Preclinical Testing of Candidate Therapeutics in a Pediatric Spinal Cord High-grade Glioma Model

Background

Spinal cord high-grade gliomas (HGG) of childhood are rare and clinically devastating. Recent genomic studies have demonstrated that the majority of pediatric spinal cord HGG exhibit the H3K27M mutation (1, 2) that is characteristic of and specific to other HGG of the midline of the childhood central nervous system such as diffuse intrinsic pontine glioma (DIPG) and thalamic glioma (3, 4). While high-grade gliomas arising in different locations in the childhood central nervous system are developmentally and clinically distinct, this shared pathophysiology of the “oncohistone” H3K27M suggests that some therapeutic strategies may be applicable to all H3K27M HGGs. My laboratory, in collaboration with DIPG researchers internationally, recently completed a drug screen and subsequent preclinical validation to identify new therapeutic strategies for DIPG (5). We then brought a lead candidate from that study, panobinostat, to phase I clinical trial for children with DIPG (NCT02717455). We recently established neurosphere cultures of a pediatric spinal cord HGG expressing the H3K27M mutation.

Project Goals

In the present proposal, we seek support to test the leading therapeutic candidates identified in the drug screen for DIPG against this patient-derived H3K27M+ pediatric spinal cord HGG model.

Progress Reports and Updates

Project Update (January 2017)

Innovation Grantee Michelle Monje, MD, PhD, from Stanford University is studying a promising new therapeutic strategy for spinal cord high-grade gliomas, a type of childhood spinal tumor that is difficult to treat and often has a poor prognosis.

Surgery for patients battling spinal cord tumors is often impossible because of the critical structure of the spinal cord. In addition, samples from a biopsy are often only enough for a clinician to use to determine the diagnosis, with little left for research purposes. Recently, Dr. Monje’s lab received a donation of spinal cord high-grade glioma tissue samples from a family after their child had passed away. This profound and meaningful donation has provided Dr. Monje with enough samples to replicate, model and study this tumor in a way not possible before.

The donated spinal cord tumor exhibited a mutation, called H3K27M, that is also a characteristic of DIPG, a brain tumor that occurs in the pons (the area of the brain that houses the brain stem) and other midline childhood central nervous system tumors. Researchers study the genetic structure of cancer tumors to determine ways to attack the cancer. In 2016, the World Health Organization re-classified midline childhood central nervous system tumors that share the H3K27M mutation as one category of childhood cancer. This new group of tumors has the potential to be treated the same way.

Dr. Monje has been studying tumors with the H3K27M mutation for several years. She received an ‘A’ Award from ALSF in 2011, a grant that contributed to work published in a 2015 Nature Medicine paper and a current phase I clinical trial for Panobinostat. Panobinostat is an epigenetic modifying agent, a type of drug therapy that modifies the mutation and makes it less likely to cause cancerous cells to form and grow. Dr. Monje is leading this clinical trial at 10 institutions to determine a safe dosage of the drug for patients battling DIPG.

Dr. Monje will use the findings from her studies of DIPG to work toward breakthroughs in the treatment of spinal cord high-grade gliomas. Since both have the same H3K27M mutation, Dr. Monje believes that Panobinostat and other drugs found to hold promise for DIPG could be a potential therapies for patients battling spinal cord tumors.

During her current ALSF Innovation Grant, Dr. Monje will fully study the donated tumor--characterizing it molecularly, developing a model and using it to validate the possible therapeutic use of Panobinostat for spinal cord high-grade gliomas. If her findings do show promise, then the DIPG clinical trials could be expanded to include spinal cord patients, offering hope for patients who previously had few options.

“The amount of progress that has been made in the study of gliomas of childhood in the past 5 years, is more than has been made in the last 50. It is a really exciting moment of progress and hope,” said Dr. Monje.

Dr. Monje’s research was published in the May 8, 2017 edition of Nature Medicine. Read the article here.

Project Update (May 2020)

Because of their sensitive locations, diffuse midline gliomas (DMGs) are hard to remove surgically and often radiation is the only treatment. Children with these tumors urgently need more therapeutic options.

Dr. Michelle Monje’s recent Innovation Award established a patient-derived pediatric H3K27M-mutant spinal cord glioma model, which has been a previous limitation in being able to successfully study this disease. Having a dependable model system for the disease allowed her team to bring forward promising lead drug candidates studied in DMGs of the brain to those of the spinal cord. They found that pediatric spinal cord DMG responded similarly to the experimental therapies as did DMGs of the brain.

They studied two therapeutic approaches: a GD2-targeted CAR T cell therapy and a combination drug therapy of panobinostat and marizomib. Both therapies extended survival in their pediatric spinal cord glioma model system which has led to the initiation of two new clinical trials to study these encouraging new therapies in H3K27M-mutant gliomas.

Learn more about Dr. Monje’s work on high-grade gliomas in recent publications, “Therapeutic Strategies for diffuse midline glioma from high-throughput combination drug screening” and “Potent antitumor efficacy of anti-GD2 CAR T-cells in H3K27M+ diffuse midline gliomas”.

Institutions