These data will provide evidence for the genetic drivers of functional diversity in
subclonal populations on DIPG and point to the prioritisation of specific somatic
variants as relevant for therapeutic targeting versus those that may be functionally
redundant. This work will begin in the first 12 months, but will only be completed within
a proposed second year of this project.
The ultimate aim of this work is to use our increased functional understanding of the
heterogeneity within DIPG to devise novel therapeutic strategies which aim to exploit
the evolutionary dynamics of these tumours. Functionally relevant mutations present
in all tumour cells may be predicted to be a more advantageous target than those
present only in selected subclones. By building up a phylogenetic tree of branching
evolution, we will identify these 'trunk' and 'branch' variants in the primary tumour16
and select functionally relevant mutations for which targeted agents are available for
future in vitro drug efficacy studies. Although the variants found only in subclonal
populations may not be thought of as driving the tumour as a whole, phenotypic
convergence may occur where distinct subclonal populations independently acquire
distinct mutations in the same gene 15,18
. We have preliminary evidence for this in
DIPG, where we have observed different regions of the same tumour to harbour one
or other activating PIK3CA mutations, an observation recapitulated in vitro, whereby
cells acquire a distinct mutation from that present in a subclone of the original tumour.
Thus these data will answer fundamental questions of how best to target the
evolutionary processes at play.
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