Quick Summary: Defeat GBM-funded research finds that depriving tumor cells of cholesterol may be a useful clinical strategy to treat glioblastoma
The brain contains more cholesterol than any other organ, accounting for about 20% of the body’s total quantity of the molecule. When brain cells are healthy and functioning normally, the amount of cholesterol is tightly controlled. However, glioblastoma (GBM) cells become “addicted” to cholesterol and turn off the control system that typically limits cholesterol concentration in healthy cells.
A new study from Defeat GBM Research Collaborative principal investigator, Dr. Paul Mischel of Ludwig Cancer Research, shows how GBMs exploit the brains unique metabolism to import vast amount of cholesterol to feed their addiction, and, importantly, how attacking the mechanisms these tumors use to do so may halt this cancer’s growth.
Healthy levels of cholesterol are critical for brain cells, as the molecule is a major building block for cell membranes and other functions. But as every person learns early on in their health education, too much cholesterol is unhealthy. So, normal cells have a process to limit the amount of cholesterol they produce or import.
When ordinary cells have sufficient cholesterol they convert any excess into another molecule called “oxysterols.” Oxysterols travel to a cell’s nucleolus and bind to a protein called the “liver X receptor,” or “LXR.” LXR controls the production of cholesterol by stopping uptake and signaling for the excess to be transported out of the cell.
Dr. Mischel’s new study discovered that GBMs shutoff of import controls by suppressing the production of oxysterols, which ensures LXRs stay inactive (LXRs need oxysterols to bind to them to get activated).
“So when normal cells get enough cholesterol, they stop making it, stop taking it up and start pumping it out,” said Dr. Mischel. “We found that in GBM cells, this mechanism is completely disrupted…they steal cholesterol and don’t have an off switch. They just keep gobbling the stuff up.”
Dr. Mischel and colleagues at Ludwig Cancer Research then used a compound called LXR-623 that therapeutically activates LXRs. Importantly, Dr. Mischel and his team found that LXR-623 crosses the Blood-Brain-Barrier (BBB), which typically keeps most molecules out of the brain and thus far has been a major barrier to drug development in the neuro-oncology field. Further, when the drug was given to mice with GBM tumors – which were implanted from human patient tumor samples – their tumors shrank drastically and they lived considerably longer than mice with GBMs not given the drug.
“Disrupting cholesterol import by GBM cells caused dramatic cancer cell death and shrank tumors significantly, prolonging the survival of the mice,” said Dr. Mischel. “The strategy worked with every single GBM tumor we looked at, and even on other types of tumors that had metastasized to the brain. LXR-623 also had minimal effect on astrocytes or other tissues of the body.”
Dr. Mischel and the rest of the Defeat GBM Research Collaborative are now interested, and seeking, to use LXR-623, or other similar drugs that are in development, in early clinical trials to see if this strategy could ultimately be successful in treating human GBM patients.
The study was published in the current issue of the prominent biomedical research and scientific journal Cancer Cell. Other Defeat GBM researchers participated in the study, including Drs. Frank Furnari and Webster Cavenee (also from Ludwig Cancer Research) as well as Dr. Timothy Cloughsey of UCLA.
“This study demonstrates the innovative and ‘outside-the-box’ approaches that the brain tumor experts within the Defeat GBM Research Collaborative are taking to try and find solutions for glioblastoma patients who desperately need them,” said David F. Arons, Chief Executive Officer, National Brain Tumor Society. “This potential new treatment strategy is entirely novel and illustrates that this collaborative will leave no stone unturned in our quest to double the percentage of GBM patients who survive five years or more. We are very encouraged by this preclinical work, and hope we can help move this promising approach into the clinic in the very near future.”
Dr. Mischel’s work is unique in that, for years, drugs that were identified and considered for treating GBMs were selected based on analyses of the tumors’ genome – i.e. the identification of therapeutic targets based on mutated or altered genes that drive cancer, called “oncogenes.” And despite the landscape of oncogenes in GBM tumors being very well characterized, none of the targeted drugs that have been tested to-date have been successful in treating these patients. A major reason for these failures has been that most of the targeted cancer drugs have been developed without BBB-penetrability in mind and barely cross into the brain, thus reaching their target at sub-optimal, or sub-therapeutic, doses (or not reaching the actual target at all). This often leads to the tumor developing resistance to the drug’s intended effect. Dr. Mischel and his team hypothesized that since oncogenes can ultimately “rewire” or “reprogram” a cell’s underlying biochemistry, there could be certain other cellular molecules that – though not themselves altered or mutated – the tumor comes to depend on in order to maintain its growth. This is called “non-oncogene addiction,” “non-oncogene co-dependency” or “oncogene-induced dependency.” One type of co-dependency is specific to oncogenes that cause a reprogramming of tumor metabolism. And, since Dr. Mischel had previously observed that the most common oncogene found in GBMs – the EGFR gene – alters cells’ unique metabolism, the researcher surmised there could be a non-oncogenic metabolic co-dependencies in brain cancer. Such co-dependencies present an alternative approach to therapeutically target GBM tumors and broadens the range of drugs that could be used to treat the disease. Such drug candidates may be under development to treat other types of diseases, including central nervous system indications, where the compounds have been designed specifically to cross the BBB to reach their targets.