Outsmarting glioblastoma and delivering novel drug combinations

Fast facts

• Official title: Systems approach to therapeutic combinations for glioblastoma: new targets and agents delivered and sequenced for synergy
• Lead researcher: Professor Neil Carragher
• Where: University of Edinburgh
• When: September 2019 – August 2024
• Cost: We will fund £2.96 million (total grant award £6.2million, with Cancer Research UK) 
• Research type: Adult, Glioblastoma (high grade), Academic

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What is it?

A multi-disciplinary collaboration, this research programme includes international experts in genomics, protein analysis, creation of pre-clinical models, and drug delivery.

Funded by us, through this grant, Professor Carragher will adopt a systems approach to find new drug targets and new drug combinations to treat glioblastomas. In addition to discovering new combinations of drugs, they’ll continue their work by testing drug combinations already discovered by their team.

Identifying drug targets

The research team will search through various drug databases to identify molecules that could be useful in combination with the current standard of GBM treatment (temozolomide and radiotherapy).

They’ll then conduct phenotypic screens. This tests the way cells respond to drugs and analyses this through changes in the cells’ appearance. The team will also go further and use a technology called CRISPR-i to identify ways to prevent treatment resistance, helping improve survival rates.

Validating drug targets

Pre-clinical models will be used to determine which genes are involved in causing tumour development and growth, as well as testing which drugs will be effective in killing the tumour cells and preventing resistance to treatment.

Multiple tumour models will be used because no single model accurately represents everything that happens within all people. By evaluating the drug combinations in multiple models, the team will ensure that these drugs have the highest chance of success in people diagnosed.

Understanding how drugs work

Researchers will use various lab tests to help them understand the cell signalling pathways that the drugs activate. Cell signalling is a cascade of reactions that happen within a cell. These reactions help coordinate a cell’s activities such as growth and repair, and can be manipulated to stop tumour growth.

By understanding these signalling pathways, the researchers will have a better understanding of how these drugs are working and what causes resistance to treatment.

Optimising drug delivery

Delivering drugs to brain tumours is challenging due to the presence of the blood brain barrier – tightly packed cells that line the walls of the blood vessels in the brain. These cells allow only some substances such as water, oxygen and essential nutrients to pass through in order to protect the brain. However, it can have a negative affect when trying to treat a brain tumour as it will stop the treatment reaching the brain and, therefore, the tumour.

The team will build upon previous research to develop a chemical ‘courier’ to deliver the drug combinations, as they play a key role in crossing the blood brain barrier.

Why is it important?

The prognoses for people diagnosed with a glioblastoma is dismal. Even with the current gold standard of care, which includes surgery, followed by radiotherapy and temozolomide, less than 5% of people with a glioblastoma survive for more than five years.

The poor prognoses can be attributed to what makes up the tumour (its composition), as glioblastomas are composed of different types of cells. This diverse composition results in the failure of chemotherapeutic and targeted treatments, as they tackle only one kind of cell within the tumour. Combination therapies would allow doctors to target multiple aspects of glioblastoma, allowing for more effective results.

This grant will allow researchers to suggest new combinations of therapies which have the greatest chance of being effective and well-tolerated in people. We hope that these new therapy combinations will signify a real step-change in the lives of people with a glioblastoma, improving quality of life and length of survival.

Who will it help?

The treatment for people with a glioblastoma has not changed in a decade and there’s an urgent need for new treatments. This research programme aims to address this need and go one step further by determining combinations of drugs to help people diagnosed with a glioblastoma as well as identifying new ways to avoid treatment resistance.

This could make a real and positive difference to people being treated for a GBM, and their loved ones.

Milestones

Identifying drug targets

The team have made great progress to date. They have begun the phenotypic screens on the best prospects from their screening of over 3000 potential drugs (compounds) to see which will have the greatest effect on GBM cells. They’ve also created new cells in the lab that survive current treatments (temozolomide and irradiation) and are trying to find effective ways to improve the drug effects.

Next steps: continue to test the most promising drugs and developing new cell lines that are resistant to (survive) different treatments.

Validating drug targets

Using human tumour, grown in complex lab models, the team have found a combination of compounds that had a significant effect in killing the tumour cells. They are now testing more likely combination in the models and writing up their results to share with the scientific community.

They are also developing new ways of growing cells in the lab that more closely mimic the way tumour cells grow in people. These models will mean that when testing potential drugs the results will be more like they would in human tumours.

Next steps: continuing to improve the GBM cells models to test compounds and combinations, using them to work their way through the best candidates that have been identified by the investigations above.

Understanding how drugs work

Researchers are using various lab tests to help them understand the cell signalling pathways that the drugs activate. Cell signalling is a chain of reactions that happen within a cell. These reactions help coordinate a cell’s activities such as growth and repair, and can be manipulated, or blocked, to stop tumour growth.

The team have also been looking at the changes in RNA and proteins between paired cells lines that either are OR are not resistant to irradiation. They treated these cells with a popular anti-cancer drug and generated lots of data! This data is being used to inform artificial intelligence (AI) and machine learning work, creating a new tool to predict compound combinations and relevant biomarkers.

Next steps: using the computational tool to rank the most promising drug targets and match them with the compounds most likely to disrupt the tumour cell growth. This will help them to prioritise the experiments needed to confirm their data theories.

Optimising drug delivery

The team are developing three aspects of nanoparticle delivery to find the combinations that work the best: 1) a protein ‘key’ that allows the nanoparticle across the blood brain barrier; 2) an outer layer that can get it into a GBM cell (but stops it taking harmful drugs into healthy cells); and 3) the compounds that the nanoparticle will deliver to the tumour cells.

So far they have put their best candidates into a small number of mice. They were able to watch through “cranial windows” as the nanoparticles crossed from the blood vessels into the surrounding brain.

Next steps: continue testing other combinations of protein ‘key’, outer layer and compound combinations to find the most effective one/s.

If you have any questions about this, or any of our other research projects, please contact us on [email protected]