Monday, 14 November 2016

*Sirolimus and Hydroxychloroquine with TMZ increases survival to a 28 month minimum*

I came across this study and the results looked very promising in comparison to standard of care alone for GBM.  However, the sample size is very small and not statistically significant.  With that said, I still think these results are hard to ignore.  Especially since only 3 of 20 patients used this combination and the minimum survival time of the 3 was 28 months. (this individual also had dosage reduced because of grade 2 fatigue so there may be some dosage dependance)

Results: The median survival time of the 20 patients was 13.7 months (range: 2.2 to 37 months). Surprisingly, the 3 patients who received sirolimus and HCQ as an add-on treatment survived for a longer period of time (median 34 months). Transient grade 3 myelotoxicity and grade 2 fatigues were rapidly resolved by treatment interruption or dose reduction.

These patients were much older so would we interesting to see how this therapy would work in younger patients with stronger immune systems.

From Kwan-Hwa Chi, MD in an email to me: " this regimen works better in mesenchymal type of GBM, the worst prognosis one and multiple recurrent case."

See the below link to investigate

Sirolimus and Hydroxychloroquine as an Add-On to Standard Therapy for Glioblastoma Multiforme: Case Report

15 comments:

  1. I agree these results are hard to ignore. Given the longer-term survival of these 3 patients, I would have liked to see a much more detailed description including MGMT status, EGFR status etc., but alas there is no genetic information given. Their ages were 71, 62, and 69, making IDH1 mutation rather unlikely.

    Patient 3 died at 28 months from diagnosis, and the other two patients seem to have been without disease progression at 34 and >36 months from diagnosis. It would have been fairer to say median survival wasn't reached at a median follow-up time of 34 months (median survival can't be determined when 2 of 3 patients are still alive without progression).

    I'm inclined to believe that this treatment regimen is superior to standard of care for some subgroup of patients. Without any genetic info on these patients (MGMT, EGFR, PTEN etc.) that is a matter of speculation. I would have expected more genetic information to be available for three patients diagnosed in 2013.

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    1. I contacted the authors based in Taiwan to see is they had any genetic information. Hopefully they'll reply.

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    2. From Kwan-Hwa Chi, MD in an email to me: " this regimen works better in mesenchymal type of GBM, the worst prognosis one and multiple recurrent case."

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  2. And special thanks to Michael for bringing this study to our attention. Oddly, it doesn't seem to be on pubmed.

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  3. Interesting. Thanks Michael for sharing. Can someone help me understand the difference between Hydroxy Chloroquine and Chloroquine phosphate? I give my husband chloroquine phosphate since HCQ was not proven to be effective in a previous study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4203513/

    Thanks
    Noha

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    1. Chloroquine and hydroxychloroquine are nearly identical, except for the hydroxyl group (one atom each of hydrogen and oxygen) tagged onto the end in the case of hydroxychloroquine. Because of this very minor molecular difference "Hydroxychloroquine is more polar, less lipophilic, and has more difficulty diffusing across cell membranes."

      I wouldn't recommend changing to hydroxychloroquine if you're already using chloroquine. Chloroquine may be superior anyway because of the pharmacokinetics properties quoted above.

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    2. The phosphate part of chloroquine phosphate is relatively unimportant. Most drugs as consumed are in the form of a salt [in the technical sense of the term "salt", not necessarily containing sodium]:

      chloroquine phosphate, hydroxychloroquine sulfate, sildenafil citrate, metformin hydrochloride etc, etc.

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  4. Thanks Stephen .. Really appreciate the help.
    Noha

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  5. 1. Everolimus and Temsirolimus are analogues of Rapamycin (Sirolimus).

    Because the results of the studies showed poor efficacy of Everolimus and Temsirolimus (https://clinicaltrials.gov/ct2/show/results/NCT00553150 and https://www.ncbi.nlm.nih.gov/pubmed/27143690), can a combination of Rapamycin + Сhloroquine phosphate add to the cocktail?

    Adding these drugs to the cocktail looked promising, but now I doubt it.

    Or to make a decision about their addition, it is necessary to conduct a specific genetic study?

    2. What kind of research can determine the type of glioblastoma?
    Since according to the message above this combination works better in the mesenchymal type of GBM.

    3. What reasons can there be for this combination to use Hydroxychloroquine in place of Сhloroquine phosphate?

    https://www.omicsonline.org/open-access/sirolimus-and-hydroxychloroquine-as-an-addon-to-standard-therapy-for-glioblastoma-multiforme-case-report-2167-7956-1000141.pdf

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    1. I feel that the combination of rapamycin + chloroquine could be effective due to synergy. The fact that a drug does not add to survival when used in isolation doesn't mean it is useless in a cocktail. This realization is at the heart of combination schemes ("cocktails") such as CUSP9, etc. Sometimes a two (or more) drug combo can be effective where none of the drugs would have much effect in isolation.

      Rapamycin is an mTOR inhibitor. mTOR complex 1 is a node in one of the most common upregulated signaling pathways in GBM and other cancers: Receptor tyrosine kinases (for example EGFR) -> PI3K -> AKT -> mTOR -> protein translation and increased cell proliferation. (This is an extremely simplified version and only shows a small fraction of the proteins involved in this very complex pathway). Genetic testing could reveal common mutations such as EGFR or PIK3CA, but mTOR could be upregulated even in the absence of these mutations.

      2. The mesenchymal type is one of the three transcriptional subclasses of GBM (the others being proneural and classical. there is some evidence showing the "neural" subtype is really just the signature of healthy brain in samples with a low proportion of tumor cells). Assigning a tumor to one of these subclasses involves measuring the levels of mRNA for each gene ("gene expression profiling"). This is typically done in academic labs, and I'm not sure if there are any companies offering this as a commercial service (I haven't looked into it).

      3. The main reason I can think of is that hydroxychloroquine is easier to find and more commonly used for malaria. Chloroquine may actually be the better choice but some have used hydroxychloroquine rather than chloroquine in their cocktails simply because chloroquine was more difficult to obtain. The main clinical evidence for the use of these drugs for GBM were the clinical trials in Mexico which used chloroquine and not hydroxychloroquine.

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  6. My mom is now taking Avastin + Chloroquine 250mg/day.
    We are thinking about adding Rapamycin 2mg/day.

    I found this study:

    2017 https://www.ncbi.nlm.nih.gov/pubmed/28812437
    "Antiangiogenesis with bevacizumab, an antibody against vascular endothelial growth factor (VEGF), has been used for devascularization to limit the growth of malignant glioma. However, the benefits are transient due to elusive mechanisms underlying resistance to the antiangiogenic therapy. Glioma stem cells (GSCs) are capable of forming vasculogenic mimicry (VM), an alternative microvascular circulation independent of VEGF-driven angiogenesis.
    ...We found that rapamycin increased the number of vasculogenic mimicry (VM) and enhanced KDR/VEGFR-2 phosphorylation. Treatment with chloroquine, or knockdown of the autophagy gene ATG5, inhibited the formation of VM and KDR phosphorylation in GSCs."

    Stephen, how would you interpret it? I can not understand.

    I'm not sure, will there be any benefit from adding Rapamycin to Avastin+Chloroquine a month after chemoradiotherapy with a large residual tumor?

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    1. Vasculogenic mimicry is a way for tumor cells to "modify their morphology to form a network of fluid-conducting tubular structures, establishing an angiogenesis-independent alternative perfusion pathway into the tumor"
      https://www.nature.com/articles/s41598-017-07622-w

      The role of rapamycin in this study is as an inducer of autophagy: rapamcycin inhibits mTOR and causes metabolic stress in the cells, to which they respond with autophagy (digesting intracellular structures in order to increase nutrient supply). They found that vasculogenic mimicry was autophagy-dependent, and by blocking autophagy either pharmacologically (with chloroquine) or genetically (knocking down ATG5) they could inhibit VM.

      I'm not sure there would be any benefit from adding rapamycin either, but that is the nature of the cocktail approach: one is never sure if any individual addition is going to help or not.

      There was a phase 1 study testing rapamycin + BEV in advanced cancers:
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116678/

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    2. I, like many inspired this report (link above) about cases with the use of Chloroquine + Rapamycin. And since the dose 2mg / day of Rapamycin is low, and the side effects are controlled, I considered its addition ..
      But now I'm not sure (
      As I read, at the moment there is a study of this combination + TMZ (the link could not find).

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    3. The main rationale for combining rapamycin with chloroquine in the Chi 2016 case series, was to cause metabolic stress with rapamycin, and then deactivate the resistance mechanism (autophagy) with chloroquine. In the study, they called this the "autophagy paradox". Autophagy is often a resistance mechanism when cells are under stress, and chloroquine is one way to deal with that resistance.

      Avastin itself can increase tumor hypoxia, to which the cells react by increasing autophagy as a survival/resistance mechanism. That is also the rationale for combining Avastin with chloroquine.

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    4. One of the studies considers the issue of inhibition autophagy/mTOR (that can be realized with Chloroquine + Rapamycin):
      2015 https://www.ncbi.nlm.nih.gov/pubmed/26022108

      "Since the aggressiveness and lethality of GBM is defined by local invasion and resistance to chemotherapy, we believe that our evidence provides a further rationale for including autophagy/mTOR-based targets in the current therapeutical regimen of GBM patients."

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