Fighting H3K27M Diffuse Glioma

Gunnar Heinrich Foundation

DMG Problem

Why is DMG such a Problem?

At present, we have no way to predict this cancer.

DMG brain cancer is not currently linked to specific genetic markers except for a couple of well-characterized syndromes that can predispose people to be more cancer prone in general (Li-Fraumeni, mismatch repair deficiency syndrome, Turcot syndrome, to name a few) are associated with high-grade glioma. In many cases, including Gunnar’s case, there is no reported association between a particular mutation/chromosomal abnormality and high-grade glioma. Detection of tumoral mutations are only possible after tumor diagnosis; we do not have genetic or blood tests for predicting children with an increased risk of developing high-grade gliomas, except in the known predisposition syndromes.

Children now diagnosed with DMG (and other childhood cancers) may be asked to participate in DNA sequencing [KidsCanSeq], as science has precious little data as of yet. We hope that in time more correlation will allow new advances in gene identification that recognize cancer predisposition. If unique genetic markers can be found, a screening protocol can be developed for newborn sequencing, which in turn could help identify children at risk for DMG.

Detection – No way to easily detect this cancer

You can not detect brain cancer from a blood test. The challenging issue with brain tumors in general is that brain cancer markers are not present in the blood, due to the tight blood-brain barrier. This feature of the immune system prevents pathogens, along with cancer markers, from crossing from spinal fluid into the bloodstream. It is not like most cancers in that detection is only achievable through imaging. A fully sedated MRI for a child is not something a parent undertakes lightly, nor is it a conventional procedure performed during Pediatrician visits. Typically, kids only get an MRI if there is severe cause for neurologic concern such as seizures, unexplained dizziness and incoordination, recurring debilitating headaches or other indicators. With DMG, this means the cancer has likely already started to spread and is the cause for loss of function. It’s almost impossible to get a very young child to tell you they have headaches. There’s simply very little warning of this aggressive cancer growing in your child. Normally patients and families don’t find out until it’s really too late to do much, or enjoy the remaining time they have with their child.

Even if the cancer is detected early in its progression, monitoring progression is also difficult as MRI is not something that can be done regularly due to inherent risks. New techniques are being studies that include feasibility of detecting circulating tumor DNA or urine proteins, but as mentioned, these don’t currently work with brain cancer and are unlikely to help in the next 50 years.

Methylation profiling performed on tumor tissue is an exciting new area of research and may be a useful genomic tool in the near future. It adds a more sophisticated level of testing that would potentially lead to epigenetic therapy (treatment that reverses or restores broad and complex multiple regulatory mechanisms of gene expression), as compared to the current targeted drug approach that only inhibits/promotes 1 specific genetic pathway (drug X inhibits pathway Y). Methylation profiles are now routinely done on the research side of multiple tumors, but the technology (takes about 2-3 weeks from testing to results) and cost are preventing the real-time application to real-world treatment, but this barrier should be overcome in the next 4-5 years. It also has the added advantage of detecting a tumor-specific methylation signature, such that it can be used as a diagnostic tool (signature X means that you have a brain tumor, and Y means that you have a breast cancer, etc.). Use of this technique is still in its infancy in identifying brain cancer, again, due to difficulty detecting brain tumor DNA circulating in the bloodstream.

Treatment or Prevention – No prevention, no treatment and certainly no cure

Several areas of research are concerned with understanding tumor mechanisms and characterizing the genomic and epigenetic features of DMG in order to understand how potential differences in the DMG immune microenvironment could influence treatment efficacy.

Collecting live and post mortem tumor tissue is a critical element in these studies. Correlating DNA sequencing is also hoped to be helpful in characterizing these tumors.

Unfortunately, there aren’t any targeted or effective therapy for these midline diffuse high-grade gliomas with H3K27M mutation. Given that more than 50-60% of these tumors presumably have this driver mutation, many teams of researchers are actively searching for treatment strategies. The current standard of care for DMG is resection (surgical removal, if possible), radiation and chemotherapy. There are clinical trials, but none that show promise.

Currently brain tumor research is under-funded. The public remains unaware of the magnitude of this disease.

Less than 4% of NIH/NCI’s budget is directed at childhood cancer research with a miniscule fraction of these funds being utilized for targeted children’s brain tumor research.

Only 2 new treatments for brain tumors have been approved in the past 25 years. There are over 126 different types of primary brain tumors, which complicates the development of effective treatments.
The cure rate for brain tumors is significantly lower than that for other types of childhood cancer.

Private institutions, foundations and concerned individuals are the only ones that can move the needle. In Gunnar’s memory, it our goal to provide much-needed data for current and future researchers. We hope that one day physicians, researchers and the general public look back at this cancer the way we moderns look back at small pox; a beaten disease, largely eradicated, and generally confined to history books.

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