Autophagy is one of the most complex subjects in terms of tumor biology. For example, autophagy can be critical for immunogenic cell death, and knocking out autophagy genes can actually lead to worse survival when combined with radiation in an immunocompetent rodent model. http://www.nature.com/cdd/journal/v21/n1/full/cdd2013124a.htmlGoing further, how this all relates to the use of an autophagy inhibitor like chloroquine is quite uncertain, as the degree of autophagy inhibition in the tumor with oral chloroquine intake is likely partial and variable - clinical trials with hydroxychloroquine showed unreliable inhibition of autophagy in the tumor with tolerable doses. Chloroquine and derivatives also likely have a number of additional mechanisms of action, and studies that cleanly knock out autophagy with genetic manipulations can't really be extrapolated to available autophagy inhibitors, unless highly potent and precise autophagy inhibitors are developed.
It's a mixed bag, isn't it? One thing enhances autophagy and another inhibits it, both pointing to promising avenues in this fight. I find myself reading abstracts for hours on PubMed and SciFinder and sometimes I come away quite frustrated. Then, like you, I reach out to others for their opinions. I am so grateful to have found Stephen and this blog.I guess we should take the proof-in-the-pudding approach? Michael W., if you do try chloroquine and it shows promise, please post!
The wonderful/terrible thing about biology is its infinite complexity. You can always find a study to contradict the study you just finished looking at.Autophagy can be both a survival mechanism, or a precursor to cell death (autophagic cell death). Autophagy inhibitors and autophagy inducers can be therapeutic, depending on the context and combinations. I don't blame anyone for coming away from PubMed feeling frustrated. These papers are written for professionals not for the general public. It's only because standard of care is not satisfactory in this disease that we're forced to become independent researchers to some extent.
ABMy son has used chloroquine for about 18 months and we recently stopped. He went about 15 months before recurrence and now is on his second recurrence. Both his NO's call him an outlier. We are approaching 2 years since the GBM and 9 years since his lower grade Oligo 2 was resected. His recurrence is small but multifocal. We are in the middle of changing his cocktail approach, and prescribed treatment. His tumor is also IDH-1 mutated so how much of his"outlier" status is due to the cocktail or the IDH - 1 status is an unknown. Undoubtedly he has benefited from his mutation. We dropped chloroquine since there is some evidence that autophagy inhibition might interfere with artemether/artemisinin which he is now on.
I see. That does give reason to give chloroquine a second look, though. Docs tend to brush off anecdotal things like this, I know. How many times have I heard, "A population of one is not significant." ?? I don't see anecdotes and outliers as insignificant. I see them as sign posts, possibly pointing the way to something that should merit a second look. So thanks for your input. Much appreciated!