Award Title: High-grade glioma treatment design through mapping spatial differences in the DNA damage response of cancer stem cells
Funder: The Academy of Medical Sciences

Abstract: These studies aim to develop surgically-relevant preclinical models of glioblastoma which reflect the spatial intratumoural heterogeneity of parental tumours to help understand why certain tumour regions may be more resistant to current treatment, and design new targeted combination therapies to overcome this resistance.

Objectives:
1) Generate and characterise spatially-defined preclinical models of glioblastoma using MRI-guided intra-operative neuronavigation.

2) Validate the extent to which cultured glioblastoma stem cell (GSC) models reflect GSCs within their native microenvironmental niches using single-cell RNA sequencing (scRNAseq).

3) Confirm spatially-defined GSC models can be used to characterise subclonal differences in the DDR of cells from the same tumour and design targeted treatment combinations with pan-tumour efficacy.

Glioblastoma is the most common brain cancer and contributes to ~190,000 brain tumour related deaths/year globally. These tumours demonstrate extraordinary intratumoural heterogeneity, however increasing understanding of genetic diversity within tumours has not yet led to improvements in patient survival. Despite surgical resection followed by DNA damaging radiotherapy and temozolomide chemotherapy, average survival remains close to one year. Critically, tumours harbour difficult-to-treat subpopulations of GSCs, which possess unlimited regenerative potential and enhanced DNA repair capabilities. However, our early data suggests GSCs from spatially-distinct tumour regions exhibit divergent responses to DNA damage. Consequently, we anticipate the spatially-defined models proposed here will be transformational in understanding how spatial variation impacts resistance to current DNA damaging treatments functionally, and this will allow us to rationally design new targeted treatment combinations with pan-tumour efficacy.

Lay Abstract: Patients with a glioblastoma normally have surgery followed by radiotherapy and chemotherapy to tackle cancer cells left behind. Unfortunately, despite these treatments, average survival remains close to 1 year. Chemo- and radiotherapy work by damaging the DNA of cancerous cells. But within every tumour there are various groups of difficult-to-treat cells which have different treatment resistance properties based on their location.

During operations to remove a brain tumour, surgeons typically use neuronavigation to cross-reference their exact location with a patients MRI scan. In the proposed studies we will use this ‘GPS-for-brain-surgery’ to sample different geographical locations of a tumour. In the laboratory these samples can be processed to grow the cells from each of these areas within a single patient’s tumour and compare their properties. Our aim is to understand how separate groups of difficult-to-treat cells find different ways to survive current treatments.

By comparing how these groups of cells respond to DNA damage using detailed molecular and genetic testing, our studies will provide new insight into how they survive treatment. We will search for a common weakness or Achilles’ heel in DNA repair processes shared by cells from all regions of a tumour, then through testing  treatments that target these particular weaknesses, we will identify new ways to tackle the treatment resistance often observed in glioblastoma. The studies should provide ways to kill different groups of difficult-to-treat cells in all parts of a tumour simultaneously leading to better patient survival rates in the future.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS