Tuesday 30 January 2018

Chloroquine for GBM with EGFRvIII mutation

EGFRvIII expression triggers a metabolic dependency and therapeutic vulnerability sensitive to autophagy inhibition
http://www.tandfonline.com/doi/pdf/10.1080/15548627.2017.1409926?needAccess=true

Some of the data contained in this study was used as justification for the CHLOROBRAIN trial
https://clinicaltrials.gov/ct2/show/NCT02378532



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6 comments:

  1. Semyon31 January 2018 at 10:36

    "...we retrospectively
    analyzed 43 GBM patients that were included in a randomized,
    placebo-controlled phase II trial. Of the analyzed
    patients, 28 patients received CQ in combination with carmustine
    and radiotherapy. EGFRvIII expression was assessed
    immunohistochemically and observed in 22 of 43 (51%)
    patients...
    Although the number of analyzed patients is low, these
    results are encouraging as CQ treatment improved median
    survival from 5 to 10 mo in patients with EGFRvIII-negative
    GBM (Fig. 6C, p = 0.0002). Strikingly, median survival of
    patients with EGFRvIII-positive GBM increased from 3 to 15
    mo (p = 0.0006), confirming our pre-clinical findings and
    the therapeutic potential of CQ in the treatment of EGFRvIII-expressing
    tumors."

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  2. Unknown1 February 2018 at 09:59

    Stephen, I recall discussing other studies that pointed to the effectiveness of Chloroquine in the case of EGFRvIII about 3 years ago now. Seems there is some pretty solid evidence for CQ with EGFRvIII tumors. Thank you for continuing to bring important studies to our attention!

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    Replies
    1. Stephen W1 February 2018 at 10:08

      Yes, this recent publication is showing the same clinical data that we were discussing several years ago. At that time it was unpublished, and finally it has been published.

      Delete
  3. Semyon18 June 2018 at 01:54

    1. As is now known, tumors with a mutation EGFRvIII use autophagy more for survival under stress, such as hypoxia and fasting and chloroquine is more effective in case of such a mutation.
    However, then what kind of survival method does the tumor use without EGFRvIII mutation?

    2. In this new study, chloroquine is proposed to be combined with calcium-mobilizing compounds.
    https://www.ncbi.nlm.nih.gov/pubmed/29902340
    Unfortunately, the full version of the study is not yet available through http://sci-hub.tw/
    It is interesting which calcium-mobilizing compounds can be used?

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    Replies
    1. Stephen W19 June 2018 at 15:58

      Autophagy is a mechanism used by all cells to promote survival under stress. It's just that EGFR+ tumor cells seem especially reliant on it.

      It's strange the article is "open access", yet there's no link given for the full PDF download.
      https://onlinelibrary.wiley.com/doi/10.1111/cas.13695

      In any event, the abstract makes it sound like nigericin is the calcium mobilizing compound.

      "Nigericin in combination with ATG5 deficiency synergistically suppressed spheroid formation by glioma cells in a manner mitigated by Ca2+ chelation or CaMKK inhibition, indicating that in combination with autophagy inhibition, calcium-mobilizing compounds contribute to efficient anti-cancer therapeutics."

      Delete
    2. Stephen W19 June 2018 at 16:00

      You can download the "supporting information", but not the study itself. I think this is an error by the journal to not provide a link to the PDF of the study.

      https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1111%2Fcas.13695&attachmentId=2218747904

      Delete

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