Summary: DIPG cancer cells exposed to MI-2 fail to maintain healthy levels of cholesterol and die quickly, by inhibiting lanosterol synthase. Additionally, while MI-2 destroys glioma cancer cells, the drug does not damage healthy brain cells.
Source: Rockefeller University
There could be new treatments on the horizon for diffuse intrinsic pontine glioma, or DIPG, a devastating form of brain cancer that afflicts young children and is currently incurable. Recent experiments in animal models of the disease have identified an experimental drug that effectively destroys DIPG cells. And a team of Rockefeller scientists just figured out how this promising compound works.
The research, described in Proceedings of the National Academy of Sciences, shows that the drug acts on cellular cholesterol pathways, and suggests that these pathways may be fruitful targets for treating a variety of brain cancers.
DIPG tumors are located in the pons, a highly sensitive structure that connects the brain to the spinal cord. Surgical removal of tumors is effectively impossible since it poses the risk of fatal brain damage. And although radiation can be used to temporarily reduce symptoms, the cancer inevitably grows, with an average survival rate of less than one year. Which is to say: there is a pressing need for new ways to treat children with the disease.
An auspicious development came in 2014 from a collaboration between the labs of C. David Allis, the Joy and Jack Fishman Professor, and Viviane Tabar, Chair of the Department of Neurosurgery at Memorial Sloan Kettering Cancer Center (MSKCC). The team showed that a compound known as MI-2 stops tumor growth in a mouse model of DIPG. The drug was already on scientists’ radar for the treatment of leukemia, and was known to work on leukemia cells by interacting with menin, a protein that regulates gene expression. So when Allis’ team began investigating the effect of MI-2 on DIPG cells, they initially suspected that it would work in a similar manner.
“Our first hypothesis was that the drug switched off genes by interacting with menin,” says Richard Phillips, a neuro-oncologist at MSKCC and a visiting fellow in the Allis lab who spearheaded this effort. “But as we probed a little bit further, many of the things that we would expect to see didn’t pan out.”
For example, when the researchers genetically removed menin from glioma cells, those cells remained sensitive to MI-2, indicating that the compound exerted its effects via a pathway distinct from that observed in leukemia. The scientists then discovered that DIPG cells exposed to MI-2 failed to maintain healthy levels of cholesterol, and quickly died; but the cells could be rescued with a dose of supplemental cholesterol–suggesting that, in the case of glioma, MI-2 works by depleting the nutrient. Eventually, the researchers discovered that MI-2 directly inhibits lanosterol synthase, an enzyme involved in cholesterol production.
The researchers also found that, while MI-2 destroys glioma cells, the drug doesn’t damage normal brain cells. This finding is consistent with other research showing that some cancer cells are particularly vulnerable to cholesterol disturbances.
Building better drugs
This study contributes to a growing body of research pointing to cholesterol interference as a promising new way to treat cancer. Moving forward, Phillips and his colleagues hope to develop compounds that are optimized for targeting brain cancer. As a starting point, they are studying a number of cholesterol-reducing compounds that are already on the market.
“Some existing drugs, initially made for people with high cholesterol, were designed to target lanosterol synthase–but they were never really thought of as cancer drugs,” he says. “One of them is even more potent than MI-2, so we’re now working with a team of chemical biologists to see if we can modify the drug so that it reaches the brain.”
More broadly, this research highlights the importance of knowing not just that a drug works, but how it works. In this case, the discovery that MI-2 acts on lanosterol synthase revealed that DIPG tumors are sensitive to cholesterol interference–a finding that opens avenues for the production of even more effective compounds.
Says Phillips: “You can’t assume that what it says on the label is actually how a drug works.”
Katherine Fenz – Rockefeller University
The image is credited to Laboratory of Chromatin Biology and Epigenetics at The Rockefeller University.
Original Research: Closed access
“Target identification reveals lanosterol synthase as a vulnerability in glioma”
Richard E. Phillips, Yanhong Yang, Ryan C. Smith, Bonne M. Thompson, Tomoko Yamasaki, Yadira M. Soto-Feliciano, Kosuke Funato, Yupu Liang, Javier Garcia-Bermudez, Xiaoshi Wang, Benjamin A. Garcia, Kazuhiko Yamasaki, Jeffrey G. McDonald, Kivanç Birsoy, Viviane Tabar, and C. David Allis. PNAS published ahead of print March 28, 2019 doi:10.1073/pnas.1820989116
Target identification reveals lanosterol synthase as a vulnerability in glioma
Diffuse intrinsic pontine glioma (DIPG) remains an incurable childhood brain tumor for which novel therapeutic approaches are desperately needed. Previous studies have shown that the menin inhibitor MI-2 exhibits promising activity in preclinical DIPG and adult glioma models, although the mechanism underlying this activity is unknown. Here, using an integrated approach, we show that MI-2 exerts its antitumor activity in glioma largely independent of its ability to target menin. Instead, we demonstrate that MI-2 activity in glioma is mediated by disruption of cholesterol homeostasis, with suppression of cholesterol synthesis and generation of the endogenous liver X receptor ligand, 24,25-epoxycholesterol, resulting in cholesterol depletion and cell death. Notably, this mechanism is responsible for MI-2 activity in both DIPG and adult glioma cells. Metabolomic and biochemical analyses identify lanosterol synthase as the direct molecular target of MI-2, revealing this metabolic enzyme as a vulnerability in glioma and further implicating cholesterol homeostasis as an attractive pathway to target in this malignancy.