Animal study shows depriving deadly brain cancer of cholesterol kills tumour cells.


Adult brain cancers are almost always universally fatal, due in part to the biochemical composition of the central nervous system and the blood-brain barrier, which selectively and protectively limits the passage of molecules from the body into the brain, and also blocks most existing chemotherapies, contributing to treatment failure.  Glioblastomas (GBMs), the most common and most aggressive form of brain cancer, are extremely difficult to treat. The median survival rate is just over 14 months, with few treated patients living five years or more past diagnosis.  Now, a study from researchers led by the University of California San Diego shows that depriving these deadly brain cancer cells of cholesterol, which they import from neighbouring healthy cells, specifically kills tumour cells and caused tumour regression, prolonging survival in mouse models.  The team state that their findings present a potential alternative method for treating GBMs.  The study is published in the journal Cancer Cell.

Earlier studies from the lab show that GBM cells cannot synthesize cholesterol, instead, GBM cells derive what they need from brain cells called astrocytes, which produce cholesterol in abundance. Roughly 20% of total body cholesterol is found in the brain.  When normal cells have sufficient cholesterol, they convert some of it into molecules called oxysterols, which activate a receptor in the cell’s nucleus, the liver X receptor (LXRs), to shut down the uptake of cholesterol.  So when normal cells get enough cholesterol, they stop making it, stop taking it up and start pumping it out.  The current study shows that in GBM cells, this mechanism is completely disrupted, with GBM cells acting like parasites of the brain’s normal cholesterol system; they steal cholesterol and don’t have an off-switch.

The current study shows that GBM cells ensure their cholesterol supply by suppressing the production of oxysterols, ensuring cells’ LXRs remain inactive.  The team also identifies an experimental metabolic disease drug candidate named LXR-623 that activates LXRs.  Results show that LXR-623 easily crossed the blood-brain barrier to bind with LXRs in normal cells, stimulating the production of oxysterols and the reduction of cholesterol.  Data findings show that there was no effect upon healthy brain cells, however, GBM cells were deprived of vital cholesterol, resulting in cell death and tumour regression.

The team surmise their findings suggest that disrupting cholesterol import by GBM cells causes dramatic cancer cell death and shrinks tumours significantly, prolonging the survival of the mice.  They go on to add the strategy worked with every single GBM tumour they looked at and even on other types of tumours that had metastasized to the brain; LXR-623 also had minimal effect on astrocytes or other tissues of the body.  For the future, the researchers state that their GBM strategy could be implemented in clinical trials using drug-candidates under development or in early trials.

Source: University of California San Diego School of Medicine

Recurrent glioblastoma multiforme (GBM) in a 55-year-old man before and after hypofractionated stereotactic radiotherapy by intensity modulated radiation therapy (HS-IMRT). Before HS-IMRT, two enhanced lesions (long and short arrow) were demonstrated in the left temporal lobe on T1-weighted magnetic resonance imaging (A). 11C-methionine positron emission tomography (MET-PET) demonstrated a MET high-uptake on the region of short arrow, which was defined as the Gross Tumor Volume (red line) (B). 5 months after HS-IMRT, there was no tumor recurrence on the lesion (long arrow, C &D). The enhanced lesion (short arrow) was increased in size (C), although MET uptake decreased relative to normal tissue, which suggested a necrotic change in the irradiated region (D). The patient had no neurologic deficits or quality of life issues. KPS was 90%.   Re-irradiation of recurrent glioblastoma multiforme using 11C-methionine PET/CT/MRI image fusion for hypofractionated stereotactic radiotherapy by intensity modulated radiation therapy.  Iwama et al 2014.

Recurrent glioblastoma multiforme (GBM) in a 55-year-old man before and after hypofractionated stereotactic radiotherapy by intensity modulated radiation therapy (HS-IMRT). Before HS-IMRT, two enhanced lesions (long and short arrow) were demonstrated in the left temporal lobe on T1-weighted magnetic resonance imaging (A). 11C-methionine positron emission tomography (MET-PET) demonstrated a MET high-uptake on the region of short arrow, which was defined as the Gross Tumor Volume (red line) (B). 5 months after HS-IMRT, there was no tumor recurrence on the lesion (long arrow, C &D). The enhanced lesion (short arrow) was increased in size (C), although MET uptake decreased relative to normal tissue, which suggested a necrotic change in the irradiated region (D). The patient had no neurologic deficits or quality of life issues. KPS was 90%. Re-irradiation of recurrent glioblastoma multiforme using 11C-methionine PET/CT/MRI image fusion for hypofractionated stereotactic radiotherapy by intensity modulated radiation therapy. Iwama et al 2014.

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