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.

5 comments:

  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:

    http://meetinglibrary.asco.org/content/151704-156

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    Replies
    1. Thank you so much for the information Stephen.

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  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?

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

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  3. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway
    http://www.nature.com/articles/ncomms12700

    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."

    ReplyDelete