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 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.
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 the 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 the lead author. "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.
This study contributes to a growing body of research pointing to cholesterol interference as a promising new way to treat cancer. Moving forward, the team 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," the author 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.
https://www.eurekalert.org/pub_releases/2019-04/ru-nhf040419.php
https://www.rockefeller.edu/news/25535-new-hope-treating-childhood-brain-cancer/
https://www.pnas.org/content/early/2019/03/27/1820989116
Blocking cholesterol biosynthesis enzyme to treat childhood brain cancer
- 2,089 views
- Added
Edited
Latest News
TB blood test which could d…
By newseditor
Posted 27 Mar
Propionate supplementation…
By newseditor
Posted 27 Mar
Role of human Kallistatin i…
By newseditor
Posted 26 Mar
Addressing both flu and COV…
By newseditor
Posted 26 Mar
How the brain senses body p…
By newseditor
Posted 26 Mar
Other Top Stories
Trigger for Alzheimer's disease found!
Read more
People with anxiety show fundamental differences in perception
Read more
Genetically elevated 'good' cholesterol may actually be bad
Read more
Yoga improves quality of life in patients with atrial fibrillation
Read more
Protecting against oxidative damage and improving healthspan
Read more
Protocols
All-optical presynaptic pla…
By newseditor
Posted 23 Mar
Epigenomic tomography for p…
By newseditor
Posted 20 Mar
A mouse DRG genetic toolkit…
By newseditor
Posted 17 Mar
An optogenetic method for t…
By newseditor
Posted 13 Mar
Profiling native pulmonary…
By newseditor
Posted 08 Mar
Publications
Balancing neuronal activity…
By newseditor
Posted 28 Mar
OSBP-mediated PI(4)P-choles…
By newseditor
Posted 28 Mar
Integrated plasma proteomic…
By newseditor
Posted 27 Mar
APP antisense oligonucleoti…
By newseditor
Posted 27 Mar
Targeting Erbin-mitochondri…
By newseditor
Posted 27 Mar
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar