PMC7434092_01
Clinical response to panobinostat and palbociclib in H3.3-K27M mutated,
cyclin-dependent kinase 4 (CDK4)-amplified glioblastoma. (A) A 5-year-old
patient (PO-3151) with a history of unilateral thalamic glioblastoma underwent
partial resection and focal radiation. Sequencing of his tumor revealed
CDK4 amplification. (B) Loss of heterozygosity plot shows
one copy loss of TP53. (C) Somatic tumor mutations in H3F3A
K27M mutation and TP53 mutation and outlier expression (RNA) of
CDK4 were also seen. (D) Magnetic resonance imaging of the brain (T1 with
contrast) showed increase in size in enhancing mass after three cycles of
adjuvant lomustine (CCNU)/temozolomide. He was treated with the oral histone
deacetylase (HDAC) inhibitor panobinostat, with later addition of the CDK 4/6
inhibitor palbociclib. After 18 months of targeted therapy, magnetic resonance
imaging (T1 with contrast) showed 67% reduction in size of the lesion. TP53,
tumor protein 53; XRT, radiation.
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F2
Sequencing of his tumor revealed H3F3A K27M mutation, TP53 mutation and copy loss, and CDK4 amplification and outlier expression (all category III; Figs 2A to 2C). He has had an ongoing partial response now for 18 months (25 months from diagnosis; Fig 2D).
PMC7434092_02
Genomic landscape of high-risk pediatric and young adult patients with
brain tumors at diagnosis and recurrence. Activating DNA lesions (mutation,
amplification, or fusion) were seen in 19 tumors (48%), most frequently in the
mitogen-activated protein kinase signaling and mechanistic target of
rapamycin/phosphoinositide 3-kinase pathways. Tumor suppressor mutations or
deletions (germline and/or somatic) were seen in 32 tumors (80%), most
frequently in DNA damage or apoptotic signaling pathways. AT/RT, atypical
teratoid/rhabdoid tumor; DIPG, diffuse intrinsic pontine glioma; GBM,
glioblastoma multiforme; SNV, somatic nucleotide variant.
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F3
Activating alterations (mutation, amplification, or fusion) in platelet-derived growth factor receptor (PDGFR) or fibroblast growth factor receptor (FGFR) pathways was seen in nine (45%) of 20 glial tumors (Fig 3), which is higher than previously published in any of these tumor subtypes.