Monday, 22 August 2016

mTOR inhibitors

Does anyone have any knowledge of mTOR inhibitors and availability?

I am looking into them as a target for MYCN amplification due to the
 H3F3A G34r mutation that my daughter has.

We have today had recurrence confirmed in inoperable areas and are trying to decide what may be the best way forward.
There don't seem to be a lot of options with this mutation.


  1. There are numerous inhibitors of PI3K, AKT and mTOR (key nodes in the PI3K/AKT/mTOR signaling pathway) currently in trials for glioma and other solid tumors. But only approved inhibitors of mTOR are rapamycin and the rapamycin analogs everolimus and temsirolimus. The latter two, as novel oncology drugs, are very expensive. They are not entirely satisfactory inhibitors as they inhibit only mTOR complex 1 (not complex 2), and they can also induce upregulation of AKT as a form of negative feedback. In addition they can have uncertain effects on the immune system (the main indication of rapamycin is actually as an immunosuppressant to prevent organ rejection for organ transplants). They've not been that successful in GBM trials to date as single agents.

    Since there is very little evidence to help design a cocktail specifically for H3F3A G34 mutant GBM, I would also make of use of the much more plentiful evidence that exists for the usual adult type of GBM (H3F3A not mutated, IDH1 not mutated, TERT promoter mutated, gains of chromosome 7, loss of chromosome 10), as you were doing with the original cocktail you posted.

    Celebrex, metformin, histamine 2 receptor antagonists (cimetidine, famotidine, ranitidine, the first two have the most evidence), minocycline (or doxycycline if that is not available), melatonin, PSK, vitamin D3, Boswellia, these are all things on your list that I generally recommend for GBM.

    See my new pharma/non-pharma spreadsheet with an attempt at a very approximate ranking system in the Brain Tumor Library (folder 0).

    The manipulation of hormones and hormone receptors is a strategy that has appealed to me lately. Especially the combo of propranolol and etodolac (a cheaper alternative to Celebrex) plus low dose temozolomide as in this impressive study:

    1. Thank you so much for the information Stephen.

  2. Stephen do you know if it would it be possible to use the combination of propranolol and etodolac if you normally have low blood pressure?

    1. I think an actual MD would be more qualified to answer that. Is there a doctor in the house?

  3. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

    Long story short, from the end of discussion in the article:
    "The novel PTEN-independent mode of mTORC1/2 activation
    via mutated IDH/2HG/KDM4A/DEPTOR revealed here may
    provide an additional molecular explanation for the oncogenic
    activity of IDH1/2 mutation in brain cancer. This would indicate
    a potential therapeutic strategy to target oncogenic mTOR
    signalling in cancers harbouring IDH1/2 mutations."

    This large research was to be completed in 2016. I can not find results anywhere! (

      Phase II Study of Radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in Patients with Newly Diagnosed Glioblastoma without MGMT Promoter Hypermethylation (EORTC 26082).

  5. Can anyone explain the results of a study in 178 treatment centers from 2007 to 2017?

    1. The OS-12, median OS, time to progression, and PFS-6 values are all comparable to recent phase 3 trials results with standard treatments alone (RT + TMZ). Everolimus does not seem to add much value in this patient population which was unselected for signs of mTOR pathway activation.

  6. Some articles report the benefit of inhibiting glutaminase by inhibiting MTOR:

    "Expression of GLS (glutaminase) following mTOR inhibitor treatment promoted GBM survival in an α-ketoglutarate–dependent (αKG-dependent) manner. Combined genetic and/or pharmacological inhibition of mTOR kinase and glutaminase resulted in massive synergistic tumor cell death and growth inhibition in tumor-bearing mice. These results highlight a critical role for compensatory glutamine metabolism in promoting mTOR inhibitor resistance and suggest that rational combination therapy has the potential to suppress resistance."

    "Our study provides new insight into GBM resistance mechanisms to targeted therapies and offers a compelling rationale for the simultaneous inhibition of mTOR and GLS (glutaminase) as a promising combination therapy for this challenging brain cancer."

    "The results show that combination of negative modulation of GA (glutaminases) isoforms arising from GLS gene with the introduction of the GLS2 gene product, GAB, may in the future provide a useful means to curb glioblastoma growth"

    Your thoughts on inhibiting glutaminase when combined with an MTOR inhibitor? What drugs can inhibit glutaminase?

    1. Glutaminase is the enzyme that can convert glutamine to glutamate. Inhibiting glutaminase might be more effective in vitro than in vivo, because in the brain there is an abundance of glutamate already (it is one of the key neurotransmitters in the brain).

      Another enzyme target would be glutamate deyhdrogenases (GLUD1 and GLUD2) which convert glutamate to alpha-ketoglutarate before feeding into the citric acid cycle.

      Unfortunately there are no widely clincially available glutaminase or glutamate dehyodrogenase inhibitors, to my knowledge.

      Some are available in trials:

      Chloroquine has been suggested as a GLUD inhibitor, but it may be too weak to have much effect on GLUD1 or GLUD2 in vivo. According to one study, IC50 for GLUD1 is around 50 micromolar and around 140 micromolar for GLUD2. These concentrations are far higher than achievable plasma concentrations of chloroquine.

      I would love to find an effective, potent and available GLUD2 inhibitor, but I don't know of any.

    2. Stephen, thank you very much for the detailed answer!

      Perhaps with an MTOR inhibitor it is worth considering using Memantine or Sulfasalazine instead of a glutaminase inhibitor?

    3. Memantine would block NMDA glutamate receptors and therefore some of the neurotransmitter effects of glutamate, but it would not prevent glutamate from being fed into the citric acid cycle and being used as an energy source.

      Sulfasalazine inhibits the transporter (system XC) that exports glutamate from cells in exchange for cystine, so again this drug wouldn't prevent glutamate from being used as an energy source.

      Both of those drugs may have uses in GBM therapy, but probably not in this particular context (cells compensating for mTOR inhibition by increasing the flux of glutamine-derived carbon into the citric acid cycle (aka tricarboxylic acid cycle, Krebs cycle).

    4. As a glutaminase inhibitor, "Compound 968" is now being investigated. However, all studies are only invitro.,EMD_BIO-352010

    5. And another glutaminase inhibitor unfortunately in studies in vitro and in mice in other types of cancer.

      "BPTES is a selective inhibitor of Glutaminase GLS1 (KGA), which is found in the kidney and brain, and is positively regulated by myc and strongly expressed in many tumors and tumor cell lines. Glutaminase converts glutamine to glutamate, which is an important excitatory neurotransmitter in brain and can be further oxidized to α-ketoglutarate to feed the tricarboxylic acid (TCA) cycle and to glutathione, which is important for controlling the level of reactive oxygen species (ROS), particularly important for cancer cell growth. BPTES was found to slow growth of glioma cells."

  7. Shocking research results:
    everolimus SHORTENS survival of newly diagnosed glioblastoma patients.

    "Unfortunately, everolimus did not improve either PFS or OS in the trial subjects. In fact, those taking the medication died sooner by an average of
    4.7 months and they experienced more frequent grade 4 and 5 adverse events. Among them, serious infections were more common in the experimental group than in the control population."

    Your opinion?

    1. I'm sure this trial has been discussed here before.

      What's new is the theory that the negative results of this trial are due to suppression of immune effector cells by everolimus. It's a valid concern, and may apply to rapamycin as well.

  8. 1. In this unsuccessful study of Everolimus, the daily dose of Everolimus was 10 mg.
    In a small successful study with Sirolimus and HCQ (Chi 2016), a dose of 2 mg of Sirolimus per day equals 3-5 mg of Everolimus per day:

    "The maximal tolerated daily dose of everolimus with standard RT-TMZ was reported as 10 mg in a phase I study [30]. Moreover, the reduced dosage was expected to be less than 5 mg if coupled with HCQ.
    A common long-term maintenance dose for transplantation recipients is 2 mg sirolimus 2 mg, which is about 3-5 mg of everolimus [31,32]."

    In addition, in the Chi study, the dose of Sirolimus sometimes decreased to 1 mg per day or was interrupted due to meilotoxicity and fatigue.

    So, apparently, there is a hope that a dose of Sirolimus 2 mg per day will not lead to such negative consequences as a dose of Everolimus 10 mg per day?

    2. I am also worried about the average weight of patients in Taiwan and, for example, in the US or Russia.
    This affects the received dose of the drug (eg chloroquine and sirolimus) per kg of the patient's body!
    In Asian countries, the average weight of men is 58 kg, women - 45 kg.
    In the USA, the average weight of a man is 88 kn, women - 75 kg.
    But why, then, do the doses of chloroquine, sirolimus and other additives not depend on weight?
    It's strange, why in all studies everyone use the same doses of experimental drugs, not counting because of body weight?

    1. I think the thing to remember is that both the tumor cells and the immune cells are using similar pathways for proliferation (such as mTOR). If you lower the dose, there might be less immunosuppression but there will also be less tumor suppression. And because of the blood-brain barrier the circulating immune cells are probably getting more exposure to the drug than the tumor cells. In some types of brain tumos (subependymal giant cell astrocytoma) the tumor suppressive effect of everolimus apparently outweighs any immunosuppressive effect in importance. I think the clinical trial shows the same is not true in the general GBM population. Whether the same is true in the case of individual patients is another matter though, and the combination of sirolimus + chloroquine is yet another matter.

      Lots of drugs have a recommended dose that is not based on the patient's weight. I'm not sure why that is, as adult human weight and body surface is extremely variable.