3D models to understand invading GBM cells

Fast facts

• Official title: Ex-vivo 3D models of post-surgical residual disease in glioblastoma to improve biological understanding and treatment
• Lead researcher: Mr Ola Rominiyi
• Where: Sheffield Teaching Hospitals NHS Foundation Trust
• When: March 2020 – December 2022 
• Cost: £120,000 
• Research type: Adult, Glioblastoma (High Grade), Academic, Treatment resistance
• Grant round: Expanding theories

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What is it?

This innovative research project will develop a new 3D model of glioblastoma (GBM) for lab assessments. The researchers, based in Sheffield, will also use the model to prioritise some of the best potential drugs to enhance current therapies.

GBM tumours are highly invasive and researchers have long suspected that the GBM cells that are left behind after surgery (residual cells) behave differently to those that are removed with the bulk of the tumour mass (resected cells).

Usually, when someone has surgery for a GBM, the surgeons take out as much of the tumour as possible while leaving the rest of the surrounding brain alone. But there are some cases when removal of a larger portion is medically appropriate, known as a partial lobectomy. For researchers, this provides a unique opportunity to compare the resected cells with those cells that would otherwise be residual cells.

Mr Rominiyi is a Specialty Registrar in Neurosurgery. He and his team have pioneered a method of growing cells in a three-dimensional way that retains the key features of GBM and more reliably predicts clinical response compared to 2D models.

For the first time, this model will be used to grow both the resected cells and the residual cells and test drugs in a more accurate way.

The aims of the project are to:

• Collect and grow 8-10 paired samples of residual and resected tumour cell in the 3D models
• Determine the key characteristics of each group of cells (residual and resected)
• Use the key characteristics to compare the groups
• Treat the cells in the 3D models with combinations of drugs called DNA Damage Repair inhibitors as well as current standard treatments (namely radiation therapy and temozolomide chemotherapy). The theory behind this is that if we can stop tumour cells repairing themselves, then the chemo therapy or radiotherapy will kill more of the tumour
• Share their models with the wider scientific community

We believe this work will help fast-track new treatments into the clinic to improve survival rates for glioblastoma.

Mr Ola Rominiyi

Why is it important?

Glioblastoma is the most common malignant primary tumour occurring in adults and affects 2,200 individuals in England, annually. Glioblastomas have extremely poor survival rates, with only 5% of patients surviving 5 years beyond diagnosis. 

When it comes to studying GBM, we urgently need new techniques to assess possible treatments. The high failure rate of treatments when they get to the clinical trial stage can only be improved by having more accurate and informative lab models.

Who will it help?

This study will help people who are diagnosed with a GBM in the future. It has the potential to provide greater understanding of the cells that usually remain after surgery so they can be targeted more effectively by treatment.

By validating and sharing the 3D model with other researchers, the team will provide a new tool in the search for a cure for GBM.

Mr Rominiyi also aims to bring new drugs to the clinic with a strong evidence base that will enhance current treatments and ultimately double survival.

Milestones and findings

The Team have successfully developed GSC models of residual and resected disease that demonstrate differential expression of GBM stem cell markers and DNA response genes. They have also correlated these models with clinical data.

A number of differences have been observed between paired residual and recurrent models, and have seen a correlation in the expression of key DNA damage response genes/ proteins and glioma stem cell markers.

• Researchers have generated 40 cell models from tissue taken from ten glioblastoma patients, revealing distinct genetic differences between resected and residual tumour cells.
• DNA repair processes and cancer stem cell genes play a role in treatment resistance, and targeted therapies may be needed to address these differences.
• Inhibiting the DNA repair protein ATM can make glioblastoma cells more sensitive to radiotherapy, showing promise for future treatment approaches.
• The research has contributed to the Sheffield Living Biobank, which contains a large collection of glioblastoma cell lines and is a valuable resource for brain tumour research.

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