Read the August Brain Tumor Research Highlights Here.
Over the years, NBTS has given more than $32 million to brain tumor research projects. We’re very proud of the impact this funding has made in advancing the neuro-oncology field closer to better treatments and ultimately a cure. And while NBTS is currently focused on driving our flagship research projects – like the Defeat GBM Research Collaborative – forward, there also continues to be great scientific research efforts happening in the neuro-oncology field, en masse. This is critical, as no one researcher, one lab, or one institution can cure this disease alone. Below are highlights of some newly published research from the brain tumor scientific and medical community, compiled by NBTS Director of Research & Scientific Policy, Ann Kingston, PhD and NBTS Research Programs Associate, Amanda Bates. As September is Childhood Cancer Awareness Month, this edition focuses on three new pediatric brain tumor studies:
Common genetic variations in cell cycle and DNA repair pathways associated with pediatric brain tumor susceptibility: Adel Fahmideh, M., Lavebratt, C., Schüz, J et al (2016) Oncotarget. 7 (39), 63640-63650; DOI: 10.18632/oncotarget.11575 – link to paper
Brain tumors are the leading cause of cancer-related death in children. Relative to adults, there have not been a large number of studies of the underlying genetic factors that lead to pediatric brain tumors. It has been suggested that genetic variations in DNA repair, cell cycle, metabolism, and inflammation may lead to brain tumor susceptibility in children. This study looked at saliva DNA from 245 cases and 489 controls, ages 7-19, to study a number of gene sequence variations called single nucleotide polymorphisms (SNPs) in astrocytoma and non-astrocytoma types of tumors. The genes (68) that were targeted for study were selected because of their reported role in adult brain tumors.
Among the genes studied, several were identified as relating to pediatric brain tumor susceptibility: ERCC1, CHAF1A, XRCC1, EME1, ATM, GLTSCR1, and XRCC4. EGFR appears to be related to grade of pediatric brain tumors, and certain alternative forms of the EGFR gene (called alleles) seem to be related to decreased risk of pediatric brain tumors whereas ERCC1 variants may increase the risk of pediatric brain tumors. Changes in CHAF1A and XRCC2 are associated with risk specifically in astrocytoma, while EME1, ATM, GLTSCR1, and XRCC4 are associated with risk for non-astrocytoma subtypes. Many of the changes in the DNA repair pathways that are associated with risk in pediatric brain tumors are similar to those in adult brain tumors, suggesting some commonalities in the pathways in pediatric and adult brain tumors.
The authors of this paper did recognize that further study would need to be completed to validate these findings, as well as explore possible mechanisms for these susceptibilities and to investigate how gene-environment interactions may contribute to cause of pediatric brain tumors.
Medulloblastoma initiation and spread: where neurodevelopment, microenvironment and cancer cross pathways: Martirosian, V, Chen T, Lin M, Neman J. (2016) J. Neuro Res DOI: 10.1002/jnr.23917 – link to paper
Medulloblastoma is the most common type of malignant pediatric brain tumor. This review highlights the neurodevelopmental factors that affect medulloblastoma formation and spread, as well as the microenvironmental impact on medulloblastoma. Medulloblastomas are always found in the cerebellum, a part of the brain rich in neurotransmitters and growth factors. The review looks at research that describes the development of the cerebellum. This includes research that shows that in order for normal development of the cerebellum, strict regulation of the developmental mechanisms is necessary.
The review points out that evidence has shown that after birth, the cerebellum contains neural stem cells. Medulloblastoma cells have been shown to have a tendency to self-renew and form different tumor cell types. Depending on their expression of different receptor proteins, these cells have either a high tendency toward self-renewal or invasion. The review also emphasized the contribution of the epithelial–mesenchymal transition (EMT) to leptomeningeal dissemination and the spread of medulloblastomas. EMT is a process by which epithelial cells change their adhesion characteristics, and gain migratory and invasive properties to become mesenchymal stem cells which are multipotent stromal cells that can differentiate into a variety of cell types.
The authors of the review point out that by focusing research only on changes in the tumor, we may miss the contributions of neurodevelopment and brain microenvironment to the initiation and propagation of tumor growth. Therefore, by also studying neurobiology developmental process we can gain new perspectives in understanding medulloblastoma biology.
Next-generation personalized medicine for high-risk pediatric cancer patients – The INFORM pilot study: Worst BC, van Tilburg CM, Balasubramanian GP et al (2016) Eur J Cancer 65, 91-101 – link to paper
Until recently, the genetic underpinnings of many pediatric cancers were largely unknown. Large scale genomic and molecular sequencing efforts have identified a number of new potential therapeutic options. The ‘Individualized Therapy for Relapsed Malignancies in Childhood’ (INFORM) precision medicine study is a nationwide German program for children with high-risk relapsed/refractory malignancies, which aims to identify therapeutic targets on an individualized basis. This paper is a report of a pilot study that was carried out with 57 patients with a variety of childhood cancers including brain tumors in which comprehensive analyses were conducted to provide a molecular profile of each individual tumor, which was then assessed for clinical relevance by an expert panel. The whole process from sample delivery to molecular target report was completed in less than 4 weeks. Analyses were conducted on frozen material from a biopsy of the relapsed tumor rather than archived material (from initial diagnosis). The results support previous reports showing substantial spatiotemporal differences in the molecular profiles of multiple samples acquired from the same patient and underlines the need for tissue analysis of the most current tumor sample in order to base treatment decisions. Some of the specific molecular alterations were not restricted to individual tumors which underlines that an approach that includes different types of diagnostic entities will be necessary for prospective studies. Although not all tumors with a specific alteration will respond identically, this approach is a more rational way to identify biomarkers of efficacy than the traditional ‘one-size-fits-all’.
The group are also establishing analysis to investigate and predict individual drug response and toxicity profiles. Although gathering of detailed follow-up data was not the main aim of this pilot phase, for some patients, the INFORM pilot results influenced further treatment strategies, diagnosis and/or outcome, although for most, the impact on clinical course was not substantial.
To further expand knowledge on pediatric relapsed tumor biology, and increase the patient recruitment pool, the currently ongoing INFORM registry (the follow-up to the pilot phase; https://www.dkfz.de/en/inform/) will soon be open to several other countries. Trials with targeted drugs are also being designed as a second phase (INFORM2 trials).
Next month’s Brain Tumor Research Highlight’s blog will be a special edition, focusing on topics and key takeaways from the upcoming National Brain Tumor Society Scientific Summit.
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