1. Molecular classification of glioblastoma
Understanding glioblastoma: where are we now?
Patient distribution in the G1-G7 molecular subgroups
Patient distribution in the G1-G7 molecular subgroups
We currently understand only the tip of the iceberg. We know how glioblastoma looks, i.e. the histology of the tumor, and we know gene mutations (identified through genomics). But this is not enough to understand how glioblastoma grows and invades the brain, and this is not enough to comprehensively classify the cases. The genetic informa
We currently understand only the tip of the iceberg. We know how glioblastoma looks, i.e. the histology of the tumor, and we know gene mutations (identified through genomics). But this is not enough to understand how glioblastoma grows and invades the brain, and this is not enough to comprehensively classify the cases. The genetic information is transmitted to RNA and proteins (comprehensively analyzed by transcriptomics and proteomics, respectively) that function in pathways directing cell growth and invasion. Only by integrating these genomic/transcriptomic/proteomic data with the demographic, radiologic and histologic information, we will be able to understand how glioblastoma develops and how to personalize patient treatment.
=> Integrated analysis is the future!
More on integrated analysis:
https://doi.org/10.3390/cancers16020361
Patient distribution in the G1-G7 molecular subgroups
Patient distribution in the G1-G7 molecular subgroups
Patient distribution in the G1-G7 molecular subgroups
By performing integrated analyses, two related growth pathways stood out and allowed the classification of all the glioblastoma tumors: the MAPK (mitogen-activated protein kinase) and the PI3K/PTEN (phosphatidyl-inositol-3 kinase) pathways. The starting point for both pathways is a cell membrane receptor called receptor tyrosine kinase (R
By performing integrated analyses, two related growth pathways stood out and allowed the classification of all the glioblastoma tumors: the MAPK (mitogen-activated protein kinase) and the PI3K/PTEN (phosphatidyl-inositol-3 kinase) pathways. The starting point for both pathways is a cell membrane receptor called receptor tyrosine kinase (RTK). There are many RTKs, but the most frequently activated in glioblastoma are EGFR, FGFR3, PDGFRA and MET, the latter being frequently co-activated with other RTKs, hence the G6/Multi-RTK subgroup. The RTK subgroups G1, G2, G5 and G6 make up over 50% of glioblastomas.
But not all glioblastomas signal through an RTK. About 30% activate the upper arm of the MAPK pathway immediately downstream of RTKs. These are the cases with NF1 and RAF mutations from subgroups G3 and G4. The G3/MMR (mismatch repair) spin-off branch of the G3/NF1 subgroup shows RAS activation in the context of MMR gene mutations, and these tumors are susceptible to immune checkpoint inhibitors. Roughly 20% of glioblastoma cases form the G7/Other subgroup and signal mainly through the PI3K/PTEN pathway.
Prognosis by molecular subgroup
Patient distribution in the G1-G7 molecular subgroups
Prognosis by molecular subgroup
Preliminary data on patient median survival:
- G1/EGFR: 11.3 months
- G2/FGFR3: 20 months
- G3/NF1: 10 months
- G3/MMR: 3.25 months
- G4/RAF: 5.3 months
- G5/PDGFRA: 10 months
- G6/Multi-RTK: 9 months
- G7/Other: 5.3 months
These survival differences prompt aggressive management for tumors from subgroups with poor survival, including identification of personalize
Preliminary data on patient median survival:
- G1/EGFR: 11.3 months
- G2/FGFR3: 20 months
- G3/NF1: 10 months
- G3/MMR: 3.25 months
- G4/RAF: 5.3 months
- G5/PDGFRA: 10 months
- G6/Multi-RTK: 9 months
- G7/Other: 5.3 months
These survival differences prompt aggressive management for tumors from subgroups with poor survival, including identification of personalized regimens for these patients. For example, the G3/MMR is a novel glioblastoma subgroup that may benefit from immune checkpoint inhibitors, whereas the G3/NF1 and G4/RAF subgroups may benefit from MAPK inhibitors.
More on the first all-inclusive molecular classification proposed by Dr. Georgescu:
https://doi.org/10.3390/cancers16020361
https://www.youtube.com/watch?v=6iQzC80CQ5k
https://doi.org/10.3390/cancers13184532
https://www.uni-muenster.de/Ejournals/index.php/fnp/article/view/5892/6271
2. Pediatric brain tumors: Pathways, Targets and Markers
New paradigms in diffuse midline glioma H3 K27M-mutant (DMG/K27M)
NHERF1: the most sensitive and specific maker for microlumen detection in ependymoma
Pathway analysis reveals new therapeutic targets in syndromic medulloblastoma
DMG/K27M is a glioblastoma-like brain tumor affecting children and showing the same dismal survival as glioblastoma in adults. A seminal autopsy study led by Dr. Georgescu contributed new pathogenetic concepts:
- genetic tumor predisposition
- patterns of tumor spread
- tumor multifocality demonstrating genomic&proteomic heterogeneity
- biopsy requi
DMG/K27M is a glioblastoma-like brain tumor affecting children and showing the same dismal survival as glioblastoma in adults. A seminal autopsy study led by Dr. Georgescu contributed new pathogenetic concepts:
- genetic tumor predisposition
- patterns of tumor spread
- tumor multifocality demonstrating genomic&proteomic heterogeneity
- biopsy requirements for accurate genomic assessment
- activation of a multitude of growth and invasion pathways
- RTK reprogramming as mechanism of drug resistance
Pathway analysis reveals new therapeutic targets in syndromic medulloblastoma
NHERF1: the most sensitive and specific maker for microlumen detection in ependymoma
Pathway analysis reveals new therapeutic targets in syndromic medulloblastoma
Watch the video to see how genetic and pathway analyses change the management in pediatric brain tumors and open new avenues for treatment:
NHERF1: the most sensitive and specific maker for microlumen detection in ependymoma
NHERF1: the most sensitive and specific maker for microlumen detection in ependymoma
NHERF1: the most sensitive and specific maker for microlumen detection in ependymoma
In 1997, Dr. Georgescu identified NHERF1 as an interactor of the PTEN tumor suppressor. She generated NHERF1 knock-out mice to study NHERF1 function. The animals developed hydrocephalus, which is a complication of pediatric brain tumors such as ependymoma and choroid plexus papilloma. Expanding the research to humans, she tested hundreds
In 1997, Dr. Georgescu identified NHERF1 as an interactor of the PTEN tumor suppressor. She generated NHERF1 knock-out mice to study NHERF1 function. The animals developed hydrocephalus, which is a complication of pediatric brain tumors such as ependymoma and choroid plexus papilloma. Expanding the research to humans, she tested hundreds of brain tumors and discovered that NHERF1 is the most sensitive and specific immunohistochemical marker for the diagnosis of ependymoma, a common tumor in children.
More on NHERF1 in brain tumors: