https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215606/#!po=0.595238
Has this been shared here yet?
The AKT/mTor pathway is related to glucose metabolism. 5- Fu is the chemo ancient used in the Tocagen trials which have had complete responses in all IDH1 patients. It’s probably safe to assume that these patients had IDH1 mutations.
It is also interested to me because I’ve been in contact with a number of IDH1 mut patients who are having good success with a keto diet. It was been a little counter intuitive since it’s said that IDHmut tumours use glutamine as their metabolic preference. I have read that rather than using glutamine to profilerate perhaps they use it to invade surrounding cells but this seems to have lost out in favourite of using it for their metabolism.
Maria
I wonder if we could deduct from this that Statins might work well for IDH1mut tumors, since my understanding is that these meds can target this pathway.
ReplyDeleteStatins target the enzyme HMG-CoA reductase, an important enzyme in the early stages of cholesterol synthesis. One might think this would work well for IDH mutants, in which many of the cholesterol biosynthetic enzymes are increased compared to IDH wild-type GBM.
DeleteHowever, one lab study showed that the use of high concentrations of atorvastatin (5 micromolar) caused a compensatory increase in SREBP2, a master regulator of fatty acid and cholesterol synthesis, which further led to increased IDH1 expression in mutant IDH1 cell lines, and increased 2-hydroxyglutarate production.
Source: Sterol Regulatory Element Binding Protein Regulates the Expression and Metabolic Functions of Wild-Type and Oncogenic IDH1.
https://www.ncbi.nlm.nih.gov/pubmed/27354064
The concentration of atorvastatin used in this study (5 micromolar or 5000 nanomolar) is overkill, since only 40 nanomolar is required to inhibit half the HMG-CoA reductase activity in human liver microsomes, and achievable plasma levels after repeated dosing are only ~ 100 nanomolar (total) to 2 nanomolar (free, unbound to plasma proteins). This means that the conclusions of this study are not necessarily applicable in the real world where statin concentrations would be much lower. It does show that unexpected feedback mechanisms could produce a result opposite of the one intended.