Identifying the mechanisms responsible for low- to high-grade transformation in IDH mutant astrocytoma

Background: IDH mutant (IDHmut) astrocytoma is an incurable brain cancer that typically presents as a low-grade lesion but high-grade transformation occurs uniformly, after which average survival is 2-years. There is a lack of understanding as to how this transformation occurs. The low-grade state provides a novel (and prolonged) therapeutic window that remains unexploited, currently.

IDH mutation causes 2-hydroxyglutarate production, inhibiting 2-oxoglutarate-dependent dioxygenases (2-OGDD) leading to hypermethylation (via TET inhibition), aberrant chromatin configuration, and oncogene activation. Little is known about how IDHmut affects other 2-OGDDs and subsequent transcription factor (TF) binding.

Hypothesis: Aberrant metabolism and 2-OGDD dysfunction dysregulate epigenomic/transcriptional networks causing high-grade transformation in IDHmut astrocytoma.

Aims: Aim 1: Map transforming IDHmut astrocytoma across human resection specimens High-grade IDHmut glioma contain significant co-existent areas of low-grade disease.

I reason that by looking ‘back in time’ from the high-grade regions, and sampling regions sequentially from this area, in multiple directions, we will map the molecular landscape of transformation ‘in reverse’ by layering different spatial and single cell -omic technologies.

My approach eliminates inter-patient variation (e.g. genomic/epigenomic differences), sampling bias (published literature explore primary/recurrent disease, with spatially incongruent regions compared) and treatment bias (intervening surgery, chemotherapy, radiotherapy).

We will perform: a) Multi-region mass spectrometry imaging (MSI) of sequential high to low-grade areas using ultra-rapid intraoperative freezing (