In terms of mRNA expression, IDHmutant gliomas tend to have much higher expression of many enzymes involved in cholesterol biosynthesis, as well as higher expression of LXR-beta, compared to IDH non-mutant GBM. This suggests that inhibiting cholesterol biosynthesis could be a better strategy than an LXR-beta agonist for low grade IDHmut gliomas.
However, the actual target of statins, HMG-CoA reductase, or HMGCR, is approximately equally expressed in IDH1 mutant gliomas and IDH non-mutant GBM. In my mind the potential role of statins for either of these glioma types is still not well established.
Are you saying that reducing cholesterol levels might be beneficial for LGG? I was just reading studies on the Ketogenic diet which would/could increase cholesterol. Some people say they have success eating vegan, mostly raw. Perhaps that is why?
I just wanted to chime in about the Keto Diet. I have been digging into it for the past few months and have even done a 1 month 'trial' to see what it takes to implement it. Lets just say it was pretty unpleasant and very hard to achieve the target glucose levels from the studies.
In general the science on it is complicated and poorly proven so far. Plus there are some definite 'zealots' around it that publish rather overstated claims and untested theories.
Also for Oligo our tumor metabolism is quite different from GBM and many other cancers that are discussed around keto diet. It does have a bit more hope of benefit though in combination with radiation, but even that is only tested in mice and has some complicating data (some indication it may reduce mutant IDH1 activity and thus reduce NAD+ depletion which would reduce radiation sensitivity).
I'm going to continue looking into though and will share any useful findings.
I'm not saying that exactly, because as it explained in the study the cholesterol in the bloodstream doesn't really have access to the central nervous system and most of the cholesterol in the brain is synthesized there locally by astrocytes.
"However, the brain cholesterol pool is virtually separate from cholesterol metabolism in the periphery. Because cholesterol cannot be transported across the blood-brain barrier into the CNS, almost all brain cholesterol is synthesized de novo. Astrocytes synthesize the majority of brain cholesterol from glucose, glutamine, or acetate-derived acetyl-coenzyme A (CoA) and supply cholesterol to neighboring cells, including neurons"...
The problem with trying to inhibit cholesterol biosynthesis directly in the brain is that healthy cells depend on this process as well. "The brain, for instance, is the most cholesterol-rich organ of the body, containing approximately 20% of total body cholesterol", and cholesterol obviously has an important role in the healthy brain.
My guess would be that statins haven't shown that much overt toxicity in the nervous system because high enough concentrations haven't been achieved to really affect cholesterol synthesis in the brain. If such concentrations were achieved, it would probably be toxic to the healthy brain as well and not just the glioma cells, given the importance of cholesterol to the healthy brain.
Okay. I'm trying to understand this part of your statement: This suggests that inhibiting cholesterol biosynthesis could be a better strategy than an LXR-beta agonist for low grade IDHmut gliomas.
I made that statement without having any particular therapy in mind. It would be a great strategy if they could figure out a way to target cholesterol synthesis only in the glioma and spare the healthy brain.
For GBM, the LXR-beta agonist drug described in the study seems promising.
I'm trying to understand why this was an exciting discovery in 2016? It seems researchers have been on this for a while so what happened in 2016 to change this info? NBTS says: Researchers at Ludwig Cancer Research, San Diego – funded through NBTS’ Defeat GBM Research Collaborative – discovered, how glioblastoma (GBM) tumors exploit the brain’s unique metabolism to import vast amounts of cholesterol, creating a dependency, and, importantly, how attacking the mechanisms these tumors use to do so may halt this deadly cancer’s growth.
As far as I know the specific strategy of using an LXR-beta agonist to target cholesterol use in GBM is a fairly recent discovery. Have you seen any research on this prior to the 2016 publication in Cancer Cell?
http://btcocktails.blogspot.ca/2016/10/an-argument-against-statin-use-for-gbm.html
ReplyDeleteThank you.
ReplyDeleteIn terms of mRNA expression, IDHmutant gliomas tend to have much higher expression of many enzymes involved in cholesterol biosynthesis, as well as higher expression of LXR-beta, compared to IDH non-mutant GBM. This suggests that inhibiting cholesterol biosynthesis could be a better strategy than an LXR-beta agonist for low grade IDHmut gliomas.
ReplyDeleteHowever, the actual target of statins, HMG-CoA reductase, or HMGCR, is approximately equally expressed in IDH1 mutant gliomas and IDH non-mutant GBM. In my mind the potential role of statins for either of these glioma types is still not well established.
Hi Stephen,
ReplyDeleteAre you saying that reducing cholesterol levels might be beneficial for LGG? I was just reading studies on the Ketogenic diet which would/could increase cholesterol. Some people say they have success eating vegan, mostly raw. Perhaps that is why?
Hi Maria,
DeleteI just wanted to chime in about the Keto Diet. I have been digging into it for the past few months and have even done a 1 month 'trial' to see what it takes to implement it. Lets just say it was pretty unpleasant and very hard to achieve the target glucose levels from the studies.
In general the science on it is complicated and poorly proven so far. Plus there are some definite 'zealots' around it that publish rather overstated claims and untested theories.
Also for Oligo our tumor metabolism is quite different from GBM and many other cancers that are discussed around keto diet. It does have a bit more hope of benefit though in combination with radiation, but even that is only tested in mice and has some complicating data (some indication it may reduce mutant IDH1 activity and thus reduce NAD+ depletion which would reduce radiation sensitivity).
I'm going to continue looking into though and will share any useful findings.
I'm not saying that exactly, because as it explained in the study the cholesterol in the bloodstream doesn't really have access to the central nervous system and most of the cholesterol in the brain is synthesized there locally by astrocytes.
ReplyDelete"However, the brain cholesterol pool is virtually separate from cholesterol
metabolism in the periphery. Because cholesterol cannot be transported across the blood-brain barrier into the CNS, almost all brain cholesterol is synthesized de novo. Astrocytes synthesize the majority of brain cholesterol from glucose, glutamine, or acetate-derived acetyl-coenzyme A (CoA) and supply
cholesterol to neighboring cells, including neurons"...
The problem with trying to inhibit cholesterol biosynthesis directly in the brain is that healthy cells depend on this process as well. "The brain, for instance, is the most cholesterol-rich organ of the body, containing approximately 20% of total body cholesterol", and cholesterol obviously has an important role in the healthy brain.
My guess would be that statins haven't shown that much overt toxicity in the nervous system because high enough concentrations haven't been achieved to really affect cholesterol synthesis in the brain. If such concentrations were achieved, it would probably be toxic to the healthy brain as well and not just the glioma cells, given the importance of cholesterol to the healthy brain.
https://www.hindawi.com/journals/cholesterol/2012/292598/
Okay. I'm trying to understand this part of your statement: This suggests that inhibiting cholesterol biosynthesis could be a better strategy than an LXR-beta agonist for low grade IDHmut gliomas.
DeleteI made that statement without having any particular therapy in mind. It would be a great strategy if they could figure out a way to target cholesterol synthesis only in the glioma and spare the healthy brain.
DeleteFor GBM, the LXR-beta agonist drug described in the study seems promising.
Hi again, Stephen,
ReplyDeleteI'm trying to understand why this was an exciting discovery in 2016? It seems researchers have been on this for a while so what happened in 2016 to change this info? NBTS says: Researchers at Ludwig Cancer Research, San Diego – funded through NBTS’ Defeat GBM Research Collaborative – discovered, how glioblastoma (GBM) tumors exploit the brain’s unique metabolism to import vast amounts of cholesterol, creating a dependency, and, importantly, how attacking the mechanisms these tumors use to do so may halt this deadly cancer’s growth.
As far as I know the specific strategy of using an LXR-beta agonist to target cholesterol use in GBM is a fairly recent discovery. Have you seen any research on this prior to the 2016 publication in Cancer Cell?
DeleteI thought I did today. At least studies mentioning both cholesterol and LXR but I guess I'm not certain now.
Delete