IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced

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

GBM suck up cholesterol

http://www.cell.com/cancer-cell/pdf/S1535-6108(16)30443-3.pdf

Any thoughts/further info on this method?

An argument against statin use for GBM

A new study by a joint team from UCLA, UCSD etc. has important implications for the use of statins as a repurposed GBM therapy.   The study shows that statins were selectively toxic to Normal Human Astrocytes, and relatively ineffective against two GBM cell lines (U87EGFRvIII, and GBM39 - a patient derived line with EGFR amplification and EGFRvIII expression).

This can be understood by the fact that normal astrocytes rely on de novo cholesterol synthesis, while GBM cells have much less reliance on cholesterol synthesis, but instead import cholesterol from the brain environment via low density lipoprotein receptors (LDLR), in a parasitic manner.  The study showed that GBM clinical samples have increased expression of LDLR and suppressed levels of enzymes involved in cholesterol synthesis.

A different strategy was found to be far more effective, which involved an experimental drug called LXR-623, an LXR-beta agonist.   In an orthotopic GBM mouse model this drug extended mouse survival significantly without toxicity in the healthy brain.  By stimulating LXR-beta, the drug suppresses LDL uptake into cells and increases cholesterol efflux from the cell, selectively depriving the GBM cells of cholesterol.  The drug is brain-penetrant and has already been in phase 1 safety and pharmacokinetic/pharmacodyamic trial with healthy volunteers.

As a non-approved drug, LXR-623 is not generally available to patients, but we hope to see a trial for GBM initiated based on this excellent preclinical work.

Study abstract:  An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers  (full study will be uploaded to the Library, folder 2)

News article:  Depriving Deadly Brain Tumors of Cholesterol May Be Their Achilles’ Heel