Saturday, 16 April 2016

What to avoid during stable period

Sorry for repeating my earlier question, but I thought a broader category would help get us talking. My question is whether anyone is aware of mechanisms of action of melatonin or metformin that might make them undesirable for a low grade oli with deletions to take during stable period (either them not being efficacious apart from cocktail or might exacerbate mutation)?

The larger topic is; What should be avoided during stable period that might exacerbate mutation?
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13 comments:

  1. Stephen W16 April 2016 at 10:55

    I think we should first distinguish between agents that damage DNA and can actually cause new mutations, especially in the absence of effective mismatch repair, such as temozolomide. Random mutations in mismatch repair genes (like MSH6) can turn TMZ into a strong mutagen.

    On the other hand, there are agents that don't physically cause new mutations to occur, but may exert a strong enough selection pressure to allow any random mutation that favors survival or treatment resistance to spread within the tumor cell population. I would put any strongly cytotoxic therapy (eg chemotherapy) in this category.

    I think there is far less chance of creating resistant subpopulations with more moderate therapies like metformin or melatonin.

    However, a tumor is a dynamic entity and will respond to any changes in its environment, so if any drug or therapy is creating a more hostile environment for the tumor, the tumor is likely to adapt to those new conditions over time.

    This adapatation is not necessarily based on genetic mutations, but may instead be based on epigenetic changes that influence gene expression, what proteins are being produced, and overall cell behaviour (phenotypic changes rather than changes/mutations in the genome).

    More to the point, I think more moderate therapies that strengthen the immune system (eg. melatonin), or cell differentiation strategies (eg retinoids, vitamin D), or metabolic strategies (eg. metformin, diet etc.) are appropriate during the stable period. But a more aggressive strategy is probably warranted in the case of higher grade tumors like GBM.

    As a rule, the harder you push, the harder the pushback will be in terms of tumor evolution and resistance. It is a continual, dynamic, evolutionary process, and as such it is difficult or impossible to create rules about what should be done or not done in terms of therapy. In theory the goal should be to have therapy be as adaptive as the tumor, although this is easier said than done, as it would involve much more detailed knowledge about how tumors adapt to each therapy or combination than currently exists.

    I'd recommend the work of Robert Gatenby for anyone wanting to follow up on these ideas in greater detail.

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    1. Danny Mercer17 April 2016 at 15:51

      Thanks Stephen. I guess I would put Curcumin in that same category. I know there is not a definitive answer, but, being stable I struggle balancing wanting to be proactive, yet not doing harm, and not wanting to waste limited monthly resources on supplements that have no discernible efficaciousness.

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    2. Matjaz18 April 2016 at 00:44

      Hello Danny,

      I also have/had low grade oligodendroglioma with full resection. For my "long term maintenance" I am taking metformin, omega 3, curcumin, PSK and also decided to give DCA a try (the plan is to take 200 grams and then stop). Also thinking about adding resveratrol.

      Best regards

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    3. Danny Mercer19 April 2016 at 18:36

      Unfortunately I didn't have a full resection. I think my next surgery will be better. I didn't go to a center of excellence with intraoperative MRI technology. After my surgery another surgeon on call wanted to do another surgery because MRI showed residual tumor, but my dr said no. I had some hemorrhaging and was out of it and not part of the deliberations.

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    4. Matjaz20 April 2016 at 03:05

      Where are you from if you don't mind me asking? I was operated on by dr. Duffau in Montpellier, France - even though I don't live in France I went there by car, because he is really good at what he does. So if you are from Europe, I highly recommend looking him up. There is also his retrospective study (mean follow up duration 11 years) in Stephen's library.

      Although I think they don't have intraoperative MRI. If possible he resects the tumor with some safety margin of healthy tissue around the tumor (tumor cells in low grade gliomas are often found in the margin 3cm from the tumor seen on MRI). The surgery is in awake state, so he can see when he gets close to centers for speech, movement,... and stops the resection there.

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  2. Stephen W16 April 2016 at 11:14

    Another important point is that using a single agent targeting a single pathway is much more likely to allow adaptive evolution in the tumor than a multiple agent, multiple-targeted approach. This is the foundation upon which the "cocktail approach" is built. See the "Nile Distributary Problem" discussed in the second CUSP9 publication (2014).

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    1. oldcookie4817 April 2016 at 22:38

      "I'd recommend the work of Robert Gatenby for anyone wanting to follow up on these ideas in greater detail."
      Stephen, I not familiar with this work. Can you send a link?
      Thanks, Candy

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    2. Matias18 April 2016 at 12:21

      I´m also interested, Steph! Thank you!

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    3. Stephen W18 April 2016 at 14:18

      One of Gatenby's most notable concepts is the idea of "adaptive therapy" in which the dose of chemotherapy varies according to how the tumor is responding. I've not seen this tried in humans, but it has been tried in mice. See for example one of their most recent publications:

      "Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer."

      http://www.ncbi.nlm.nih.gov/pubmed/26912903

      I will upload this to the library.

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    4. Stephen W18 April 2016 at 14:23

      I just created a "Robert Gatenby" folder in the library and uploaded the study. I will upload similar studies here soon.

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    5. Stephen W23 April 2016 at 21:41

      3 more Robert Gatenby papers uploaded to the Library

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  3. Anonymous17 April 2016 at 01:18

    Thank you. What do you guys think about PSK consumption (~3g/day) - on my bottle it says it's not recommended to consume this product on high dosages more than 3 continous weeks.
    Also I found a study http://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-8-78 which says PSK could be cytotoxic in vitro - but I guess in vitro dosage is hard to achieve in vivo so cytotoxicity shouldn't be the case but it works more as immunomodulator?

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  4. Stephen W17 April 2016 at 10:35

    Virtually anything can be cytotoxic if you boost the concentration high enough, and unfortunately most in vitro work that gets published uses concentrations of drugs/compounds that are far beyond what is achievable in the body.

    PSK is very well tolerated and there are numerous clinical trials carried out in Japan showing that. I think of it primarily as an immune modulator.

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