Understanding differences within brain tumours to find common weaknesses

Dissecting spatiofunctional heterogeneity in the DNA damage response of glioblastoma to establish common therapeutic vulnerabilities

Official title: Dissecting spatiofunctional heterogeneity in the DNA damage response of glioblastoma to establish common therapeutic vulnerabilities
 
Lead researcher: Mr Ola O. Rominiyi
Where: Sheffield
When: 2021-2024
Funding awarded: £17,990
Research type: pre-clinical, glioblastoma

Background to the project

Patients with a glioblastoma normally have surgery to remove as much of the tumour as possible, followed by radiotherapy and chemotherapy to tackle any cancer cells left behind. Unfortunately, survival rates continue to be poor. Although these treatments work by damaging the DNA of cancerous cells, within every tumour there are groups of difficult-to-treat cancer cells which have different levels of treatment resistance based on their location.

In this project we plan to use a 'neuronavigation' system typically used by surgeons to sample different geographical locations of a tumour (such as ‘dark tumour core’ or ‘oxygen rich area near a blood vessel’).

In the laboratory, these samples can be processed to ‘grow’ the cells from each of these areas of the tumour and compare their properties. Our aim is to establish how spatially-separated groups of difficult-to-treat cells find different ways to survive current treatments, and if there is a common weakness that can be used to tackle all difficult-to-treat cells simultaneously to yield better patient survival rates.
 
Why this research is needed

Glioblastoma is the most common brain cancer and contributes to approximately 190,000 deaths globally each year. Difficult-to-treat cells (or 'cancer stem cells') have been shown to have unlimited potential to multiply and can repair DNA damage caused by radiation and chemotherapy more quickly. However, our recent work suggests not all cancer stem cells are created equal. Rather, different groups of these cells within the same tumour can respond differently to therapy. This can make treating glioblastoma almost like trying to treat multiple different types of cancer in the same person and may explain why many promising treatments from the laboratory fail to improve survival for patients.

By linking location to function and treatment resistance, our studies should be able to find new, more effective treatment strategies that overcome the complex therapy-resistant landscape these tumours present.

Methodology

We have developed a safe, practical way to sample cells from different locations within a single tumour. We then 'grow' these cells within traditional 2D and customised 3D 'scaffolds' to create a ‘model’ of the various regions inside a single glioblastoma tumour.

By comparing how these models respond to DNA damage using detailed molecular and genetic testing, our studies will provide new insight into how glioblastoma cells in different locations survive treatment. By searching for a common weakness shared by cells from all regions of a tumour, then testing new treatments that target these particular DNA repair processes, we will identify new strategies to tackle the complexity of glioblastoma. We believe this work will help fast-track new treatments into the clinic to improve survival rates for future patients.