High-grade glioma (HGG), the most common and deadly type of brain cancer, affects both adults and children. Patients with HGG have a 5-year survival rate of 10% with standard therapy. Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive form of pediatric HGG that is almost universally fatal. While recent studies have dramatically improved our understanding of the mechanisms employed by HGG to grow and invade, this knowledge has only marginally improved patient outcomes over the past 50 years. Given this dismal progress, new therapies for HGG and DIPG are urgently needed.
Approaches such as whole genome sequencing, next-generation sequencing, single cell sequencing, epigenetic analysis and the development of patient-derived cell lines have helped identify the key oncogenic signalling pathways that drive the tumorigenicity of HGG. These approaches have also highlighted the heterogeneity observed in HGG across patients and even within a single patient. Indeed, HGG genetic evolution is highly branched, both before and after treatment, leading to a range of cellular clones with differing genetic mutations. The impact of these different mutations also depends on the cell of origin; the same genetic mutation produces a different cell phenotype in oligodendrocyte lineage cells compared to neural stem cells. This extraordinarily complex heterogeneity means that efficacious treatments for HGG will require combinations of therapeutics or completely new approaches.
A unique feature of neural cells is their high degree of plasticity, a trait that allows them to adapt to changes in their environment. This ability allows them to function in processes such as memory formation or injury response. There is growing recognition of the plasticity nature of HGG cells. In particular, the local tumor environment is now known to have a major impact on the phenotype of the HGG cells. There are several well-defined sub-types of HGG, but as the microenvironment around a HGG cell changes (e.g. as a cell invades a surrounding area) it can freely swap between the sub-types. Furthermore, the microtumor environment can cause glioma stem cells to transition between stem and differentiated states. This plasticity of HGG cells, on top of the heterogeneity, makes it even more challenging to develop new therapeutic approaches for its treatment.
This Research Topic aims to show how the insights gained from over a decade of genetic analysis can be used develop new therapeutic strategies for the treatment of adult and pediatric HGG. This includes the identification of novel therapeutic targets and the development of new drugs, especially those that cross the blood brain barrier. There will be two areas of special interest: 1) HGG heterogeneity and 2) HGG plasticity. Articles that provide new insights into these biological phenomena and how they contribute to therapeutic resistance will be particularly welcome. We will receive Original Research, Clinical Reports, Reviews, Perspective and Opinion articles, focusing on these and related areas:
• Genomic and expression analysis of HGG (including ependymoma) that provide new insights into its tumorgenicity
• Novel therapeutic targets expressed in HGG
• The development of drugs that cross the blood brain barrier
• Insights into the mechanisms that drive HGG plasticity
• The challenge of overcoming HGG heterogenicity therapeutically
High-grade glioma (HGG), the most common and deadly type of brain cancer, affects both adults and children. Patients with HGG have a 5-year survival rate of 10% with standard therapy. Diffuse Intrinsic Pontine Glioma (DIPG) is an aggressive form of pediatric HGG that is almost universally fatal. While recent studies have dramatically improved our understanding of the mechanisms employed by HGG to grow and invade, this knowledge has only marginally improved patient outcomes over the past 50 years. Given this dismal progress, new therapies for HGG and DIPG are urgently needed.
Approaches such as whole genome sequencing, next-generation sequencing, single cell sequencing, epigenetic analysis and the development of patient-derived cell lines have helped identify the key oncogenic signalling pathways that drive the tumorigenicity of HGG. These approaches have also highlighted the heterogeneity observed in HGG across patients and even within a single patient. Indeed, HGG genetic evolution is highly branched, both before and after treatment, leading to a range of cellular clones with differing genetic mutations. The impact of these different mutations also depends on the cell of origin; the same genetic mutation produces a different cell phenotype in oligodendrocyte lineage cells compared to neural stem cells. This extraordinarily complex heterogeneity means that efficacious treatments for HGG will require combinations of therapeutics or completely new approaches.
A unique feature of neural cells is their high degree of plasticity, a trait that allows them to adapt to changes in their environment. This ability allows them to function in processes such as memory formation or injury response. There is growing recognition of the plasticity nature of HGG cells. In particular, the local tumor environment is now known to have a major impact on the phenotype of the HGG cells. There are several well-defined sub-types of HGG, but as the microenvironment around a HGG cell changes (e.g. as a cell invades a surrounding area) it can freely swap between the sub-types. Furthermore, the microtumor environment can cause glioma stem cells to transition between stem and differentiated states. This plasticity of HGG cells, on top of the heterogeneity, makes it even more challenging to develop new therapeutic approaches for its treatment.
This Research Topic aims to show how the insights gained from over a decade of genetic analysis can be used develop new therapeutic strategies for the treatment of adult and pediatric HGG. This includes the identification of novel therapeutic targets and the development of new drugs, especially those that cross the blood brain barrier. There will be two areas of special interest: 1) HGG heterogeneity and 2) HGG plasticity. Articles that provide new insights into these biological phenomena and how they contribute to therapeutic resistance will be particularly welcome. We will receive Original Research, Clinical Reports, Reviews, Perspective and Opinion articles, focusing on these and related areas:
• Genomic and expression analysis of HGG (including ependymoma) that provide new insights into its tumorgenicity
• Novel therapeutic targets expressed in HGG
• The development of drugs that cross the blood brain barrier
• Insights into the mechanisms that drive HGG plasticity
• The challenge of overcoming HGG heterogenicity therapeutically
