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

Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?

This is a new paper (click here for abstract) brought to us by some of the same authors who earlier produced:

Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma

The group concluded:

"This secondary analysis of two large glioblastoma trials thus was unable to detect evidence for an association of the use of statins, ACEI or sartans with outcome in patients with newly diagnosed glioblastoma."

As with the previous study, there are some important caveats.  Some of the most intriguing data supporting the potential for angiotensin system blockers was in combination with bevacizumab:

Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab

It would have been interesting to look at outcomes in those using/not using ACE inhibitors or sartans in combination with bevacizumab, for example in the Avaglio and RTOG-0825 trials.

Angiotensin-II has been shown to increase tumor-promoting macrophages in preclinical models:

https://www.ncbi.nlm.nih.gov/pubmed/23333075

and these tumor-infiltrating myeloid cells may play a significant role in resistance to anti-VEGF therapies such as bevacizumab.

https://www.ncbi.nlm.nih.gov/pubmed/26404753

Simvastatin positive evidence in an orthotopic GBM model

The study is called MYC-regulated Mevalonate Metabolism Maintains Brain Tumor Initiating Cells

This study constitutes in my view the first solid evidence that statins could be useful in GBM therapy. In accordance with my research, simvastatin was the statin selected which has better blood-brain barrier abilities versus some other statins, for example atorvastatin (see figure below).  The drug in this study was injected intraperitoneally rather than given orally as would be the case in humans, but at least they used a brain-implanted (not subcutaneous flank-injected) model with relatively recently created GBM cell lines (rather than the ancient U87).

Figure above from the study Statins as Neuroprotectants: A Comparative In Vitro Study of Lipophilicity, Blood-Brain-Barrier Penetration, Lowering of Brain Cholesterol, and Decrease of Neuron Cell Death by Sierra et al. Journal of Alzheimer’s Disease 23 (2011) 307–318.

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

Ibuprofen and Care Oncology

Hi all,

My Mum was sadly diagnosed with Glioblastoma in July. I have been meaning to post her cocktail here and get involved in this blog, so bare with me, I plan to write a full post this weekend. This blog has been so helpful and Stephens website too so I am keen to start contributing.

I have an update from the COC (Care Oncology Clinic) in London. I went to speak with them yesterday. My Mum is seeing them and they have prescribed the four drugs for her on top of the standard treatment which is great. As I live in San Francisco I was unable to go with my Mum for her first appointment, but as I am over here in the UK for a few weeks I booked an appointment to go and speak with the Doctor there and ask my long list of questions.

One thing that I really wanted to share was that apparently there is a new form of Ibuprofen that is going to become available in the next few months that does not cause stomach irritation. The Doctor said that the COC will be looking at adding this to their list of prescribed medications. They have held off recommending it at the moment as it can cause stomach problems so with this new version they are hoping it will be a great addition to people fighting GBM.

I will let you know if I hear more and if they prescribe it to my Mum in a few months time.

The drugs they prescribe for GBM are Atorvastatin, Metformin, Mebendazole and Doxycycline and they all sound really worthwhile taking. They have been chosen by the COC as they seem to have the least side effects of all the potential complimentary drugs. I really recommend seeing these guys if you are in the UK or contacting them wherever you are in the world.

I will post Mums cocktail soon. She is keen to keep it as streamlined as possible and that is what we are trying right now.

All the best to everyone.

Alison

What about statins?

So my brothers tumor has high PKB/AKT . As far as I understood Ben states in his pdf that lovastatin can suppress the PKB/AKT. I noticed that somebody in this group is using statin but not with the temozolomide but with another chemo agent. What do you think about adding it to the mix? My brother does have a high cholesterol.