leaders
          was to use ketotic press along with glycolytic pulse. It would probably be very helpful if we all use a common terminology and
          talk in terms of pulse and press. This way we will not be confused by the terminology, while the actual procedures are largely the same.

          There are a few recent videos that give a good flavor of the current thinking. Basically turn’em and let’em roll.

          https://ca.video.search.yahoo.com/search/video;_ylt=A2KLfRbI0ztc8u8ArwHrFAx.;_ylu=X3oDMTB0N2Noc21lBGNvbG8DYmYxBHBvcwMxBHZ0aWQDBHNlYwNwaXZz?p=metabolic+theory+of+cancer&fr2=piv-web&fr=mcasa#id=26&vid=b54d2db2944c63aa7a5ace0ff254d88e&action=view
          9 months ago

          Press Pulse Theory
          https://www.ncbi.nlm.nih.gov/pubmed/28250801

          https://ca.video.search.yahoo.com/search/video;_ylt=A2KLfRbI0ztc8u8ArwHrFAx.;_ylu=X3oDMTB0N2Noc21lBGNvbG8DYmYxBHBvcwMxBHZ0aWQDBHNlYwNwaXZz?p=metabolic+theory+of+cancer&fr2=piv-web&fr=mcasa#id=28&vid=c228f2468b8cf17075aff795c5f0832e&action=view

          Living Outside of the Matrix Episode 71

          Knowledge is now to take it to the next level.
          Need help, hBOT, insulin much much greater pressure,
          Stage 1 of therapy
          Knowledgable oncologist
          1 month ago

          https://ca.video.search.yahoo.com/search/video;_ylt=A2KLfRbI0ztc8u8ArwHrFAx.;_ylu=X3oDMTB0N2Noc21lBGNvbG8DYmYxBHBvcwMxBHZ0aWQDBHNlYwNwaXZz?p=metabolic+theory+of+cancer&fr2=piv-web&fr=mcasa#action=view&id=99&vid=94abf4849750f8cb179e447dc87cae0a
          4 months ago

          26:52 Figure Glucose and Tumor Weight
          Anyone know of a similar Figure for humans?
          I would love to how low low glucose changed tumor weight.
          The numbers that I typically see are high.
          Yet, we know that glucose needs to be low.
          Cancer needs glucose!

          This why I was so concerned when I saw the glucose number from Jess of 95!
          In a previous video linked above (Episode 71 1:30), ketosis by itself with high glucose levels was refered to as stage 1.
          The real cancer therapeutic effect only occurs when glucose is lowered.

          Highlighting the importance of glucose lowering is of substantial importance, as this was not emphasized strongly enough
          on forum.

          1. Indeed, there are so many angles to try and defeat cancer. It’s tempting to prefer one way over the other, and I have no doubt that’s why so many times cancer eventually wins the battle, if that’s what it is. Diet being one of the most overlooked anti-cancer strategies by modern medicine. Diet alone isn’t enough in most cases, but it should be a pilar of any serious attempt of defeating cancers. I’m a big fan of the work of dr fuhrman. That man is trying so hard to get a simple message across: you can use food to make you sick, but you can also use it to protect you from illness.

            1. This is great!

              We have a global team here so if I wake in the middle of the night with an idea, someone out there in the cosmos might give me a fast reply!

              I had a real brain storm today and I would love to hear some comments.
              I was reading about the keto diet and I was thinking further about the seeming paradox that high glucose can occur with ketosis.

              The, while surfing, I came across this truly startling claim:
              Carbs are non-essential! I had not thought of that one before.

              Glucogenesis in the liver can use lactate from glucose metabolism/tumors, glucogenic amino acids from proteins and/or glycerol from fatty acids. This is shocking! The Cori cycle!

              What I found even more startling is what I will call the Cori-Warburg cycle.
              What I thought would be very neat is if one removed glucose and then let the lactate generate the glucose which would then generate the lactate. Many cancer patients have high lactate levels. Some patients have truly massive
              lactate levels with all the resulting problems that this can cause. What were to happen if lactate levels were calibrated so that they were on a “just in time” production schedule. Basically dynamic equilibrium of possibly zero lactate!

              This could profoundly change cancer!
              Basically, no glucose would need to be consumed, the glycerol and glucogenic amino acids could be given at their minimal level.

              Anyone out there? Please respond!

  12. These miR tests are described as “inexpensive, noninvasive blood sample”.

    “The harms of a high number of false-positives in screening for pancreatic cancer using an inexpensive, noninvasive blood sample from individuals with or without symptoms should be quantified in the future.”
    https://jamanetwork.com/journals/jama/fullarticle/1817797

    Yet, they have been individually annotated as to their specific function.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015885/pdf/fonc-08-00226.pdf
    This is exciting!
    These annotations give considerable insight into what is occurring in the biology of the tumor.
    With a simple inexpensive blood test it appears that one could peer deeply into the biology of a tumor in real time and adjust treatments accordingly. Most notable for the metabolic perspective are miRs 124, 29a and 29b. These reduce MCT-1 expression!
    That is they might shut down 3-BP entry into pancreatic cancer cells! Additional metabolic annotations could also be informative.
    It should not be totally unexpected that these miRs would also be involved in a range of metabolic functions that are of interest to us.

    lncRNA HOTAIR Pancreatic cancer
    Increased expression of PRC2 complex members; genome-wide changes in transcription
    process due to epigenetic chromatin silencing; downregulation of p21(WAF/CIP1); repression
    of G1/S cell-cycle arrest; increased proliferation rate; reduced DNA-damage response

    lncRNA HOTTTIP
    Pancreatic cancer
    Increased expression of transcription factor HOX13; cell cycle deregulation

    lncRNA linc-ROR
    Pancreatic cancer
    Inhibition of p53; inhibition of the expression of miR-200 family; increased expression of the
    transcription factor ZEB1; induced EMT

    miR-124
    Pancreatic cancer
    Liver cancer
    Reduced expression of SLC16A1

    miR-1291
    Pancreatic cancer
    Increased expression of ABCC1

    miR-200b
    Pancreatic cancer
    Induced EMT

    miR-29a
    Pancreatic cancer
    Liver cancer
    Reduced expression of SLC16A1(115)

    miR-29b
    Pancreatic cancer
    Liver cancer
    Reduced expression of SLC16A1

    miR-374b
    Pancreatic cancer
    Increased ATP7A expression

    miR-27b
    Pancreatic cancer
    Reduced expression of CYP3A4—resulting in cyclophosphamide resistance due to
    missing drug activation

  13. I just do not understand why metabolic approaches have not bee put at the center of cancer treatment.
    Given what is given below can anyone on the forum now be overly surprised that the melanoma patient’s LDH treated with 3-BP and paracetamol essentially reached ZERO? Anyone want to guess what his BRAF genotype might have been? Given this background it makes very little sense to me why people would spend $100s of thousands without also combining with a metabolic treatment such as 3-BP. Doing this would amplify the response as has happened with Jess’s dad, while reducing the risk of resistance.

    Pretty startling 93.7% of pancreatic cancers have KRAS mutations!!! So, pancreatic cancer should be a massively metabolic cancer type. Not surprising that Cage sees pancreatic as perhaps a lead indication fro cyclo-3-BP https://www.ncbi.nlm.nih.gov/pubmed/25326230 The article below also explains that low glucose levels drives mutations in KRAS and BRAF. It also upregulates GLUT1. Phloretin? Thinking metabolically gives so many profound insights into cancer. Now try to piece everything together only thinking with respect to chemotherapy as a reference point. Can’t do it! Metabolism is the centrally defining feature of biology.

    “Studying the transcriptomes of paired colorectal cancer cell lines that differed only in the mutational status of their KRAS or BRAF genes, we found that GLUT1 , encoding glucose transporter-1, was one of three genes consistently upregulated in cells with
    KRAS or BRAF mutations. The mutant cells exhibited enhanced glucose uptake and glycolysis and survived in low glucose conditions, phenotypes that all required GLUT1 expression. …

    We suspected that the upregulation of GLUT1 would result in increased glucose uptake in the clones with mutant KRAS or BRAF
    alleles. To test this hypothesis, we incubated cells with 2-deoxy-D-[3H] glucose (2-DG), a non-hydrolyzable glucose analog, and measured its uptake. We found that the upregulation of GLUT1 was accompanied by significant increase in glucose uptake in all cells with mutant KRAS or BRAF alleles compared to the isogenic cells with wt alleles (Fig. 2A). …

    In aggregate, our results suggest that low glucose environments are a driving force underlying the development of KRAS and BRAF mutations during tumorigenesis. …

    The glycolysis inhibitor 3-BrPA is selectively toxic to cells with mutant KRAS or BRAF alleles.”
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2820374/pdf/nihms174392.pdf

    “Baseline ctDNA KRAS detection rate was 93.7% (86.4% in patients with non-elevated CA19-9).”
    https://www.ncbi.nlm.nih.gov/pubmed/29228650

    1. KRAS and BRAF must regulate something else, since a slow growing Ovarian Cancer called Low Grade Serous Micropapillary Adenocarcinoma has very often this both mutations. This type is very fatty acid driven and the uptake of Glucose during PET-Scan is also low. It also doesn´t respond to metabolic therapies as ketogenic diet…

  14. D, remember a while back we talked about iontophoresis as a treatment delivery tool?
    https://www.cancertreatmentsresearch.com/high-dose-vitamin-c-cancer/ {Search phrase “iontopatch”}

    Below thread is talking about this possibly going into trials for pancreatic cancer (use search term “iontophoretic”)
    {Next post after this then goes on to talk of a new pancreatic chemo regimen called PAXG.}
    https://www.cancercompass.com/message-board/message/all,63127,92.htm

    Ionotophroesis for pancreatic cancer? Interesting! Iontophoresis devices are already FDA approved in other indications. Would it really be possible to direct treatment to the pancreas with such precision? Think of how much concentration of chemo or metabolics could be achieved!

  15. Propranolol?
    https://www.cancertreatmentsresearch.com/a-list-of-mitochondria-inhibitors/ {Search Term “propranolol”}

    Propranolol doubled survival in mice with pancreatic cancer.
    Propranolol is an OXHPOS inhibitor, so this could be combined into the metabolic treatment.
    https://cancercompass.com/message-board/message/all,63127,85.htm {First Post on page 85}

    Hmm, iontophoretic propranolol?

    https://www.pancreatic.altervista.org/#Emerging

  16. Metronomic chemotherapy in pancreatic cancer appears to have a considerable amount of promise.
    Up till this point metronomic dosing has been understood largely in relation to chemo and in particular its effect on tumor vasculature. A “chemoswitch” strategy is suggested whereby metronomic chemo is followed by normal dosed chemo. Metronoimic dosing would increase the tumor perfusion and this would then be followed by chemo that was better absorbed by the tumor. https://www.ncbi.nlm.nih.gov/pubmed/?term=pancreatic+cancer+metronomic

    A range of interesting findings have emerged. For example, chemo resistance can be overcome, hypoxia reduced, higher access to chemo drugs, various combinations have been studied.

    “Recently, we reported that oseltamivir phosphate (OP) is an effective anticancer agent capable of sensitizing GEM-resistant pan-creatic cancer cells to GEM, …”
    https://www.ncbi.nlm.nih.gov/pubmed/?term=26309402

    “The aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy.”
    https://www.ncbi.nlm.nih.gov/pubmed/?term=26961182

    Retrospective study
    ” … A reduction in CA19-9 tumor marker levels by 90% or greater on theraphy was associated with significantly longer median survival: 28 months versus 15 months.”
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6096752/

    Metronomic gemcitabine in pancreatic cancer
    “Tumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors’ avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor’s vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia.”
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819514/

    Large effect of triple combination
    http://clincancerres.aacrjournals.org/content/14/1/270.long

    Review Article
    https://www.ncbi.nlm.nih.gov/pubmed/?term=28232048

  17. This article provides amazing insight into metronomic GEM!
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819514/pdf/10456_2016_Article_9503.pdf

    Perhaps all of those on the forum should think carefully about how this could be of help to them. This clearly is most particularly for pancreatic cancer, though the same idea broadly applies to other cancers. Metronomic chemo changes the tumor vasculature which has significant implications for tumor metabolism. This is another major key idea that will need to be added to the next generation of the metronomic metabolic protocols.

    Figure 3 is quite counterintuitive. What happens is that MET GEM results in much better profusion of the tumor, while slowing
    its growth. The authors appeared to be completely baffled by this! Though on this forum, it is exactly what we would expect.
    What happened was that the tumor became more oxidative! Oxidative tumors are more normalized.

    “Interestingly, FDG uptake in tumors treated with Met-Gem was lower as soon as day 3, whereas tumor volume data gave no indication of any response to metronomic treatment at this early time point ”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819514/pdf/10456_2016_Article_9503.pdf

    There are profound insights for us to integrate from this study from the metabolic perspective. If MEt GEM gives us a lever to manipulate profusion of the tumor, then there is a wide range of powerful metabolic hits that could be tried against the tumor.
    For example, the tumor rapidly switches over to OXPHOS (by day 3) from glycolysis as the tumor becomes more perfused. One certainly wonders what might happen if one were to first dose up on OXPHOS inhibitors and then try met GEM. What would happen to the tumor then? The tumor seems to need to rapidly stop glycolysis when perfusion starts: might this be because of the acidity and the ROS that are present with perfusion restarted? Once perfusion is restarted then the switchover strategy to go back to full strength GEM could result in another knockdown. Of course, now that oxygen is back in the tumor environment, ROS strategies such as vitamin C etc should be all the more effective. One could imagine cycling through this several times: hypoxic — high glycolysis —> normoxic –OXPHOS –ROS —hypoxic — etc. This would create enormous stress on the cancer cells. It would also at the same time nearly completely eliminate the cancer’s ecosystem. With such ongoing chaos in the cancer’s symbiotic life support system, at certain point one might expect that this support system would simply collapse. Without the acidity the immune system could again recognize its target. Proton Pump inhibitors?

  18. You might not be following the citrate thread, though an interesting insight has been gained over there.

    There appears to be another metronomic metabolic treatment pathway that should be considered: Citrate!
    High doses of citrate inhibits PFK! This is to say citrate shuts down glycolysis! Cancer is typically glycolytically overactive.
    There is a range of patient reports (though mostly from only one source) that has found success with citrate dosing.
    However, this should not be too exotic to us as there was a very impressive article combining citrate with 3-BP
    https://www.ncbi.nlm.nih.gov/pubmed/?term=22318356

    Here’s a medical formulation.
    https://www.drugs.com/dosage/oracit.html

    Further, research noted on the citrate thread found that gluconate decreases citrate uptake through pmCIC irreversibly in cancer cells (including pancreatic cancer cells). Zinc gluconate appears to be freely available online.

    Adding this into the plan, even a first generation treatment of citrate and/or gluconate metronomically seems reasonable.
    More involved versions of the idea including hydroxycitrate, alpha lipoic acid, DCA etc. could follow in time.

    Might also be worthwhile to think in terms of amino acids in the diet.
    Amino acids can be used as a fuel source by cancer.
    Limiting some of the nonessential amino acids also seems reasonable: another metronomic metabolic treatment.
    Some amino acids are glucogenic, some are ketogenic and some are both.
    Research found that even giving a supplemental of essential amino acids sent the signal for cancer cells to shut down.

  19. Jess, I am sorry for the setback.

    Here are a few ideas that I hope will help.

    – More frequent- labs.
    Having more frequent labs could be very useful, if possible. Measurement gives you insight into what is and is not effective. Metabolic treatments can often work quite quickly. For example, patients have felt better after only a few hours of 3-BP treatment. Research that I have read noted that some OXPHOS inhibitors such as fenofibrate can take effect within minutes. With closer monitoring perhaps it could even be possible to adaptively adjust treatments. I am glad to see that in your latest labs that you have the LDH measure. This is a great one to have as it might give some indication of the activity of glycolysis.

    Perhaps even home real time monitoring would be worthwhile. For example, there is now continuous glucose monitors available.

    – Metronomic GEM?
    Countering cancer rebound with an anti-angiogenic strategy could be considered. The article below notes that low dose metronomic GEM was able to overcome GEM resistance. It is very impressive how the tumor was reperfused with this approach.
    This reperfusion pushed the cancer to a more oxidative and less aggressive phenotype.
    https://www.ncbi.nlm.nih.gov/pubmed/?term=26961182

    Best Wishes, Jcancom

  20. D, could you help me out?
    I recently read an article about exercise and cancer, though I am unable to locate it at the present time.
    The idea that I am trying to bring to mind from this article was something like this:
    If the extracellular (or intracellular not sure which) pH is adjusted (e.g. extracellular pH is lowered more acidic),
    then this would dramatically shift the acidity of the cancer cell. The diffusion of lactate from outside that would have occurred
    would now not occur and the cancer cell would then retain acidity (retain lactate). If you might be able to clarify this for me it would be appreciated. I realize that you wrote a paper about this and have a science background, so this might be a very basic level question, yet I am very interested in the potential of this. If one could manipulate pH levels through exercise or by my above idea about the Cori-Warburg cycle, then this approach might be very relevant for cancer.

      1. finnan, thank you so much!!!
        I couldn’t sleep for a night or two because of this.

        {How did you find it?
        My computer is so filled with pubmed articles that it isn’t possible to find anything.
        Any suggestions about how to organize all this information would be appreciated.
        It would help so much if there were information organizing software built directly into the Operating System (e.g. a program that kept a log of all websites visited by date and downloads by date would help quite a bit, as would having the ability to add tags to files).}

        This was the quote that I was trying to recall.
        It is quite startling and perhaps very important as a possible cancer strategy.

        “If the acid concentration in the blood is increased, vascular outflow of acid from the tumour dramatically decreases and the intra-tumoural pH declines precipitously. As a result, local acid concentrations exceed the tolerance of even the tumour cells, triggering extensive tumour necrosis. …”

        The basic idea above clearly makes a great deal of sense: Increase the acidity outside of the cell and this forces the cell to retain its own acid. Considering the fact that a nearly universal feature of cancer cells is that they are producing lactic acid/lactate, then this could certainly have profound anti-cancer effects. One might then suggest that this idea should not work because the body has pH homeostasis. Acidifying the blood has been said to be impossible. A rebuttal would be that it is more that the intra-tumoral environment due to the tumor’s output of lactic acid/lactate is acidic. Adding in sodium lactate could then intensify this acidity.

        I was specifically interested in “the intra-tumoural pH declines precipitously”. What equation would govern this biological relationship? Let’s say we increased the blood acidity from 7 to 6.8, then what would happen to the intra-tumoural pH? What would the curve look like? pH is a log scale, so even a decrease from 7 to 6.8 is substantial.

        The quote goes on to note that this could have clinical relevance. Tumors disappeared in half versus a quarter of the rats injected with sodium lactate.

        “The solution was injected subcutaneously for three weeks into 34 rats with transplanted sarcoma 39, each animal receiving one dose daily. At the end of the experiment, the tumours had disappeared in 16 cases (47%), compared with 23% in the control group. The authors concluded that an increase in the level of lactate in the organism produced by the injection of sodium lactate inhibited the growth of transplanted rat sarcoma and was able to produce a complete disappearance in a certain number of cases [74].”

        D quoted the journal article from the 19th Century in which acids were found to have large clinical effects in humans on the citric acid thread. As we saw on that thread citric acid also apparently has strong potential as an anti-cancer treatment. I was quite surprised to see in the article comparing 3-BP and citric acid that citric acid in cell culture actually seemed to have even more anti-caner effect than 3-BP.

        This would need to be done carefully.
        Ill considered manipulation of pH could push the body beyond its ability to cope with acidity.

        This could be a useful strategy that we should discuss further.

        1. Hi J, this can indeed be a useful strategy but I think that would be the case only when done locally as the pH around the tumours is already very low in many cases, compared to what we could influence via the blood route. As a local treatment it is indeed a good idea. Systemically, I think we better work with proton pump inhibitors and cell acidifiers to achieve the same goal.

  21. Jess, I greatly hope that you are following the online forum discussion about lowering glucose levels.
    Producing ketones without glucose lowering might have limited anti-cancer effect.
    With lower glucose levels you have a window on lowering lactate levels and manipulating other metabolic network states which could be crucially important.

    To demonstrate this idea more vividly, when I was online I found a site that treats pets with a metabolic protocol. 6 million dogs develop cancer every year in America! Shockingly 20-30% of American pets are now obese. Even more shockingly apparently 80% of some dog foods are carbs. When a metabolic treatment protocol was developed and applied to these animals with cancer, they found that it achieved considerable success. I have not seen good clinical trial type information, though they claim that 55% of the dogs that graduate from their program have good outcomes, though not necessarily cures. The site quotes research from all the well-known human metabolic researchers.

    The site makes the claim that ketosis does not occur unless ketones are 0.5 mM and glucose less are 75 mg/dL.
    After a great deal of experience treating dogs with cancer, they have found that:

    “What are the numbers we want to hit for blood glucose and blood ketones?
    Blood Glucose: 75 mg/dL or lower
    Blood Ketones: 0.3mmol or higher”

    The low blood ketones seem to result from a species difference in this biological pathway.
    It would be best to check whether the 75 mg/dL is in fact applicable to humans.

    Applying this evidence based approach to your treatment could offer benefits. Pets now likely receive higher quality of treatment based upon metabolic therapies that are based upon science based objectivity than do people. In fact, given the overwhelming control that people can exert over animals (in terms of food provided, exercise required, outside play behavior etc.) the scientific validity of these animal studies might never have the same scientific rigor if they were conducted on humans. If I barked and ran around on all 4s would they take in human patients? I certainly wonder whether they have given 3-BP a try.

    The protocol they used was:

    https://www.ketopetsanctuary.com/#features

    “Ketogenic Diet

    A high fat, adequate protein, low carbohydrate diet designed to lower blood glucose and induce ketosis.
    FDG-PET/CT Scanning

    Diagnostic imagery using fluorodeoxyglucose positron emission tomography (typically used only in humans) at day 0, 60, and 120 days into the program.
    World-Class Care

    The highest standard of veterinary and oncology care was provided to each shelter or rescue dog.

    Metabolic Conditioning (METCON)

    Each dog went through an exercise program optimized to their physical limitations, metabolic needs, and overall health
    Hyperbaric Oxygen Therapy (HBOT)

    Dogs were treated with HBOT therapy, which has been shown to successfully reduce the size of tumors.
    Blood Monitoring

    Blood glucose and blood ketones were measured six days a week to ensure the dogs were in a state of ketosis.”

    The Turkish clinic reported that even patients with advanced stage IV cancer often did not rigidly adhere to the diet and other programs that they were prescribed.

  22. Jess, GVAX is worth a look. Perhaps you could obtain this through right to try.
    It is now in phase 2 trials and it has a successful phase 2 clinical trial in pancreatic cancer.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397277/

    There are a few things to note here.
    The comparison they are using is between 2 groups both receiving the active treatment, it only that one
    treatment arm received more. Also, the patients that were included were fairly advanced so the survival
    statistics that they provided seem quite favorable. Adding a metabolic intervention could further enhance
    the results.

    Best Wishes, Jcancom

  23. Jess, I think there is something that you should look into.
    The below article has a very interesting figure showing fasting glucose levels before a diagnosis of pancreatic cancer was made.
    What is truly quite remarkable about this figure is that it seems to be suggesting that pancreatic cancers somehow make glucose.
    I am not sure, though this could be a unique feature of pancreatic cancers.

    If this were in fact true, there are numerous implications for pancreatic cancer treatment.
    For instance, pancreatic tumors must surrounding themselves with simply overwhelming amounts of glucose.
    In actuality the pancreatic tumors apparently are able to make the entire body diabetic simply through their production
    of glucose. This suggests to me that even a normal glucose level of 95 would still mean that when this tumor were active
    there would be a large local concentration of glucose. Determining the metabolic origin of his glucose would be of interest as it might be metabolically costly for these cells to make it. It also suggests that going more fully ketogenic might (though not necessarily be of significant value).

    https://www.ncbi.nlm.nih.gov/pubmed/?term=29723506

  24. D, I am becoming very excited about mito-HK. I posted about this one a few months ago after an article was published mid-last year. Related to this article https://www.ncbi.nlm.nih.gov/pubmed/30428319

    We have seen that with mito drugs, i.e. drugs that directly dragged into the mitochondria there can be very potent anti-cancer effects. For example, with mito-3BP there was a ten fold increase in potency, and this was independent of MCT-1 status. So, basically any cancer cells would be targets. But the big problem of course is that we have not seen much in vivo for it. Is it safe? Is it selective? These questions still after all of these years remain unanswered.

    What is different with mito-HK is that HK is a natural chemical that is itself reasonably safe. In the report above they went from dosing mice at 10 mg/kg with straight HK to 1 mg/kg with mito-HK. When you use the reduction factor of 12 to move to human dosing after applying the mg/kg conversion you are moving into a treatment range that is already used for other mito drugs such as mito-Q. So, in terms of the potential toxicity of the mito part of the chemical you are in range. While it is not directly comparable because the HK is targeted directly to the mitochondria with mito-HK, though the HK had been dosed in the mice ten fold higher at 10 mg/kg. The above research also found that 20 fold higher doses of mito-HK above the therapeutic dose used were needed for toxicity to be seen. mito-HK at least in these mice seems quite well tolerated.

    What actually caught my eye yesterday was what I saw online about an additional filing of this research that I noted in my previous post above. The researchers added in other glycolytics such as 2-DG and 3-BP and the results that they reported were even stronger. This of course should be expected, though when I saw it reported I certainly found it compelling. Such an approach could be quite powerful. Imagine combining two well formulated synergistic anti-glycolytics such as mito-HK and perhaps nanoMG or beta-cyclin 3-BP! These would be very very powerful treatments with probably minimal side effects.

    I think that this is extremely important to point this out to those on forum. We have been waiting years and years to see these well-formulated chemicals to move through pre-clinical research. This research is opening up a therapeutic opportunity for metabolic medicine. I think the synthesis method presented should be studied carefully. It would probably be a good idea also to contact those associated with this research as well. Having this on the shelf would make an enormous amount of sense for a time when nothing else were available.

  25. Thank you, johan! Your comments on the forum have been quite measured, so it is encouraging that you also see the potential.

    Combining specifically targeted anti-metabolic formulations with synergistic effect should have profound anti-cancer effects. Imagine what might happen if 2 or 3 treatments with the power of 3-BP were added together! I think this is the most effective anti-cancer approach that I have encountered to date!

    Minicells are clearly a very potent therapy, though with a monotherapy there will always be resistance that occurs sooner or later.
    With the depth of anti-glycolytics and anti-OXPHOS approaches that we have identified with powerful tumor specific formulations, one starts to wonder how resistance could emerge.

    As reference, I will start up a list which I can add to later that I am particularly excited about.
    There are numerous chitosan formulations that likely could be added for chemicals such as shikonin, DCA,
    paracetamol etc., though I will wait until I can source the exact pubmed identifiers. This list
    could offer truly profound anti-cancer effects, while avoiding side-effects due to the highly targeted
    nature of the formulations used.

    – mito-HK
    – multi-vesicular tocotrienol
    – various formulations of 3-BP (in particular beta-cyclodextrin, though not mito-3-BP)
    – minicells
    – NanoMG

  26. Jcancom these discoveries are very large but if we can translate to a practical application we will not see real reflection.Can you give me any of the patents of new formulations of 3BP for the consideration and see if they can be manufactured in a simple and publish it here

  27. marcos, I am looking at supplementary document S1 from the below url. From page 13 onward, a description is given on how to synthesize mito-HK. It seems doable. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137433/

    I have been waiting for years for a safeish mito drug to be announced. We have seen the reports for mito-3-BP and mito-DCA, though after all of these years we have never actually seen the in vivo reports for them. Even if we did, there would be a concern that side-effects would be a problem in humans.

    Finally we have in vivo results for a mito drug (mito-HK) and it looks very promising. mito-HK appears reasonably safe. The article mentions that at least in mice there was a 20 fold safety buffer with the dosing that they used. HK was dosed 10 fold higher than mito-HK in the article and side effects were not present. mito-HK is creating a level of confidence that few other anti-cancer mitocans have yet to inspire.

    I read about this a few months ago and I posted about it at that time. However, just recently I was web surfing and I found a report from these researchers that talked of how combining with 2-DG and 3-BP further amplified benefit. This is not surprising, though it certainly caught my notice.

    As I posted above combining OXPHOS and glycolytic inhibitors that are well-formulated could have very large anti-cancer effects. If the synthesis could be done, then it would be very reassuring to have waiting on the shelf.

    For example, we might then look to combine with:
    3-BP https://www.ncbi.nlm.nih.gov/pubmed/25326230

    tocotrienol https://www.ncbi.nlm.nih.gov/pubmed/30534071
    (best not to combine with 3-BP as tocotrienols appear to greatly down regulated MCT-1)

    This is very exciting!

    If we could treat with these highly formulations with simultaneous dual inhibition against OXPHOS and glycolysis, then we could large responses. Typically in the literature they will only have one highly formulated metabolic treatment and then add in other non-targeted treatments. For example, NanoMG and then add in vitamin C, creatine etc. This form of monotherapy while often impressive does not fully exhibit their potentials. Imagine what 3-BP loaded minicells with acidic targeting and mito-HK or others could achieve!

    One of the great limitations that we have been faced with is that typically the pharmacology is all wrong. You can treat with plain resveratrol or curcumin though, the results can be quite disappointing because of the low absorption that occurs. Yet, with proper formulations and wise combinations, one could start to see very strong results. Many of these syntheses have been published, so there are many to choose from.

    Best Wishes, Jcancom

    1. Jcancom I am trying to get the mitoHonokiol formulation . There is a laboratory working on it, I just hope that after studying it, they give me the ok and they tell me that it is possible
      What would be the human dose? 10 times less than the usual dose of honokiol? perhaps using the “allometric scale” and transforming the doses of rodents to humans ……
      I find the maximum dose of honokiol 14 mg / kg in rats …..
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663139/

      Best whises Manu

      1. Manuone, we have being trying for years and years to organize a synth of one of these glycolytic formulations. This is a big step forward!

        There are many many of these formulations that we have talked about, though mitoHonok is right up there near the top from what I can see. The tocotrienol formulations also look compelling as do several others. For instance, we have talked about mito-3BP. Yet, there was no research in vivo with it. mitos do give selectively, however it would be best to stay with a non-toxic metabolic inhibitor. The mito-honokiol article talked about an impressive level of therapeutic room in the mice model. It spoke of a 20 fold higher dose than was needed for therapeutic efficacy to induce safety issues in the mice. mito-Honok is a very good one to have available at the very least on the shelf if necessary. The problem as you noted is that the dosing would only be approximated from the mice. However, the recent research that I noted found that adding in other anti-glycolytics (e.g. 2-DG) increased the power of mito-Honok. It is also somewhat unclear to me about the brain penetrating properties of mitos.

        It might be highly worthwhile to contact the researchers who published the article. It is a strong product that they might be preparing for clinical trials. Perhaps they might give you an indication of what dosing they consider appropriate.

        Once again Manuone, thank you for taking this initiative. We have seen so many of these different formulations over the last many years. Clearly properly formulated drugs can dramatically improve efficacy. Combining 2 or more of these formulations likely would have very potent anti-cancer effects.

        Best Wishes, Jcancom

  28. Thanks, Jcancom!

    Hopefully more formulations will become available sooner rather than later. There’s so much potential, but as usual money often doesn’t flow in the direction we’d like to.

    For example, researchers at the University of Chile have created a nanoemulsion with curcumin, shown to be 100% effective in stopping cancer progression and metastasis in an animal model.
    http://www.uchile.cl/noticias/150076/presentaron-avance-cientifico-que-previene-la-reaparicion-del-cancer

    They are now looking for funding to get their product(s) on the market.

    Still, even plain compounds at regular doses can be beneficial. Pomi.T is an example of such a supplement, that if combined with compounds that work in synergy, can have a meaningfull effect.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020278/

    People taking curcumin should look for the best formulations currently available (lyposomal, C3 etc) and use in combination with other compounds that can enhance or enable a biological effect:Berberine, Epigallocatechin gallate, Ursolic acid, Triphala etc.

    Regards

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