brain cancer

partial immunoprivilege in the brain

surveillance from periphery - can enter via specialised barriers
microglia
meningeal lymphatic drainage
BBB

medulloblastoma subtypes

wnt
sonic hedgehog
group 3
group 4

development of wnt medulloblastoma

rhombic lip progenitors generate granule neurone precursors
best prognosis
low mets
loss of ch6 and somatic mutations in beta catenin lead to constitutive wnt signalling

sonic hedgehog medulloblastoma development

granule neurone precursors expand rapidly in germinal layer
bimodal age distribution
driven by PTCH1, SUFU and SMO mutations

group 3 and 4 medulloblastoma development

arise from vestigial part of cerebellum but needs a second hit mutation to form tumour from vestigial pearl
chromosomal aberrations are early initiating event

wnt medulloblastoma - loss of chromosome 6

mis segregation
foxo3 TSG - regulator of stress responses and cell fate, KO in rhombic lip leads to tumour formation in hindbrain
loss - progenitors fail to exit early programming and remain proliferative and more likely to form a tumour, can’t regulate oxidative stress or DDR pathways

glioblastoma mutations

RTK signalling = EGFR amplification, PDGFR amplification
PI3K = PTEN loss, PI3KCA mutation
p53 mutation and MDM amplifications

glioblastoma IDH mutation status

IDH mutations arise form lower grade diffuse tumours - alters epigenetic state via Cpg hypermthylation, grows slower
IDH wt tumours have other mutations = TERT, EGFR, more aggressive, gain ch7, loss ch10

heterogeneity in glioblastoma

stem-cell like populations maintain by developmental TFs
tumour cells can transition between stem cell and differentiated state
CSCs present - targeted by SOX2 inhibition which improves survival in models

treatment of glioblastoma

alternative electric fields disrupt mitosis - use for newly diagnosed GBM
bivalent CAR-T cells targetign EGFR and IL-13R
oncolytic viruses - HSV-G47 agent achieved increased median survival in recurrent GBM