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Section 2: Executive Summary

Diffuse intrinsic pontine glioma are high grade glial tumours arising in the brainstem

with a median survival of 9-12 months, and a distinct biology compared to similar

looking tumours arising in the cerebral hemispheres in children and adults. A major

challenge to improve outcomes for these tumours is their extensive intratumoral

heterogeneity, reflected by differing cellular morphologies and genomic imbalances

present within an individual sample. We aim to define the subclonal diversity of DIPG

with a view to better understanding the evolutionary dynamics underlying this

variation. Firstly, we will use high-depth sequencing to explore the subclonal

architecture of a series of DIPG specimens. We will generate direct evidence of

subclonal diversity by longitudinal studies of biopsy/autopsy pairs for which multiple

topographically distinct samples are available post-mortem. We will further explore the

functional consequences of this heterogeneity by studying single cell-derived colonies

derived from primary tumour specimens in vitro, using advanced high-throughput

image analysis linked to targeted resequencing. The long-term goal of such an

approach is to provide a framework for preclinical testing of evolutionary biologydriven combinatorial

therapies, and to generate data to underpin novel, rationally

designed clinical trials in these currently untreatable diseases.

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