This study suggests that using autophagy inhibitor drugs may be a way to inhibit metastasis. Here, I already discussed some autophagy inhibitor drugs.

This is an aspect that I discussed multiple times on this website, i.e. one of the important aspects to be addressed in order to increase the chance for effectiveness of immunotheraphies is the acidity around the tumors, which is there for most advanced cancer patients. Here is a post I wrote on how to address this aspect https://www.cancertreatmentsresearch.com/ph-cancer-a-top-treatment-strategy/

A few days ago, a new paper from one of my favorite organisations (AntiCancerFunds) published a review paper on the anti cancer potential of drugs used typically for treatment of erectile dysfunction and pulmonary arterial hypertension. Example of drugs discussed in this paper are sildenafil, tadalafil, vardenafil, avanafil and udenafil. Thir anti cancer mechanisms seems to be related to one or more of the following: immune modulation (MDSC- and Treg- reduction),  multi drug resistance reduction, Tumour hypoxia reduction, aromatase inhibition. Most of these actions seem to be related to the PDE5 inhibition capabilities of these drugs. As a result these drugs have been shown to be effective against multiple types of cancers in the lab such as Chronic lymphocytic leukaemia, Prostate, Colorectal, Brain, Breast, Melanoma, Multiple myeloma, Lung, Lymphoma, Liver, Head and neck, Rhabdomyosarcoma, Ehrlich ascites carcinoma. However these results were achieved in a pre-clinical setting. In humans, these drugs have been already shown to add value for patients with macroglobulinemia, penile squamous cell carcinoma, MM. Based on the evidence, the authors at AntiCancerFunds concluded the following:

“The data are strongest for clinical trials of PDE5 inhibitors, in combination with other agents, in the following cancer types (a) HNSCC (b) Glioblastoma (c) Pancreatic cancer (d) Medulloblastoma (e) Waldenstrom’s macroglobulinemia (f) Melanoma. The perioperative use of PDE5 inhibitors in combination with other perioperative therapies is also of interest in the following cancers: (a) Colorectal cancer (b) Breast cancer (c) HNSCC”

A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. In this context, scientist have recently found Mebendazole (a safe, cheap and over the counter drug previously discussed on this website here) as a potentially effective treatment for acute myeloid leukemia (AML)

  • August 2017: approval of a patent on piperazine  to treat cancer leads to share price jump of a small biotech company (an anthelminthic especially useful in the treatment of partial intestinal obstruction caused by Ascaris worms)

“Rexahn Pharmaceuticals (RNN +27.3%) is up on almost double normal volume, albeit on turnover of only 577K shares, in apparent response to the issuance of a new patent (U.S. Patent No. 9,744,167) from the USPTO covering storage-stable nanoparticulate compositions and formulations of piperazine compounds used to treat and prevent proliferative diseases, including cancer.” (Ref.)

“Researchers have known that avoiding cross-resistance is key; this investigation tells us we also need to start considering drug holidays as well,” said Dr. Scott.

Fasting-like diet with chemotherapy strips away the guard that protects breast cancer and skin cancer cells from the immune system, according to a new USC-led study on mice. “T regulatory” cells which protect the cancer cells were expelled.

Inserted through the skin and into a vein, long-term intravascular devices such as IV catheters deliver to patients a range of life-saving medications, nutrition and fluids, among other uses. But these life-saving devices also can provide a furtive pipeline for germs from the external world to gain access to the bloodstream of patients who often already are sick, resulting in a serious infection or even death. Maki’s new approach for patients with intravascular catheters is a daily “rinse cycle” with a 25- to 50-percent solution of ethyl alcohol, or medical-grade ethanol. “We fill each lumen of the catheter with the ethanol solution and then cap it off,” says Maki. “It is allowed to sit there for an hour, rapidly killing any germs that have insidiously gained access. We then simply pull it back out and reattach the IV fluids, intraveneous nutrition or intravenous medications, and the risk of later bloodstream infection caused by germs that may have gained access in the preceding 24 hours has been essentially eliminated.”

The conclusion of this study: “We propose that ABZ induces oxidative stress promoting DNA fragmentation and triggering apoptosis and inducing cell death, making this drug a promising leader molecule for development of new antitumor drugs.”
I indeed know the potential of ABZ and like it for long time, and intend to once write a post on it. It is an over the counter and FDA approved drug – an anti worm medicine, easily accessible (e.g. eBay) and cheap.

According to this case report there is a risk when combining DCA with Artemisinin in intravenous forms.

PIK3CA mutations reprogram glutamine metabolism in colorectal cancer, Nature Communications(2016)  “In layman’s terms, we discovered that colon cancers with PIK3CA oncogenic mutations are addicted to glutamine, a particular nutrient for cancer cells. We also demonstrated that these cancers can be starved to death by depriving glutamine with drugs.”

This is a nice article published by The New York Times Magazine discussing Warburg’s discovery that was left out of textbooks altogether, and in this context cancer as a metabolic disease.

Patients receiving cancer treatment could increase their chance of survival by up to 20 percent and help stop their cancer from spreading by taking a low dose of aspirin, new research suggests.

This is compared to 80 to 90 percent achieved with previous techniques. In addition, “the current form of radiation is 44 treatments given over nine weeks. In contrast, the SBRT therapy we used allows the delivery of highly focused radiation in only five treatments, allowing patients to return to their normal lives more quickly”

Common cholesterol-lowering drugs could provide relief to patients suffering from a chronic lung disease, a study has shown. The drugs — known as statins — were found to help alleviate the chronic coughing associated with the disease for some patients. Statins are commonly prescribed for people at risk of heart attack because they can reduce cholesterol levels, but scientists are increasingly finding that they also have anti-inflammatory effects.

“The rate-limiting step in eradicating cancer today is not the science but the regulatory environment we work in,”

Researchers said those taking part in the trial were left astounded at the “mind-blowing” effect of combining two drugs – Herceptin, the current standard treatment for such cases, with a second drug called Tyverb.

Metastasis of breast cancer, especially to the brain, is the major cause of mortality. The inability of anticancer agents to cross the blood-brain-barrier represents a critical challenge for successful treatment. We demonstrate that penfluridol administration to an orthotopic model of breast cancer suppressed tumor growth by 49%. On the other hand, penfluridol treatment inhibited the growth of metastatic brain tumors introduced by intracardiac or intracranial injection of breast cancer cells by 90% and 72%, respectively. Penfluridol-treated tumors from all three models exhibited reduced integrin β4 and increased apoptosis. Moreover, chronic administration of penfluridol failed to elicit significant toxic or behavioral side effects in mice. Taken together, our results indicate that penfluridol effectively reduces the growth of primary TNBC tumors and especially metastatic growth in the brain by inhibiting integrin signaling, and prompt further preclinical investigation into repurposing penfluridol for the treatment of metastatic TNBC.

Controlling cancer rather than killing it could be the best way to fight the disease, according to scientists. I do like this concept indeed. I read a few years ago about it in an a scientific paper and I found the idea very good. The idea would be to use low dose effective treatments so that you do not kill all the cells sensitive to that treatment but enough to maintain a certain size. In this way the treatment responding cells will remain majority and will not give to the resistant cells the chance to take over and proliferate. Nice approach, at least in theory.

What causes cancer to grow and metastasize is not well understood by scientists. Now researchers have found a surprising link between the death of tumor-support cells and an increased risk of cancer metastasis in mice.

This study argues that killing cancer-associated fibroblasts (CAFs) may lead to metastasis. This is totally against the common believe that when trying to kill cancer we need to focus on killing the surrounding fibroblasts that support the growth of cancer. As a result, they suggest “time-controlled knockouts”.  To me, this makes sense but also makes things more complicated. In this case, I would make sure that when using a treatment option, I would use one that targets fibroblast and the tumor at the same time, such as 3BP or other metabolic treatments. At least don’t target the fibloblast unless using at the same time an effective therapy against the tumor.

Tumors kill off surrounding cells to make room to grow, according to new research. Although the study was carried out using fruit flies, its findings suggest that drugs to prevent, rather than encourage, cell death might be effective at fighting cancer — contrary to how many of the current chemotherapy drugs work.

This is an interesting concept and reminds me of a discussion around telomerase activators which can be seen as anti aging substances. Some suggested that telomerase activators should be avoided by cancer patients as they would increase the life not only of good cells but also of bad cells. However, if is to agree with the above concept, that we may actually see the telomerase activators not only as anti aging but also anti cancer elements. One of such element with (debated – Ref) telomerase activation capability is the well known Procaine which is also used as a treatment in German clinics and  first time discovered an applied as anti aging element in Romania by dr. Aslan. In the 1950s Dr. Ana Aslan of Bucharest, Romania performed experiments on lab animals injecting 2% Procaine and found that rats and rabbits live around 30% longer if given procaine injections. She wrote a book titled GH3 and became famous treating famous people. (Ref) The Procain product is called Gerovital and is available in Romanian pharmacies withouth prescription, in the form of pills or i.m. injections.

Tumor-associated eosinophilia is frequently observed in cancer. However, despite numerous studies of patients with cancer and mouse models of cancer, it has remained uncertain if eosinophils contribute to tumor immunity or are mere bystander cells. Here we report that activated eosinophils were essential for tumor rejection in the presence of tumor-specific CD8+ T cells. Tumor-homing eosinophils secreted chemoattractants that guided T cells into the tumor, which resulted in tumor eradication and survival. Activated eosinophils initiated substantial changes in the tumor microenvironment, including macrophage polarization and normalization of the tumor vasculature, which are known to promote tumor rejection. Thus, our study presents a new concept for eosinophils in cancer that may lead to novel therapeutic strategies.

Tamoxifen-treated neutrophils produced approximately three-fold more neutrophil extracellular traps (NETs), a mesh of DNA, antimicrobial peptides, enzymes and other proteins that neutrophils spew out to ensnare and kill pathogens.

Capsaicin binds to a cell’s surface and affects the membrane, which surrounds and protects the cell. At high doses causes the membranes to come apart.

The researchers identified a particular signaling pathway as the cause of this effect on the cells. “The PI3K/mTOR pathway is activated by the BMP7 protein and conveys signals for the cells to divide as well as to migrate,” explains team leader Pellegata. In order to verify this mechanism and to test potential future treatments, the team used two molecules. One molecule inhibits the signal transmission of BMP7; the other blocks the PI3K/mTOR downstream signaling pathway.

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

Increasing Oxygen at the tumor site will increase the tumor susceptibility to natural killer (NK) cell€“mediated killing. Therefore, all the strategies focused on increseasing Oxygen in the body, such as Hydrogen Peroxide, Ozone therapy, etc. will increase the effectiveness of natural killer (NK) cell.

Clomipramine is an FDA-approved antidepressant drug.

A receptor on the surface of immune cells–the A2A adenosine receptor–is responsible for preventing T cells from invading tumors and for “putting to sleep” those killer cells that do manage to enter into the tumors. Now scientists shown that inhaling 40 to 60 percent oxygen (air offers 21 percent oxygen) weakened tumor-protecting signaling through the A2A adenosine receptor and awakened T cells that had gained the ability to invade lung tumors. And this can be further improved by the natural antagonist of the A2A adenosine receptor, which happens to be the caffeine in your coffee.

Scientists from the University of Sheffield found that when a therapy is effective in killing cancer, human body can trigger a process where white blood cells start clustering around blood vessels. These cells — called M2 macrophages — repair tissue damage and build new blood vessels, a process that sometimes helps the tumour to grow again after treatment. Using a drug available at pharmacies called Plerixafor (other names: Mozobil, AMD 3100, JM 3100, SDZ SID 791) can inhibit the repair tissue damage and build new blood vessels.

In my opinion, this is a great tool to add next to any effective anti-cancer treatment such as Salinomycin. The only challenge here seems to be the price which is about 7000 euro for a 24mg injection of Plerixafor. On the other hand, the same quantity of Plerixafor from pharma chem suppliers such as Sigma Aldrich costs a few hundred euros and it can be easily prepared as injection since it is water soluble.

Published paper: Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy

161 thoughts on “News

  1. Hi D, what do you think of Oridonin? Perhaps combining it with autophagy inhibitors would be a good strategy to go with?
    sorry about the random post, thought this part of your website is the closest to a forum.

    1. Hi A,

      That is indeed true. We addressed this point often. Lactate represents a source of fuel for tumors in two majors ways:

      1. an indirect way, via gluconeogenesis where lactate is converted in glucose by the liver. This process can be inhibited with Hydrazine.

      2. a direct way, where lactate is absorbed by cancer cells via MCT1s transporters and converted in energy via respiration – therefore, for this process to work cancer cells need access to oxygen. These are also the cancer cells that will be most responsive to 3BP treatment.

      Kind regards,
      Daniel

  2. D, wanted to follow up on your March 11, 2016 news article.

    As hard as it is to believe, commentators have suggested that these responses resulted in no long term benefit to the patient.
    This does not seem reasonable to me, though read below url.

    “The statement was that the data don’t show that adding Tykerb does anything for patients, but rather show that continuing tamoxifen is useful. … responded that this is an accurate statement.”

    https://bcaction.org/herceptin-tykerb-meeting-with-genentech-and-heard-in-the-halls/

  3. D, that August 2016 article with the charged nanoparticles is so brilliant!
    I have been waiting for the next step in the research to go in vivo.

    The logic here is so strong!

    The export of lactate
    –> removes positive surface charges on cancer cells
    –> more negatively charged surface in cancer cells
    –> opportunity for positively charged nanoparticles

    Normal cells do not have negative charges on their surfaces.

    The nanoparticles are targeted to the cancer cells and then there is one could think of anti-cancer treatments.
    Perhaps something could be attached on the outside of the NPs.

    The instructions to make these NPs looks very very simple.

    1. Could anyone help out on how this could be converted to a more general treatment?

      The news report for the positive nanoparticles used a laser for a photothermal effect.
      What would obviously be of more relevance would be a charged nanoparticle that could
      be activated by electromagnetic or X-Ray treatment or would have some inherent
      treatment effect without other interventions.

      Is anyone aware of these depth penetrating electromagnetic or X-Ray approaches and how it might apply
      with this treatment?

  4. Just had a weird idea; What would happen if instead of producing lactic acid cancer cells produced ethanol?
    As we saw above ethanol is an anti-cancer therapy.

    What cancer cells could be made to produce their own chemotherapy?

      1. Helga,
        yes it appears that beer is the cure for cancer.
        I have no idea how this works.

        It is very difficult to believe, though it seems to have been used as a remedy in developing nations for quite some time.
        The application is limited, though, to more an intratumoral treatment.
        The new research found a way to keep the alcohol as a gel and this helped it to be even more effective.

        https://www.cancertreatmentsresearch.com/community/repurposed-drugs-and-new-substances/beer-cures-cancer/#post-213

  5. D, it is absolutely amazing!
    There is this wave of powerful anti-cancer treatments approaching from all sides!
    It feels very close now.

    Look at this one.
    They give all the chemistry of how to make it.
    The only cells that use this enzyme are sperm cells and cancer cells.

    They shut down this pathway in mitochondria and then glycolysis is pushed up.
    Amazing! Metabolism is right at the center of cancer,
    https://www.sciencedaily.com/releases/2017/10/171017124347.htm

      1. Thank you for your reply W!

        I am just so excited about what is happening right now.
        As you might know I have been very interested in 3-BP for quite some time.
        Yet, I am now starting to shift to these newer metabolic approaches.

        It really is amazing!
        For example, mitochondrial transfer PMID: 28342934
        or tocotrienol vesicles PMID: 28972460
        also mentioned the HK2 targetted peptide.

        This one is also big. If you can start introducing new miRNA or siRNA, how will cancer evade this?
        When Engenic knocked down with siRNA and then treated with minicells in mice the anti-cancer effect
        was essentially curative.
        https://www.prnewswire.com/news-releases/engeneic-announces-publication-in-the-lancet-oncology-of-first-clinical-study-employing-edv-nanocell-platform-to-enable-microrna-replacement-therapy-300513513.html

        It is simply endless!
        We are moving to a time when there will be a very large range of choices of non-toxic anti-cancer treatments.
        I sincerely wish that those people who need treatment options will be able to benefit from this research.

        I will love to hear what D might say about how these approaches could all be put together for a truly massive anti-cancer effect.
        For example, the E260 I noted above amps up glycolysis and depletes ATP. Perhaps an anti-glycolytic? Would also like to see what would happen if you then blocked up MCT-1.

        1. hey Alex,

          i was following you and all the folks here but indeed haven’t written for a while.

          You made my day by writing things improved a little bit for your dear mother. Is she receiving chemo now?

          as to my situation: my last checkup was ALL clear (i am 11 months after the end of chemo). I take only basic supplements now. Seemingly I am likely to have a mild paraneoplastic process or CFS /ME which is an underdiagnosed syndrome following trauma, infection, major drug intake (like chemo) or a combination of these. I had all these.

          I am glad the symptoms (back pain, mild neuro issues ) are probably not caused by cancer. the scenario i feared (lept mets) is getting very unlikely. You know whats funny? I always wrote that DCA helped me beyond any placebo effect and
          I am 100% sure it was not psychosomatic as first I did not believe in DCA. According to studies DCA is not just helpful but also against CFS / ME… Who knows by now.

          So all in all I am fine now, bro, same symptoms but no worsening and I am in good shape in terms of physical condition.
          Of course the thought of having recurrent / active cancer does not leave for a f*cking minute, especially with the complaints i have.

          thanks for asking, brother.

    1. Wow!
      That is very interesting!

      It makes me think right off the bat, what would happen if you went in first with high dose NAC
      to knock down MCT-4 and then went in and treated through MCT-1?
      These are the two main MCTs and closing them both off to cancer cells at the same time could
      be espcially damaging. There is an MCT-1 inhibitor in trials.

    1. Thanks W. This is one of my preferred drugs. It is amazing how many anti parazite drugs are having anti cancer potential (including NTZ, Ivermectin, Mebendazole, Privium pamoate, Niclosamide, etc.). Given their good safety profile, as a cancer patient, I would start using them in cycles. For example, combo of two during one month, after that switch to another combo of two, and so on, while checking markers.

  6. Scientists have long been debating how exactly mets arise as at the end of the day it is usually the mets are leading to death and not the primary tumor.

    they found it happens as follows;

    – chromosomal instability present in every cancer (cells)
    – the instability causes a leakage of DNA from the nuclei (more then 1500 genes kick in in some cancers!!). these are inflamatory genes also active in immune responses.
    – chronic inflammation kicks in because of the leakage . cGAS-STING levels increase

    – cancer cells hijack this inflammatory response. “They start acting as if they were certain kinds of immune cells, which are normally activated by infection”.

    IT shows why a strong immune system can be even beneficial to cancer cells. Crazy, huh?

    alternative hypothesis WAS:
    “Our starting hypothesis was that chromosomal instability generates a lot of genetically different tumor cells, and that a Darwinian selection process promotes the survival of the cells that are capable of spreading and forming distant tumors,” Dr. Bakhoum said.”

    https://www.sciencedaily.com/releases/2018/01/180118142642.htm

    So the lead question is : HOW can we suppress chromosomal instability? ?

    Conclusion:

    “Undoing their ability to suppress normal and lethal antiviral response to cytosolic DNA would, in principle, kill these aggressive cancer cells swiftly, with minimal effects on other cells.”

    https://www.cancertreatmentsresearch.com/

  7. Erg, they both have been through and have published phase 1 results.
    This should mean that through Right to Try that the companies could provide them to patients, at their discretion.

    It is especially amazing because they were only using MICROgram scale dosing!

    1. Everyday,everytime i am thinking about incvax.
      They heat tumor 50 degrees centigrate and at that point immunity recognises cancer.Why nobody propagate those antigens in lab?May be after biopsy,they propagate cancer cells, heat and then give it back to tumor?

      But this finding is perfect J.

      1. Erg, this TLR7/8/9 and OX40 combo seems very powerful.

        Perhaps now might be a good time for the cancer community to converge on this one treatment approach so that
        everyone can gain from the collective wisdom. Cancer treatment has always been so highly diverse as people
        see things from an almost unlimited number of points of view. Putting the focus on this one approach might
        finally allow for a positive feedback cycle to happen in cancer treatment discovery and finally make fast and
        definitive progress towards a cure.

    1. Very exciting!
      Helga, I am glad that you found this research!
      It looks too important to miss.

      Almost hard to imagine that the phase 1 with Ox40 has been sitting on the shelf for 5 years.
      This Ox40 research has been inching forward for the last 40 years.

      From all the clinical activity below I do not see a clear legally justifiable reason why a patient could
      not access this now according to Right to Try Legislation. There clearly are completed and pulbished phase 1
      results for both Ox40 and TLR9 and this research is ongoing. This satisfies the requirments of the law.

      There are a few things to note:

      TLR7/8 could be used in place of TLR9. OX40 seems to be pivotal.
      This should be safe as there is only a specific local treatment being used.
      Activating the entire immune system to fight cancer can be dangerous.
      All you really need is to activate the T cells that are already in the tumor environment.

      They were only using MICROgrams incredible!

      Here are some snippets.
      “CpG induces OX40
      This result indicates that the effect of CpG at this low dose to up-regulate OX40 expression is predominately local.

      However, the combination of CpG and anti-OX40 resulted in complete regression of both injected and noninjected tumors. Consistent with the time needed to induce an adaptive T cell response, the kinetics of regression at the two sites was different, with the distant site following the local site by several days (fig. S1C). Tumor regressions in response to the combined treatment were long-lasting and led to cure of most of the mice

      When tumors reached between 0.5 and 0.7 cm in the largest diameter (typically on days 4 to 5 after inoculation), αOX40 (4 μg) and CpG (50 μg) were injected into one tumor site every other day for a total of three doses.

      An alternative TLR agonist, resiquimod (R848), a ligand for TLR7/8, in combination with anti-OX40 induced a similar systemic antitumor immune response

      In situ vaccination with CpG and anti-OX40 was effective not only against lymphoma but also against tumors of a variety of histologic types, such as breast carcinoma (4T1), colon cancer (CT26), and melanoma (B16-F10) (fig. S8, A to C). In all these tumor models, the systemic therapeutic effects were induced by extremely low doses of both the CpG (typically 50 μg) and the anti-OX40 antibody (typically 8 μg) or even lower (fig. S9). However, the TLR agonist worked best when it was injected directly into the tumor, consistent with its action to up-regulate the OX40 target in the T cells of the tumor microenvironment. Similar systemic effects were obtained when the OX40 antibody was given systemically, rather than into the tumor, but at higher doses

      The injected and the noninjected tumors regressed, and remarkably, the treated mice were protected against the occurrence of independently arising tumors in their other mammary glands {Vaccine Strategy?}

      Mice cured by in situ vaccination of the A20 lymphoma were immune to rechallenge with the same tumor (A20) but not to a different tumor

      This in situ vaccination does not require knowledge of the tumor antigens. Potential drawbacks include reliance on adequate immune infiltrates and the availability of a suitable injectable site of tumor.

      TLR7/8 agonists could substitute for CpG, but checkpoint antibodies against PD1, PDL1, or CTLA4 could not substitute for anti-OX40.

      Autoimmune toxicities are a common complication of systemically administered immune checkpoint antibodies (20–24). In contrast, direct injection of the antibodies into the tumor at very low doses can avoid these side effects (25, 26). In our experiments, in situ injection of microgram quantities of immune stimulants and checkpoint antibodies proved to be sufficient to induce the required local immune modulation, resulting in a systemic antitumor immune response.”

      Phase 1 Ox40
      PMID: 24177180
      https://clinicaltrials.gov/ct2/show/NCT01644968?term=Ox40&rank=5

      and others
      https://clinicaltrials.gov/ct2/results?cond=&term=Ox40&cntry=&state=&city=&dist=

      CPG ODN Phase 1/2
      PMID: 28142059

      TLR9 and OX40 Trial
      https://clinicaltrials.gov/ct2/show/NCT03410901?term=Ox40&rank=11
      https://clinicaltrials.gov/ct2/show/NCT03410901?term=BMS+986178&rank=1
      Strange the trial with TLR9 and OX40 is supposed to enrol 15 patients in the next 2 years while the
      TLR9 and IPI Nivo is set for 435?
      https://clinicaltrials.gov/ct2/show/NCT02737475?term=BMS+986178&rank=2

      TLR9 Agonist SD-101
      https://clinicaltrials.gov/ct2/show/NCT02254772?term=SD-101&rank=5
      https://clinicaltrials.gov/ct2/results?cond=&term=SD-101&cntry=&state=&city=&dist=

      Anti-OX40 Antibody BMS 986178
      https://clinicaltrials.gov/ct2/show/NCT03410901?term=BMS+986178&rank=1

    2. Helga, yes this is very very exciting!

      There is a lot of clinical experience with this.
      Under Right to Try legislation I do not see how a patient could be denied access.
      The article even notes that TLR9 is not even necessary; it could be substituted by TLR7/8.
      There are wide open lines of treatment here and only tiny doses are needed that should be safe because they
      only activated the immune system locally.

      1. Very exciting!
        Helga, I am glad that you found this research!
        It looks too important to miss.

        Almost hard to imagine that the phase 1 with Ox40 has been sitting on the shelf for 5 years.
        This Ox40 research has been inching forward for the last 40 years.

        From all the clinical activity I do not see a clear legally justifiable reason why a patient could
        not access this now according to Right to Try Legislation. There clearly are completed and pulbished phase 1
        results for both Ox40 and TLR9 and this research is ongoing. This satisfies the requirments of the law.

        1. There are a few things to note:
          TLR7/8 could be used in place of TLR9. OX40 seems to be pivotal.
          This should be safe as there is only a specific local treatment being used.
          Activating the entire immune system to fight cancer can be dangerous.
          All you really need is to activate the T cells that are already in the tumor environment.

        2. Here are some snippets from the article.
          “CpG induces OX40
          This result indicates that the effect of CpG at this low dose to up-regulate OX40 expression is predominately local.

          However, the combination of CpG and anti-OX40 resulted in complete regression of both injected and noninjected tumors. Consistent with the time needed to induce an adaptive T cell response, the kinetics of regression at the two sites was different, with the distant site following the local site by several days (fig. S1C). Tumor regressions in response to the combined treatment were long-lasting and led to cure of most of the mice

          When tumors reached between 0.5 and 0.7 cm in the largest diameter (typically on days 4 to 5 after inoculation), αOX40 (4 μg) and CpG (50 μg) were injected into one tumor site every other day for a total of three doses.

          An alternative TLR agonist, resiquimod (R848), a ligand for TLR7/8, in combination with anti-OX40 induced a similar systemic antitumor immune response

          In situ vaccination with CpG and anti-OX40 was effective not only against lymphoma but also against tumors of a variety of histologic types, such as breast carcinoma (4T1), colon cancer (CT26), and melanoma (B16-F10) (fig. S8, A to C). In all these tumor models, the systemic therapeutic effects were induced by extremely low doses of both the CpG (typically 50 μg) and the anti-OX40 antibody (typically 8 μg) or even lower (fig. S9). However, the TLR agonist worked best when it was injected directly into the tumor, consistent with its action to up-regulate the OX40 target in the T cells of the tumor microenvironment. Similar systemic effects were obtained when the OX40 antibody was given systemically, rather than into the tumor, but at higher doses

          The injected and the noninjected tumors regressed, and remarkably, the treated mice were protected against the occurrence of independently arising tumors in their other mammary glands {Vaccine Strategy?}

          Mice cured by in situ vaccination of the A20 lymphoma were immune to rechallenge with the same tumor (A20) but not to a different tumor

          This in situ vaccination does not require knowledge of the tumor antigens. Potential drawbacks include reliance on adequate immune infiltrates and the availability of a suitable injectable site of tumor.

          TLR7/8 agonists could substitute for CpG, but checkpoint antibodies against PD1, PDL1, or CTLA4 could not substitute for anti-OX40.

          Autoimmune toxicities are a common complication of systemically administered immune checkpoint antibodies (20–24). In contrast, direct injection of the antibodies into the tumor at very low doses can avoid these side effects (25, 26). In our experiments, in situ injection of microgram quantities of immune stimulants and checkpoint antibodies proved to be sufficient to induce the required local immune modulation, resulting in a systemic antitumor immune response.”

        3. Here are some snippets from the article. Part 1
          “CpG induces OX40
          This result indicates that the effect of CpG at this low dose to up-regulate OX40 expression is predominately local.

          However, the combination of CpG and anti-OX40 resulted in complete regression of both injected and noninjected tumors. Consistent with the time needed to induce an adaptive T cell response, the kinetics of regression at the two sites was different, with the distant site following the local site by several days (fig. S1C). Tumor regressions in response to the combined treatment were long-lasting and led to cure of most of the mice

          When tumors reached between 0.5 and 0.7 cm in the largest diameter (typically on days 4 to 5 after inoculation), αOX40 (4 μg) and CpG (50 μg) were injected into one tumor site every other day for a total of three doses.

          An alternative TLR agonist, resiquimod (R848), a ligand for TLR7/8, in combination with anti-OX40 induced a similar systemic antitumor immune response”

        4. Here are some more snippets. Part 2

          In situ vaccination with CpG and anti-OX40 was effective not only against lymphoma but also against tumors of a variety of histologic types, such as breast carcinoma (4T1), colon cancer (CT26), and melanoma (B16-F10) (fig. S8, A to C). In all these tumor models, the systemic therapeutic effects were induced by extremely low doses of both the CpG (typically 50 μg) and the anti-OX40 antibody (typically 8 μg) or even lower (fig. S9). However, the TLR agonist worked best when it was injected directly into the tumor, consistent with its action to up-regulate the OX40 target in the T cells of the tumor microenvironment. Similar systemic effects were obtained when the OX40 antibody was given systemically, rather than into the tumor, but at higher doses

          The injected and the noninjected tumors regressed, and remarkably, the treated mice were protected against the occurrence of independently arising tumors in their other mammary glands {Vaccine Strategy?}

          Mice cured by in situ vaccination of the A20 lymphoma were immune to rechallenge with the same tumor (A20) but not to a different tumor

        5. Part 2

          In situ vaccination with CpG and anti-OX40 was effective not only against lymphoma but also against tumors of a variety of histologic types, such as breast carcinoma (4T1), colon cancer (CT26), and melanoma (B16-F10) (fig. S8, A to C). In all these tumor models, the systemic therapeutic effects were induced by extremely low doses of both the CpG (typically 50 μg) and the anti-OX40 antibody (typically 8 μg) or even lower (fig. S9). However, the TLR agonist worked best when it was injected directly into the tumor, consistent with its action to up-regulate the OX40 target in the T cells of the tumor microenvironment. Similar systemic effects were obtained when the OX40 antibody was given systemically, rather than into the tumor, but at higher doses

        6. Helga, for your information Resiquimod (TLR 7/8) that could be used in place of TLR9 is available online.
          Yet, the 10 mg below might still be much higher a dose than would be needed. The mice dosage was in micrograms. 10 miligrams is 10,000 micrograms! I am not sure whether the “We do not sell to patients” is enforceable under Right to Try as it then becomes more about the discretion of the treating doctor.

          10 mg $100
          Resiquimod (Synonyms: R848; S28463)
          Cat. No.: HY-13740 Purity: 99.85%

          “For research use only. We do not sell to patients.”

        7. Erg, I greatly hope that this can help people.

          There are still a few questions marks with this, though there are several features of this treatment that could make it a true breakthrough. The normal timeline for this probably involves several years, though
          some of these trials have been or soon will be completed and results will become widely known. I wish that those people who can be helped will be helped without unnecessary and unreasonable delays.

          My feeling is that Right to Try legislation should be understood to mean that if a patient has entered essentially an acute stage of a terminal illness that attempts to restrict access to life saving medicine would be illegal. With such an interpretation promising drugs such as OX40 antibodies could be tried on such patients; for their possible benefit and that of others.

        8. Hi J,

          Thanks for this flurry of emails 🙂 I looked up in the orig article if they published the sequence of SD-101, the TLR9 ligand but they didn’t. It also seems to be not a natural DNA sequence but a phosphorothioated one, which is some modification compared to the natural DNA, which has phosphodiester bonds bw the nucleotides. Here is a site that would deliver such a product: http://www.alphadna.com/phosphorothioate.html However, the exact sequence is a secret, it seems. Thanks for the TLR7/8 ligand drug name, https://en.wikipedia.org/wiki/Resiquimod, is it also comparably good?

          Regarding the clinical trials of OX40-TLR9 agonist, the one just published I be damned if it ever ends up in clinical practice. Just as you observed, clinical trials abundantly recruit patients for their *umab drugs in combination with something else because these drugs are expensive as hell. JMHO

        9. Here is e.g. nivolumab: https://en.wikipedia.org/wiki/Nivolumab All the *umab drugs are monoclonal antibodies, and have severe side effects as far as I know.
          This one:
          “The drug label contains warnings with regard to increased risks of severe immune-mediated inflammation of the lungs, the colon, the liver, the kidneys (with accompanying kidney dysfunction), as well as immune-mediated hypothyroidism and hyperthyroidism.”

          Regarding the price:
          “Prices from the first quarter of 2015 show the average per-mg wholesale prices to be $28.78 for nivolumab, $51.79 for pembrolizumab (the other anti–PD-1 agent), and $157.46 for ipilimumab. Dr Saltz calculated that the treatment cost for a typical patient receiving the CheckMate 067 combination would be $295,566.”

          And I think patients quickly develop resistance to these mab-s but I have to check that.

          Boggling the mind, no?

        10. “Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment.” https://www.ncbi.nlm.nih.gov/pubmed/28407039

          “…median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients…” !!!

          “CONCLUSION:
          T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.”

          2.1 vs 1.3 months progression-free survival! clearly, this approach is a dead end.

        11. J,

          here is the answer as to why only 15 patients recruited over 2 years for this most promising combo of ox40/tlr9 and why over 400 for the less esciting *umab/tlr9 combo! Look at the sponsor! The 1st one is sponsored by Ronald Levy, the PI of the article: https://clinicaltrials.gov/ct2/show/NCT03410901?term=Ox40&rank=11

          whereas the combo with the umab drugs sponsored by BMS: https://clinicaltrials.gov/ct2/show/NCT02737475?term=BMS+986178&rank=2

          Always look for the money. Sadly. Let’s hope Dr. Levy will persevere!

        12. Oxelumab appears to have stopped at phase 2.

          Ox40 looks amazing!
          All the major pharmas are loaded up with large patients numbers with Ox40 antibodies in phase 1, 1/2, and/or 2 trials.

          The potential for this therapy must have been transparently obvious to careful observers for at least
          the last 2 or 3 years. The current phase 1 trials seem much more like phase 3 in scope.
          What is especially staggering is that collectively these phase 1 trials do not have perhaps 100 patients but
          a few thousand.

          It would certainly not be unreasonable if at some point patient advocacy groups were to lobby under Right to Try. The one problem with the constraints of being in a trial would be that they might try combinations and dosing that might be of little help. Clinical trials can often continue for many years without benefiting patients even while the underlying drug has clear and powerful anti-cancer effects.

  8. The injected and the noninjected tumors regressed, and remarkably, the treated mice were protected against the occurrence of independently arising tumors in their other mammary glands {Vaccine Strategy?}
    Helga, thank you for noting that the PI was the sponsor.
    I was not aware that was possible.

    “Mice cured by in situ vaccination of the A20 lymphoma were immune to rechallenge with the same tumor (A20) but not to a different tumor

    This in situ vaccination does not require knowledge of the tumor antigens. Potential drawbacks include reliance on adequate immune infiltrates and the availability of a suitable injectable site of tumor.

    TLR7/8 agonists could substitute for CpG, but checkpoint antibodies against PD1, PDL1, or CTLA4 could not substitute for anti-OX40.”

  9. “Autoimmune toxicities are a common complication of systemically administered immune checkpoint antibodies (20–24). In contrast, direct injection of the antibodies into the tumor at very low doses can avoid these side effects (25, 26). In our experiments, in situ injection of microgram quantities of immune stimulants and checkpoint antibodies proved to be sufficient to induce the required local immune modulation, resulting in a systemic antitumor immune response.”

  10. Hi Jcancom
    I also read yesterday that news and also locate the Resiquimod that you can buy relatively cheap in Sigma Aldrich. Be so kind as to explain what is the process to Right to Try , you should ask your doctor to companies that can provide the compound and then apply it?

    1. marcos, yes that is about right.

      Under American law once a pharmaceutical has been published in a phase 1 trial and is still under active development, then patients without other acceptable options have a legal right to seek access to such a drug under Right to Try legislation. The companies, though are not under obligation to provide such treatments. I am unsure whether one might be legally entitled to buy a medicine from a chemical supplier if the pharmaceutical company refused to provide it. Other nations have also advanced similar legislation.

      From what I can see on the internet, Ox40 antibodies that appear to be available from chemical suppliers would be extremely expensive and it is not clear if they would be safe for human use. The dosing range that is being used in the human clinical trials is
      on the order of roughly 1mg/kg and higher. The chemical houses were selling microgram doses for $100. So, a human dose at these
      prices would be $100,000.

      1. veeni, thank you very much for clarifying this.
        When I saw the iv dosing being used 1-10 mg/kg I was not sure what the intratumoral dosing would be.
        Moving it down 100 fold should make it much safer and hopefully cheaper.

        The idea of thinking of this as a local tumor vaccination makes a great deal of sense.
        They can make it a local immune response against the tumor with a small and safe dose.

        All the pharmas are doing large trials with this.
        I greatly wish that the desperate cancer patients who could quite possibly greatly benefit from this treatment
        will not be prevented from accessing it if that is there wish. Under Right to Try it would not be a great stretch
        to suggest that this is within their legal rights to have such access.

        The sooner we can declare victory against cancer the better.
        We might even begin to hear of responses within the next few days among those who tried it once the news broke.

        1. hi Jcancom,

          I am also _very_ optimistic about this.

          OK, these are just mice. BUT, all tumors of 4 kinds cancer disappeared due to micrograms. And this due to our innate immune system.

          it seems, the method can flag cancer cells as such and make them (and only them) look like what they are: freaking invaders. This is not the usual story: I am confident some human cancers will respond to this dramatically.

        2. Any actual chance this could be tried by any of us as a last resort?
          If so, what would be the difficulty in doing so? Price.
          Alex

        3. Hi Alex,

          the problem (for now ..) with this is that this is not something like 3-bp or DCA that you can try at home. you need to touch one of the tumours via surgery and inject the combination of these two compounds on / in that.

          I really hope it will be available soon if the phase 1 studies are convincing. its not dirt cheap so companies can make money of it too.

        4. Alex, there are many many trials now enrolling for OX40.
          It should be fairly easy if you live near a trial site to access OX40 in a high quality medical setting for no charge.

          The problem, though, is that for some reason these trials appear to all be using a systemic dosing approach;
          That does not seem particularly insightful given the recent research.
          It would be best to avoid creating a body wide immune response and it is not as clear whether this would
          even be as effective.

          Under Right to Try legislation pharmaceutical companies could offer OX40 to patients.
          I will be interested to learn whether any choose to do this.
          If not, I would then be interested to know whether doctors could source this treatment from other vendors for their patients. If this were difficult I would then want to know whether Germany would allow for this treatment within a supervised medical environment.

          This is too good a treatment not to think through all of the options to treatment.

        5. W, thank you for replying!

          Yes, this does not appear to be yet another breakthrough that has no benefit for patients.
          This is a breakthrough that should reasonably be expected to cure actual patients.
          It is plausible that it might not be a cure all for all patients, though for a wide range of patients
          this probably would be at least highly beneficial.

          OX40 research has been in development for many decades.
          There are phase 1 clinical trials expected to enroll thousands of patients.
          I do not consider the timeline that they have established to be ethically reasonable.
          Are they really going to inch this forward over the next 2 years while they enroll 15 patients for the TL9 OX40 intratumoral injection trial? The OX40 dosing that they likely will use will be 100 times less than what other
          clinical trials have found to be safe.

          I wish that someone in a position of authority will take what is clearly the only morally responsible decision
          and open up access to any and all cancer patients who are in critical need of this treatment now. It would soon become
          obvious whether this treatment would live up to its potential.

          Nevertheless under Right to Try legislation patients would not need to wait for such a decision.

          2018 appears to be the year that cancer will be curable.
          I hope that the power of social media will transmit this knowledge to those who need it.

        6. I went to clinical trials gov and seached for “cancer”
          There were about 60,000 clinical trials.
          I then used the filter option on the left and chose phase 1 trials; there were about 10,000 trials.
          I then chose not yet enrolling, recruiting, enrolling by invitation, active not recruiting; there were about 5,000 trials.
          I then downloaded a file choosing all the trials (in the first drop down box), all the columns (in the second drop down box), and a comma separated file (in the third drop down box).

          I opened this file up in a spread sheet (there are free spread sheet programs available online).
          I then ordered the column (descending) with the number of patients enrolled (Column N).

          What is so interesting when you do this is to look at the first 2 or 3 hundred trials with the most expected to enroll.
          A great many of these trials are immunotherapy trials.
          Of the 60,000 cancer clinical trials, nearly all the major pharma are right now highly concentrated on immune therapies. This is where they are all placing their biggest bets. In terms of emerging new directions in iummune therapy as opposed to more ipi/braf/mek trials, OX40 is fairly prominent as being their next generation choice of
          where immune treatment is headed.

          Cancer research often seems so highly convoluted and endlessly confusing. Yet, when you look carefully at the spreadsheet, it becomes clear where the major pharmas believe cancer treatment is headed (Of course, since they are steering the boat where they belief we are going is in fact where we are going.).

        7. A 10 mg/kg dose which is one of the top ends of a dose ranging study for a 100 kg person is 1 gram!
          If they were to use a dose 100 less this would still be 10 mg!

          4 micrograms of OX40 might cost $100 (rough online pricing for research uses only).
          Scaled up that would be $100,000 for rough one 10 mg injection.
          For a 1 gram injection that would be $10 million.
          The pharmas are enrolling several thousand patients using multiple injections.
          Is it actually costing them tens of billions of dollars to run these trials?

          I expect not. Wonder what the actual marginal cost of this technology is.

        8. I have set up a topic for this in the Forum. Perhaps we could migrate the conversation over there so as not to clog up the news section. As this topic develops perhaps it could be given an even greater prominence on the site. Perhaps it could even eventually be shown directly when arriving on the site so that everyone will be aware of this important news. I have noticed that oftentimes people will not be aware of what is being written elsewhere on the forum. It is important that knowledge is structured so that important news reaches people.

          We might have a banner on the top of pages or even a ticker to get the news people need to know to them.

  11. Helga, this is correct.

    Yet, Right to Try has already passed through the Senate with a unanimous vote, it has bipartisan support in the House and
    the administration is understood to be in support of it. I am not much of a gambler, though if this is not a sure thing, I am not sure what could be surer. It seems now only a question of when.

    At a certain level passing this into law is not even necessary. There are certain fundamental human rights protected by the Constitution that are inherently outside of the authority of government to either grant or deny. It is ironic that this is being
    pushed forward libertarians. A more radical stance would have been to propose that those denying others the Right to Try
    were acting in violation of the Constitution of the United States of America.

  12. Hmm, it appears that Right to Try has been passed in 38 states, and introduced in 12 others.
    Hawaii is the only state that has vetoed (so far).

    Almost impossible to believe that there might be a red state-blue state flavor to this.
    This is simple: Do you pledge allegiance to the Constitution of the United States of America? Yes or No?

    https://www.270towin.com/maps/2016-actual-electoral-map
    http://righttotry.org/in-your-state/

    It is very unclear to me why there a few red state stragglers.

  13. It has occurred to me that those who argued that Right to Try would have no real benefit for patients because no effective treatments for cancer should be expected to be in clinical trials were wrong! Why is that people who are constantly wrong are the same ones who somehow hold themselves above others as being in some way more enlightened? Cancer research would be so much closer to a cure if people who actually proposed right answers were given authority.

    Where might such a plausibly effective for cancer might be lurking. Um, let me see now, anyone help out?
    Perhaps the TLR9-OX40 that we have been discussing!
    Several friends of our forum have expressed interest in this treatment for loved ones who are in desperate need of it now.
    It should be reasonable given the thousands of patients being dosed with 100 times higher doses than needed for intratumoral injection that a super low dose would be quite safe. Several esteemed and eminent colleagues on our thread have found it likely that the TLR9-OX40 intratumoral treatment will result in substantial responses (perhaps even curative in some humans).

    Given this background, doesn’t it seem completely morally repugnant that such an option is at this very time being in someway compromised by a legislative process that has clear and strong bipartisan support?

    Right to Try would almost immediately provide a wide range of terminal cancer patients such an option. The law itself might not specifically apply to TLR9-OX40, though given the nature of its clinical trial history denying such patients access under a strict
    interpretation of the law would clearly not be within the spirit of the legislation.

    1. Hi W,

      Thanks a lot for the link! And very nice to know you remember that. Indeed, many pieces of the puzzle make me feel and think, viruses play a larger role in cancer than we know, maybe even a decisive role. And this study comes to support that view.
      This perspective came to my mind, seeing the following major facts:
      1. most of the anti cancer drugs and supplements have something in common: they have antiviral action
      2. there are multiple cases of patients I came in contact with who were diagnosed with cancer just after their parents, sisters/brothers of kids had cancer. I would connect this with emotional impact if I would not see that there is more repetitive occurring on the same genetic line vs. different genetic line (e.g. husband and wife)
      Based on this, the following perspective emerged in my mind:
      A combination of 1.weak immune system (due to stress, etc.) + 2. a genetic profile susceptible to certain virus action + 3. the virus itself, leading to tumor occurrence.
      As the study above suggests, once the virus is in, it can start to induce changes that inactivates immune system too, and from that point on we have to deal with the tumor without the help of the immune system. If this is true, even if the tumor is destroyed, if the virus is not addressed the tumor may come back (unless it was already addressed by chance).
      This is one perspective we need to consider.
      I still have the intention to write on this subject but at this point I have challenges with time as I give priority to responding e-mails from patients + some other oncology related activities that I will share asap. As soon I get the time I will work on this.
      Thanks again for sharing this and please continue sharing whenever you come across such relevant info.

      Kind regards,
      Daniel

  14. Hello, everyone I am back!
    I have been getting fan mail asking: “Where has Jcancom gone?
    Here I am!
    Humanity needs me and I will do what I can to help out!

    I am getting excited about NKTR-214!
    They reported results last November that were very strong.
    Here we are in March and the results are even stronger.
    Lots of times with cancer (well basically all the times with cancer responses are short in duration and then people relapse).
    This one could be different.
    They are all signed up for a $5 billion deal with a product that has only been through a phase 1 trial.
    NKTR-214 is in the IL-2 family so there is a strong rationale for it to be effective and there are a bunch of good combo potential.

    It has had very strong results in melanoma and RCC and other indications will also be tried in the trials. It will be starting large scale clinical trials in a few months with up to 15,000 patients. This is a big one and it might just be found to be an effective treatment for at least the medium term.

    One thing that I am not entirely clear about is whether they have only shown in humans local effects or also more systematic benefits.

    http://ir.nektar.com/static-files/de7f07a4-d680-472d-b73e-3f3dd5fd1484

    1. Hi J,

      Very nice to hear from you again and good to hear you decided to continue with your valuable contribution.

      It may be sometimes annoying seeing that potentially very valuable solutions to cancer are not getting enough attention from those actually responsible to pay attention and act. Good things take time to happen and because we can, we are responsible to consolidate the knowledge and evidence around those treatments. On short term that is valuable just because we create awareness on those subjects. On mid and long term I hope and expect we will be able to find ways to move them further than just awareness creation. We only need patience, perseverance and focus.

      These days I am traveling (it was my wife’s birthday and wanted to be at her place during this time) but as soon as I am back home I will have a closer look again at the NKTR approach.

      Kind regards,
      Daniel

    1. I hope the study brings great results in humans, maybe even better than the ones seen in mice.
      I’ve not seen much of Meech, i hope Ergin is quitting smoking, and i hope everyone is getting better. Mothers, Fathers, loved ones, friends here.
      Sadly things are very time consuming for me, i find it very hard to be at my computer anymore.
      Mother’s situation seems to be stagnating for now, but today she asked that the treatment be stopped due to side effects on her skin that she couldn’t take anymore, and the doctor agreed.
      What will be next, i will have to find out……

      Best wishes,
      Alex

      1. My bro Alex,
        You have precious friends here.Daniel,me,Hero Emad,J,W.
        Although we know more than any ordinary oncologist,we have very small knowledge about cancer.
        But we know stg special about cancer.It is metabolic treatment.
        When you need me ,pls just call.

      2. @Alex: this is sad news, but understandable (long time side effects can be exhausting).
        Usually after Erlotinib is discontinued, there is a strong rebound of the cancer, mostly reflected in markers. I suppose only Erlotinib was discontinued, not Zoledronic acid too, since that one fought the bone metastases.

        A possible alternative treatment would be metronomic chemotherapy coupled with a proton pump inhibitor. Something like:
        Cyclophosphamide 100 mg each 3 days.
        Etoposide 50 mg daily.
        Celecoxib 2x 100 mg daily.
        Lansoprazole or Omeprazole 2x 30 mg daily (2 hours after other drugs).
        But you’d have to careful and check for accumulation of the chemo, by a weekly blood count.

      3. I think first to do what you used to do before chemo , then try to add new things at least try to make things stable until they continue the treatment

        didn’t they mention anything about when they will continue the treatment or what are the alternatives ?

      4. My messages gone because i put a link i think.
        I said,maybe you also want to add an antibiotic like
        Doxcycline for an effective metabolic treatment.
        The link was about dealing with cancer like an infectious disease.I am sure you know the mechanisms and the link is already in this website.

  15. Truly sad… we lost a good friend. 🙁 Meech i hope he did not suffer much. 🙁 I will not forget him.
    Tomorrow, we take the ambulance to commute to the oncology clinic here….
    My mother’s situation is quickly worsening, her left arm is almost useless, and her right arm seems to be following soon.
    Ovidiu was right
    I’ve been crying all day.

    Take care friends.
    Alex

      1. Thank you W.. My mother’s situation is very bad. Oncologist says she has a brain metastasis, most likely. Another CT is soon to follow in the coming days. Meanwhile some IV’s are being done, but nothing special. The brain metastasis will probably be fatal quite soon. I’ve managed to say to her what i had to say before the inevitable happens. The doctor says there’s not much that can be done. I can only hope to gain sufficient time, to record her final thoughts, our memories together in an audio or video collection. In a movie i saw in the past someone said. The cure for cancer is living a life worth remembering. So i want to record that. It is not that i will not remember her, i just want to let as little as possible to be forgotten.
        Thank you for being a friend.
        Good luck.

      1. Thank you Emad. My mother’s situation is very bad. Oncologist says she has a brain metastasis, most likely. Another CT is soon to follow in the coming days. Meanwhile some IV’s are being done, but nothing special. The brain metastasis will probably be fatal quite soon. I’ve managed to say to her what i had to say before the inevitable happens. The doctor says there’s not much that can be done. I can only hope to gain sufficient time, to record her final thoughts, our memories together in an audio or video collection. In a movie i saw in the past someone said. The cure for cancer is living a life worth remembering. So i want to record that. It is not that i will not remember her, i just want to let as little as possible to be forgotten. I will copy this to W.
        Thank you for being a friend.
        Good luck.

      2. I am forced to reply here, the latest reply to me doesn’t have a reply button available…..
        Thank you for your very encouraging words.
        I’m very glad your mother is doing much better against all odds.
        Should my mother’s brain stroke be dealt with and if she should feel better, i will be more hopeful of her cancer going away maybe.
        Thinking of you and your mother.
        Thank you, i will tell this to my mother.
        You all here are with us in our conversations.
        One day maybe…. we will be better.

    1. Alex pls dont panic and dont show it to mom.Did you see my message about dapagloflozin and doxycycline?
      İ also have 2dg and can send it to you.And the other drugs which you need.

      1. Brother, i don’t know what to do.
        My mother is in an extreme situation, i try to gain time with the oncology clinic here, but it doesn’t look like it will be enough.
        I don’t know what treatment to try as last solution. I am thinking of Hydrazine Sulfate.
        I am desperate and in big pain 🙁
        My time is coming brother… it’s my turn soon. 🙁
        I will try to explain. When you said your mother died, i simply realized that anything i say will be useless.
        Words sometimes are not enough. I am sorry if my shock made you think i was cold with you, it’s quite the opposite.
        But i also realized, nothing i will say will make your void fill.

        Take care brother, tomorrow i talk with mother about you and your mother. We have little time.
        Alex

  16. And because in the last week only bad news, let us tell you our side. After many and various treatments in which cancer was growing as a beautiful fetus, my wife began treatment with irinotecan and avastin in October. At the time this treatment started because of the very bad condition, it did not get us to computer tomograph. Now after 6 months of treatment feels good, gained weight everything seemed to go well, but the doctor has to make an assessment for the two medicines. So we’re asking for a thoracic, abdominal and pelvic CT. The imaging physician and the oncologist relate to the size of the tumors now at some MRIs a year ago, when the tumors were very small, so it turns out that the disease has evolved and the treatment is stopped. There is nothing about the patient’s condition in the assessment form. We needed a CT at the end of September when the tumors were probably at their peak, because the pain was permanent and atrocious. We are in a situation where I do not see any exit, because the wife has DPD deficiency (it does not support 5 fluo and) kras mutation (does not receive small molecule drugs). If there is any idea I’m looking forward with much interest.

  17. Dear Siven ,i am very sad because of these bad news.
    When i wrote serious things and the reality,,everypeople was angry with me 2 months ago,so i stopped talking. But we all need the most effective treatments and we must be very brave.Brave that we never before.
    Brave and NEVER look back.This website is special and no1 in the world.Because there is only 1 Daniel in this world.Ofcourse he does not know the cure of all types of cancer.But he knows very effective treatments.May be cure for some patients.And i am believing that we also put some small knowledge on it with our findings.
    Please use your logic.Write on the paper your chances.
    Choose 1 and go urgently.
    İf you need any help just write me.İ am very sure that you will not use salinomycin.i know because i went from that road.i wait till the end to use phlorizin and salinomycin and 3bp but it was too late.
    Although i am not an expert or a doctor,i lost more than 20 friends from cancer this year and i learned stg very special.İt is possible to gain time with metabolic treatment.And we can talk more if you wish.

    1. i will try to explain clearly and shortly of my thoughts.
      When SGLT inhibitors are used continiously,it is clear that cancer can not take glucose although there is too much of it in blood.So this gives you a time,cancer has to switch to another type of energy which is not efficient or it will die.
      Alone inhibiting glucose maybe not enough.So we have to use it wisely with thinking of OXPHOS.
      Btw 3BP does it alone and it has 2 abilities or more .But this is another section because you will not use it at home.
      Both SGLT inhibitors and antibiotics are sold in pharmacies and used by thousands of patients.But interestingly not for cancer.
      Here is a very good article about metabolic strategies .
      http://cancerres.aacrjournals.org/content/77/7/1564

      1. Combos are very important in cancer treatment.
        And we have to stop searching for ordinary cancer treatments.Taxane is also produced from a plant.Bark of a pine tree.
        Begin to search for cancer stem cells or resistive cells which chemo does not work.We have to improve chemo effectiveness which kills not more than %10-20 cancer stem cells for most cases.We have to use combos before chemo,not after.And with cautious ofcourse.

  18. i never gave advices before to anyone.also i dont know the situation of your dear mom.i am only telling you stg very very logical.thousands of diabetic patients are using dapagliflozin.i know your situation and it is not easy for you to try sal,hyperthermia,phlorizin,3 bp etc.
    if dr said only palitative care, blocking sugar for a long time may makes the patient worser,i am talking about hydrazine sulphate.They give glucose inside nutrient bag in hospital inorder to prevent organ failure when pallitative care.
    You must be selective at this stage.
    i wonder other friends thoughts also.

    1. Hi Ergin, I have seen some very good points from your side lately but did not had the time to react.
      Regarding hydrazine, this is not blocking glucose but could be some side effects on the liver. Like you said once no one knows yet THE solution to cancer for ALL. But we are aware of some solutions that may extend, improve life or maybe even cure some. We discussed many of such potential solutions on this website, some of which are accessible to almost anyone. But it is not ethical from us to suggest we know the solution X for patient Y as long as we are not 100%. Many treatments are discussed here and we will continue doing that and help answer questions as much as we can, but the choices should remain for the patients and their doctors.

  19. Brother Alex,
    i know it is very hard to deal and to choose.i am still crying to mom and i will always blame myself that why i am not an eintstein.these days she enters to my dreams too much.i am afraiding to make stg wrong to you and to your dear mom.pls just use your logic.we are not einstein or the best oncologist,dont forget this.also they dont know the exact answers.

    1. Brother,
      My mother’s cancer is apparently stable… she is also paralyzed because of the tumor’s presence on her spine, and now she is even more paralyzed because she had a brain stroke… no… me and the oncologist were wrong, it’s not a metastasis, she has no metastasis.
      She is extremely weakened, i will wait for more information from doctors, maybe we see some improvements… so far only decline.
      Tomorrow we go see neurologist, i hope. Depends on oncologist now.
      So now….. Cancer+Paralysis+Brain Stroke, each one is bad, 2 of them can be killers…. my mother is still alive. It’s true, i don’t know how much longer.
      Many relatives have come… and many more will come.
      I still hope for a miracle, then i will believe in God. So far, only pain……..

      1. I still remember when my mother had severe ascites 1 month ago , i felt its over

        I can only say its like a miracle how bad her liver and life expectancy was , and how good she is now

        I’m sorry that your dear mother had a brain stroke, i wish she recovers from it, the most important thing for now is to see that cancer is stable

        stay strong and don’t push yourself to the limit, don’t get rid of hope, hope is a good thing

        1. Emad.

          I hope your mother is doing better. If so, what would you say helps the most? What drugs?

          Thank you very much,
          Best wishes,
          Alex

        2. Hi Alex

          I can’t replay to you directly as you know

          I hope your mothers is fine and stable now, also i will pray for her to see her improving soon

          my mother feels weak these days but because of very low blood counts, she did 1 blood transfusion today, tomorrow she will do 2 more, this is how it goes, ugly days but we should stay optimistic so we can fight

          regarding your question :-
          what I understand is that you are asking about what drugs did work against cancer ?

          well, mainly chemo as we know but the drugs that did make chemo work before was DCA, but it’s about every individual, your mother didn’t benefit so much from DCA, others here also didn’t

          other than that I tried different things but I didn’t notice any change

          but also months ago I tried Sal, 3bp and MG

          with the first and second TACE sessions , I did use Sal + 3bp as IV’s , I felt like they kept cancer stable between the first and second TACE session, also stable between the second and third, we used to take long time between the sessions and probably the cancer may grow after 6 weeks from TACE , we sometimes come late as 9 weeks after TACE and still the results were good

          also after the third TACE, I started to give Methylglyoxal orally to my mother, after 9 weeks prof Vogl got impressed because cancer did decrease in size even after we come as late as 9 weeks

          when I run-out of MG and the port was blocked, I stopped everything, we did the forth TACE, and after 11 weeks (very late) we did MRI and the results were horrible !

          okay we may say that results were horrible because we did come late, okay we did come late before (9 weeks) and still the results were very good (tumor shrinkage) but to come late as 11 weeks, is this enough alone to make cancer progress that far !!!

          I believe sal, 3bp and MG at least kept cancer stable and didn’t allow it to progress even after the TACE effect fades away

          ok I realize that its hard for you to give any IV’s to your mother but 3bp can be administrated orally, it may be hard to get, but MG looks easier to get I think, and it’s only administrated orally

          I know that people are scared from the side-effects, but nothing scares me more than chemo and cancer

          but this is my problem and my responsibility, and i’m responsible about any problem happens to my mother because of these drugs, so it’s all about : should we use these things and be responsible for what may happen ?

          I don’t know if my answer is helpful, ask me again for anything you want, please don’t hesitate

          Wish you all the best

        3. Hi Daniel

          No I didn’t receive any email from you, the last email I sent was at April 14 on Friday, it was a very long email, and didn’t receive anything after it

        4. Wow …. how inspired I was to send you this short question given the importance and urgency of the subject. I am very happy I did it. I haven’t received any e-mail from you after April 13. I checked now my e-mail and there is nothing! Could you please send it again and let me know via a comment here after you did it so I can confirm if I receive it? Thank you.

          Kind regards,
          Daniel

        5. I don’t know whats happening with gmail, the email I sent was listed in the Sent Mails

          Anyway , I sent it again now , please confirm the receive 🙂

        6. Hmmm … I confirm I did NOT receive it!

          Can you please send it again on both e-mails:
          cancertreatmentsresearch at gmail.com
          daniel at cancertreatmentsresearch.com

          Please let me know again when you sent it and if that doesn’t work I will give you another e-mail address. If that will not work, you will have to send it from another e-mail address.

        7. Yes Emad, now I receive it on both e-mail addresses. So there may be something wrong with one of your e-mails. I will respond asap, probably this evening. Kind regards, Daniel

        8. Okay good

          Don’t worry Daniel take your time, you can respond whenever you find time 🙂

          Thank you so much

      2. Alex, remember your lovely mom was continiously scratching,itching (i dont know the exact word in english)her body on skype.That was a big sign of coming paralyising.But i couldnt tell it to you those days.i very hope that she has not brain mets.You remember i gave you a promise that,your mom is my mom and i will do everything for her.We are a family although we never meet eachother.
        i wrote to you my ideas about a miracle in my previous messages,last chances.that was my understanding about cancer.we can use its metabolism.it has a clear science.You used DCA,mother of metabolic drugs.
        i saw 75 LDH on my moms blood counts.Also her blood glucose dropped too much.But still i am thinking we dont know how to use it.How to combine with others.i will work on it.
        Now i m getting lessons about healing yourself with mentally.
        Louise Hay.meditation,R2,bioenergy etc.
        My life changed too much after this.
        Louise Hay survived from cancer without any medicine.But things are going worser these days.The treatments open my subconscious so i am living my losts very hard these days which my brain closed.But experts says everything is ok,and the treatment normally going.
        Doctors know how much time you have because they saw hundreds of patients.A big experience but they normally dont tell it to us.This is not fair when you think.
        As a summary happenings are sometimes seen very clearly from outside.Solutions and chances are also seen from outside easily.We say relax brother,dont panic brother,everything will be fine brother.But not easy for you to listen.
        İ am always near you and your dear mom.

        1. Brother, one day we will have a good time together, i know you suffer very much, and i am sorry. 🙁
          One day….. after we stop the pain.
          We will meet… sooner or later. And we will smoke together.

          Try to relax very much,
          Alex

    2. Brain looks normal, results are good.
      Oncologist says the problem originates from lezion of sorts at C5 on the spine. (the way i understand this is, inflamation, tumor waste, they propagate to the brain).

      Doc decided to change treatment from Erlotinib to Gefitinib.
      Meanwhile, basic iv’s with Vit, B1, B6, Dexamethazone, etc… and now…. itraconazole oral pill.
      Mom feels just a bit better, and i am a bit more optimistic but, exhausted.
      She is constantly sleepy, requires oxigen, she is very very slow…. adrenal fatigue? Something going on and i am not sure. Help?

      Have a relaxing weekend
      Alex

      1. @Alex: you presented some confusing information, and it’s hard to give advice based on it. Please try to clarify your mother’s condition, or at least what the oncologist settled on.
        If I understood correctly, there is no brain metastasis, no stroke, just a local progression in the spine that worsened the paralysis. Please confirm if this is correct. You also didn’t specify the dosage for Gefitinib and Itraconazole.

        Gefitinib has similar side effects as Erlotinib (rash and liver problems), and Itraconazole (which can also damage the liver) increases the AUC of it by at least 60%, so the combination is risky for the liver.
        I suppose the oncologist switched to Gefitinb because he believes it has a chance to do better than Erlotinib against bone metastasis, and Itraconazole was added as an angiogenesis inhibitor, let’s hope this will work, without too much damage to the liver.

        1. Ovidiu you understood right, it seems you even predicted it. Cancer is loving Tarceva being stopped by the oncologist at my mother’s request upon seeing the side effects it had on my mother’s skin. At this time it looks to me like there is no special protocol being followed. It looks to me like it’s something to make her feel better. She has indeed recovered a bit, breathes without oxygen, appetite is back, she seems to have emotions once again. Paralysis is almost complete, nothing changed for better in there, yet.
          The doctor didn’t mentions specifics to me, the truth is that she is very very busy, being the only oncologist in our county.
          Still me and my mother are privileged to have her visit in the room, and a few short minutes to talk.
          Itraconazole doesn’t seem to be part of a protocol, she got 1 pill for 3 days of 100mg.
          Truthfully i have doubts about a gefitinib protocol, it’s similar to erlotinib… right? So i don’t know if there will be any actual changes, this is where i wish to get in her office once again and maybe convince her to have a look at some of the things being discussed over here, such as 2-DG, 3-BP, DCA, Hydrazine, etc.
          I honestly want something to be done in the best way possible, and with less risks than with doing something at home.
          I don’t think i would be able to do it myself, and i am even scared of TLS or error or who knows what else.
          As usual you are on the spot

          Thank you very much for your highly focused attention.
          Best wishes,
          Alex

        2. I do not expect Itraconazole was added by the oncologist as an anti angiogenesis (although we know it has those kind of effects). There may be a fungal infection she is treating and maybe that contributes to improvements on short term.

          Infections are very dangerous and lung cancer patients are extra susceptible to that – lungs can be fast populated by parazites. When not treated may kill the patient – when treated (antifungals, antibiotics) may make wonders.

      2. Dear Alex,

        As discussed on Skype, if your doctor is willing to help with 2DG admin and your dear mom wants to try, please let me know and will do my best to support with the required info.

        Kind regards,
        Daniel

      3. @Alex: to me it seems your mother would have to be very lucky to overcome this metastasis to the spine just with chemo, isn’t it possible to have some decompressing surgery?
        My evaluation is that the treatment was working, but not well, especially in the spine, and as soon as it was discontinued, there was a disease flare.
        Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design.
        https://www.ncbi.nlm.nih.gov/pubmed/21856766

        Itraconazole for fungal infections is given at 2x 100 mg daily for at least 14 days, maybe 7 days if the target is very susceptible, so just 3 days of 100 mg seems odd.
        You didn’t mention if Zoledronic acid is still part of the treatment, maybe it’s still useful.
        Gefitinib may (or not) be more efective than Erlotinib against bone metastases.
        Remarkable bone formation following gefitinib for extensive lytic bone metastasis: a report of two cases.
        https://www.ncbi.nlm.nih.gov/pubmed/28031519

        I found something that could help with the bone metastases, and probably without major side effects.
        Evaluation of the combined use of metronomic zoledronic acid and Coriolus versicolor in intratibial breast cancer mouse model.
        https://www.ncbi.nlm.nih.gov/pubmed/28412218

        1. Ovidiu, Thank you for your quick reply.
          After trying DCA my mother’s situation worsened, she started to paralyze.
          We went to the oncology clinic here finally….
          After investigations of CT, and MRI, surgeons in Bucharest rejected my mother for surgery saying it would kill her.
          This i strongly believe is even more out of the question today. Since after all this time her situation is even worse.
          I’m not sure why itraconazole is being given to her. I’m uncertain if Zoledronic Acid will be a part of this newly suggested protocol with Gefitinib, i am not made aware of dosages.

          I don’t know what to do next.
          I would love to have a magic solution to my mother’s cancer, but then i would be a genius of sorts, and i am not sadly.
          The reality is that this organism is very very strong and well adapted. Still i would love to give it a bad time, but with what?
          I know we are all here for the same answer, but…. what would give it a really really bad time? Without killing the host.
          I’t’s very obvious that my mother’s cancer is not dependent on tyrosine, it needs it but… it can do without it.

          Many thanks.
          As always, looking forward for your reply.
          Alex

        2. Alex maybe that was not DCA,You also used Citric Acid dont forget.
          And i would also think direct injection into tumor.

        3. Or maybe non of them, just the expected cancer evolution when not treated effectively. As long as we do not have clear facts and data to support, it easy to draw misleading conclusions. We need data. May be you can look into the blood results of that time to see if there was any specific lysis or immune reaction connected to the DCA start or CA start.

        4. 2DG+3BP is water soluble,and easy to use it with gel,cream etc.This not an advice,just keep in mind😀

        5. @Alex: the most common procedure for spinal metastases (as far as I found) is decompression surgery, but if this is not possible, some other local procedure could be tried.
          You are right, the spinal metastasis must have some other mutations besides EGFR, and Zoledronic acid wasn’t enough to overcome resistance from them.
          Unfortunately, to find out exactly what mutations occurred there, a (minimally invasive) biopsy would be needed, which would be risky too.

          If money weren’t an issue, you could try radiosurgery (coupled with a radiosensitizer). CyberKnife seems to be the most accurate.
          Single fraction radiosurgery/stereotactic body radiation therapy (SBRT) for spine metastasis: A dosimetric comparison of multiple delivery platforms.
          https://www.ncbi.nlm.nih.gov/pubmed/28291927
          An alternative would be photodynamic therapy, coupled with a photosensitizer that accumulates in bone or tumoral tissue.
          Photodynamic therapy in spinal metastases: a qualitative analysis of published results.
          https://www.ncbi.nlm.nih.gov/pubmed/25875556

          To get a better understanding of the treatment possibilities with radiosurgery or photodynamic, you need to talk to someone with practical experience in using them.

  20. Little breakthrough in advanced ovarian cancer. Patients are still alive after a combo of bevacizumab, low-dose intravenous and personalized DC vaccine:
    cyclophosphamidehttp://stm.sciencemag.org/content/10/436/eaao5931

  21. Today i ask the most important question to date, this is how i feel about the following question. I know it will be more that one question but they all point at the same “question”.

    I would like to know:

    What makes the cancerous cell special?
    What is it’s special “spot”?
    Does it have any weakness at all?
    How is it different from the normal cells?
    Does the cancerous cell actually have a definitive vulnerability that the normal cells don’t?
    Do we actually have answers to these questions?

    My apologies if my message appears a tad arrogant, it is by no means that way.
    I realize these questions are very difficult if not impossible to answer, so i have no expectations for answers.
    Still i believe that asking the right question can sometimes be more valuable than getting the answer.
    Should we have precise answers to the questions, than maybe we can find cures?

    Thank you very much for your attention,
    Alex

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