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Saturday, 22 October 2016

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)

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6 comments:

  1. Stephen W23 October 2016 at 07:54

    This is great Steve, constructive and respectful criticism is always welcome.

    As far as lovastatin toxicity to normal brain, point taken. The concentrations used in the study (1-5 uM) are not actually achievable in the blood let alone the nervous system. In one pharmacokinetic study I looked at, Cmax after repeated doses of lovastatin was only 8.5 ug/L (which translates to 21 nM or 0.021 uM). Plamsa protein binding is at least 95% according to Drugbank, leaving very low nanomolar levels of free compound in the plasma, even at Cmax.

    So yes I'd agree that concentrations of the drug reaching the plasma are not actually cytotoxic, to healthy cells or cancer cells, but of course higher levels of the drug might accumulate in specific organs.

    I can't yet agree with your statement: "The evidence seems to show glioma cells are especially dependent on circulating LDL-cholesterol to function, whereas normal brain cells are not."

    A quote from the study itself seems to counter that. This comes from the introduction:

    "The brain, for instance, is the most
    cholesterol-rich organ of the body, containing approximately
    20% of total body cholesterol (Dietschy, 2009). 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"

    If this statement is true, it would imply that levels of circulating LDL make no difference as far as glioma therapy, since virtually all the cholesterol in the brain is synthesized de novo in the brain rather than taken up from the systemic circulation. It someone can prove that statement to be false, I'm willing to listen.

    I'm aware of the epidemiological evidence, but a single study is not usually enough to convince me. The conclusions often vary from study to study. If a number of studies concluded the same thing it would be more convincing.

    I've also aware of the animal study you referenced. In spite of the increased necrosis in the simvastatin treated animals, survival was not significantly prolonged. "Simvastatin did not provide an overall advantage in survival, tumor size or vascular density". This is not a good sign in an animal model, as mouse models often show exaggerated effects, and even studies showing pronounced survival benefits in mice often don't translate to humans.

    I remain open to the possibility that statins may be helpful as a glioma therapy. There are arguments for and against. I still feel the study in question is an argument against, based on the finding that clinical glioma samples have greatly suppressed levels of cholesterol biosynthetic enzymes, INCLUDING HMG-CoA reductase, which is the actual target of statins. Lowering circulating LDL is not likely to help, if it's true that glioma cells are simply parasitizing cholesterol produced locally.

    I'd be ready to change my opinion if any truly compelling evidence came into light. Likewise I wouldn't tell any GBM patient not to take statins. There's still the possibility of benefit. My bottom line is that I feel there are many drugs with superior evidence, including superior mouse evidence, and that one needs to prioritize based on current evidence. I also grant that everyone's standard of what constitutes convincing evidence will be different.

    Again, thanks for your comments Steve. I always look forward to reading yours.

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  2. SteveMDFP23 October 2016 at 08:12

    Thanks. You're probably right on all counts. I simply assumed that if glioma cells are deficient in synthesis of cholesterol, they were reliant on bloodstream source. The existence of the blood-brain barrier affects brain physiology in myriad ways. I have more reading to do. ;-)

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  3. Stephen W23 October 2016 at 08:46

    For what it's worth, one vitro study found that a 5 uM concentration of atorvastatin was actually counterproductive in cells with oncogenic IDH1 mutations, leading to increased production of the oncometabolite 2-hydroxyglutarate (2-HG). The relevance of this is uncertain though given achievable levels of atorvastatin in the blood plasma is in the low nanomolar range.

    https://www.ncbi.nlm.nih.gov/pubmed/27354064

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  4. Semyon27 May 2018 at 04:49

    Strangely, this small study (2017) indicates a relationship between elevated cholesterol and a better patient prognosis:

    http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=20730&path[]=66040

    "Patients with low total cholesterol level showed worse OS than those with high cholesterol level (total cholesterol level: <3.91 mmol/L vs. ≥3.91 mmol/L; median OS: 5.50 vs. 10.0 months, P =0.008) (Figure 1A). Patients with HDL cholesterol level <1.32 mmol/L had a median OS of 7.0 months, whereas patients with HDL cholesterol level ≥1.32 mmol/L presented with a median OS of 10.5 months (P =0.038) (Figure 1B). Patients with low LDL cholesterol level showed remarkably worse OS than those with high LDL cholesterol level (LDL cholesterol level: <1.84 mmol/L vs. ≥1.84 mmol/L, median OS: 5.0 vs. 10.0 months, P =0.002) (Figure 1C)."

    There are also other interesting findings:

    "...the proliferation and growth of glioblastoma cells might lead to uptake of cholesterol from the blood and result in a decrease in serum cholesterol level. In our study, low serum LDL cholesterol level remained an independent prognostic factor for poor OS in patients with glioblastoma. Thus, rapidly growing glioblastoma cells might take up circulating LDL cholesterol from the blood at a high rate, resulting in lower serum LDL cholesterol level."

    "...lower serum cholesterol level is reported to be associated with suppressed immune function. A study by Muldoon et al. [23] found that individuals with low cholesterol level have significantly fewer CD8+ cells, total T cells, and circulating lymphocytes, than those with high serum cholesterol level. Low serum cholesterol level may be related to a low serum antioxidant reserve, probably increasing susceptibility to oxidative stress."

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  5. Stephen W27 May 2018 at 10:43

    Thanks for the link Semyon. It will take further work to try to identify cause and effect relationships for these observations.

    "Thus, rapidly growing glioblastoma cells might take up circulating LDL cholesterol from the blood at a high rate, resulting in lower serum LDL cholesterol level."

    This theory may be a little controversial as it isn't clear how much LDL can cross the blood-brain barrier.

    On the one hand:

    "Lipoproteins in plasma transport lipids between tissues,
    however, only high-density lipoproteins (HDL) appear to
    traverse the blood–brain barrier (BBB); thus, lipoproteins
    found in the brain must be produced within the central
    nervous system."
    https://www.cell.com/trends/endocrinology-metabolism/pdf/S1043-2760(13)00172-0.pdf

    On the other hand there may be a mechanism for transporting LDL across the blood-brain barrier:

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2138047/
    A New Function for the LDL Receptor: Transcytosis of LDL across the Blood–Brain Barrier


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  6. Sahel25 February 2019 at 03:38

    You might have seen this study that discuses about the significance of choosing the right statin (pitavastatin according to them) and the right dosing...but I thought it worth to send it here.
    My father LDL drops from 77 mg/dl (in 28th of July, when the tumor was not wild) to 59 mg/dl last week. I dont know whether it is because of radio/chemotherapy or that it is a sign of progression...but I am afraid to mess around statin, especially after reading these topics. Anybody have any experience with this Pitavastatin and the dosage (I am not even sure if I can find this in Iran)

    http://sci-hub.tw/10.1016/j.ctrv.2018.06.010

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