An important new clue for preventing and treating gliomas has been identified in research published in the journal Science, providing a rare window into the biological changes behind glioma development.
In animal models, a team of researchers from Mayo Clinic and Mount Sinai Hospital found that those with a change in DNA known as germline alteration rs55705857 developed gliomas much more frequently and twice as fast compared to animal models without the alteration. In addition to brain tumours, the findings are relevant to other cancers and diseases.
“While we understand much of the biologic function of germline alterations within genes that code for proteins, we know very little about the biologic function of germline alterations outside of genes that code for proteins. In some way, these germline alterations interact with other mutations in cells to accelerate tumour formation,” said co-lead author Robert Jenkins, MD, PhD. “Based on this new understanding of its mechanism of action, future research may lead to novel and specific therapies that target the rs55705857 alteration.”
The study offers new knowledge that may help clinicians determine, pre-surgery, whether a patient has a glioma.
“We expected that rs55705857 would accelerate low-grade glioma development, but we were surprised by the magnitude of that acceleration,” said co-lead author Daniel Schramek, PhD.
There are many alterations, likely thousands, outside of genes associated with the development of cancer and other diseases, but the mechanism of action is only understood for very few, Dr Schramek said.
This study demonstrates that, with the tools of modern molecular/cell biology, it is possible to decipher much of the mechanism of action of such alterations.
A new study reveals why people with asthma seem to be less likely to develop brain tumours than others.
Asthma causes T cell activation, and researchers discovered in a mouse study that asthma causes the T cells to behave in a way that induces lung inflammation but prevents the growth of brain tumours.
The findings, appearing in Nature Communications, suggest that reprogramming T cells in brain tumour patients to act more like T cells in asthma patients could be a new approach to treating brain tumours.
“Of course, we’re not going to start inducing asthma in anyone; asthma can be a lethal disease,” said senior author David H. Gutmann, MD, PhD, at Washington University School of Medicine. “But what if we could trick the T cells into thinking they’re asthma T cells when they enter the brain, so they no longer support brain tumor formation and growth? These findings open the door to new kinds of therapies targeting T cells and their interactions with cells in the brain.”
Based on epidemiologic observations, 15 years ago it was first proposed that people with inflammatory diseases, such as asthma or eczema, are less prone to developing brain tumours. However, there was no explanation for the link between the two very different kinds of diseases, and some scientists questioned whether the association was real.
Gutmann is an expert on neurofibromatosis (NF), a set of complex genetic disorders that cause tumours to grow on nerves in the brain and throughout the body. Children with NF type 1 (NF1) can develop an optic pathway glioma, where tumours grow within the optic nerves. Gutmann, director of the Washington University NF Center, noted an inverse association between asthma and brain tumours among his patients more than five years ago but didn’t know what to make of it. When more recent studies from his lab began to reveal the crucial role that immune cells play in the development of optic pathway gliomas, he began to wonder whether immune cells could account for the asthma–brain tumour link.
Jit Chatterjee, PhD, a postdoctoral researcher and the paper’s first author, took up the investigation. Working with co-author Professor Michael J. Holtzman, MD, Dr Chatterjee studied mice genetically modified to carry a mutation in their NF1 genes and form optic pathway gliomas by three months of age.
Dr Chatterjee exposed groups of mice to asthma-inducing irritants at age four weeks to six weeks, and treated a control group with saltwater. Then, he checked for optic pathway gliomas at three months and three months of age. The mice with asthma did not form these brain tumours.
Further experiments revealed that inducing asthma in tumour-prone mice changes the behaviour of their T cells. After the mice developed asthma, their T cells began secreting decorin, a protein that asthma researchers are well acquainted with.
Decorin is a problem in the airways, acting on lining tissues and exacerbating asthma symptoms. But the researchers found that in the brain, decorin is beneficial. There, the protein acts on microglia immune cells, blocking their activation by interfering with the NFkappaB activation pathway. Activated microglia promote brain tumour growth and development.
Treatment with either decorin or caffeic acid phenethyl ester (CAPE), a compound that inhibits the NFkappaB activation pathway, protected mice with NF1 mutations from developing optic pathway gliomas. The findings suggest that blocking microglial activation may be a potentially useful therapeutic approach for brain tumours.
“The most exciting part of this is that it shows that there is a normal communication between T cells in the body and the cells in the brain that support optic pathway glioma formation and growth,” said Prof Gutmann. “The next step for us is to see whether this is also true for other kinds of brain tumours. We’re also investigating the role of eczema and early-childhood infections, because they both involve T cells. As we understand this communication between T cells and the cells that promote brain tumours better, we’ll start finding more opportunities to develop clever therapeutics to intervene in the process.”
In a pre-clinical study, investigators identified a vulnerability in a developmental signaling pathway that can be hijacked to drive paediatric low-grade glioma (pLGG) formation.
The study, published in Developmental Cell, demonstrated that targeted treatment prevents tumor formation, long before irreversible damage to the optic nerve can cause permanent loss of vision. This finding will inform chemo-prevention therapeutic trials in the future.
Brain tumours are the most common solid tumours in children, the most prevalent of which are pLGGs, of which 10 to 15% arise in patients with the familial cancer predisposition syndrome known as neurofibromatosis type 1 (NF1). Thi increases risks of developing tumours along the nerves and in the brain.
Almost 20% of children with NF1 develop pLGGs along the optic pathway, also known as NF1-associated optic pathway glioma (NF1-OPG). Despite many advances in cancer therapy, there are no definitive therapies available that prevent or alleviate the neurological deficits (i.e. vision loss) and that could improve the quality of life.
“The evidence presented can inform chemoprevention therapeutic trials for children with NF1-OPG. This therapeutic strategy may also be applicable to children with the developmental disorders that are at high risk of developing pediatric tumors, such as other RASopathies,” said Yuan Zhu, PhD, scientific director and Gilbert Family Endowed professor at the Gilbert Family Neurofibromatosis Institute and associate director of the Center for Cancer and Immunology Research.
The mechanism of vulnerability to pLGGs during development is not fully understood. It could be that the cell population of origin for this debilitating tumour is transiently proliferative during development. The NF1 gene produces a protein that inhibits MEK/ERK signalling, thereby helping regulate normal cell proliferation, survival and differentiation. With loss of NF1 function, it abnormally activates the MEK/ERK signalling pathway, leading to tumour formation.
Certain transient cells present during development of the brain and optic nerve are vulnerable to tumour formation because they depend on MEK/ERK signalling. Researchers identified cells dependent on the pathway and grew during a transient developmental window as the lineage-of-origin for NF1-OPG in the optic nerve. They then used a genetically engineered pre-clinical model to design a transient, low-dose chemo-preventative strategy, which prevented these tumours entirely.
“When we provided a dose-dependent inhibition of MEK/ERK signaling, it rescued the emergence and increase of brain lipid binding protein-expressing (BLBP+) migrating GPs glial progenitors, preventing NF1-OPG formation,” the researchers wrote. “Equally importantly, the degree of ERK inhibition required for preventing NF1-OPG formation also greatly improved the health and survival of the NF1-deficient model.”
Clinical trials using MEK inhibitors (MEKi) are underway for children as young as 1 month old, making the design of a chemo-preventative trial using a MEKi to treat children with NF1 more feasible. This treatment approach might not only prevent OPG formation, but also other NF1-associated and RASopathies-associated developmental defects and tumours.
