Targeting treatment damage to stop recurrence

Fast facts

• Official title: Targeting astrogliosis to ablate post-treatment tumour recurrence
• Lead researcher: Dr Spencer Watson
• Where: University of Lausanne, Switzerland
• When: September 2020 – August 2023
• Cost: £180,000 over three years
• Research type: Adult, High Grade, Academic, Glioblastoma
• Award type: Future leaders

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What is it?

Glioblastoma (GBM) is a deadly disease, with a very poor rate of survival following diagnosis. Thus, there’s an urgent need to develop new therapeutic approaches. A promising alternative to current therapies is to target the non-cancerous cells that are corrupted by tumours and ultimately aid in cancer progression.

These normal cells contribute to what’s called the tumour microenvironment (TME). TME-targeted drugs, such as immunotherapies, are promising new anti-cancer treatments. This lab, led by Dr Watson’s mentor Professor Johanna Joyce, at the University of Lausanne, has demonstrated that targeting specific cells in the TME, called tumour-associated macrophages, with CSF1R inhibitor drugs resulted in dramatically increased survival in pre-clinical glioma trials. However, in long-term trials a subset of tumours recurred following treatment.

Interestingly, tumour recurrence always occurred right next to the so called ‘glial scars’ (GSs) that formed during the treatment. GSs are characterised by inflammation of common cells in the brain and lots of fibrous proteins.

Dr Watson aims to test the idea that GSs create a protective area for undeveloped tumour cells and that they also reprogramme TME cells to drive rapid tumour recurrence. Additionally, he has preliminary data that suggests these scars also form following therapies commonly used in the clinic, including radiation and surgical tumour resection.

However, almost nothing is known about tumour GSs, including what signals they use to assist cancer cells in surviving treatment. The aim of the current project is to identify exactly what tumour GSs are made up of and which signals are the main drivers of cancer recurrence.

Specifically, Dr Watson and his team have collected extensive glioblastoma samples from models treated with CSF1R inhibitors and analysed their protein makeup. Using a new approach that they’ve developed for microscopic imaging, they will determine where key proteins are in human and lab-grown tumours and which cells the proteins interact with.

Next, the team will use new bioengineered microenvironments, developed by Dr Watson, to see which proteins drive tumour recurrence.

Finally, they will stop GS formation with targeted drugs in their sophisticated pre-clinical models, to determine if this has the potential to benefit people with a GBM.

Employing drugs that inhibit glial scar formation in patients receiving treatment could dramatically increase survival by eliminating a common safe haven that cancer cells use to survive therapy.

Dr Spencer Watson

Why is it important?

This work could have profound implications for glioblastoma patients receiving any treatment that aggressively disturbs the brain TME, including radiation or surgery.

Employing drugs that inhibit GS formation in people receiving treatment could dramatically increase survival by eliminating a safe haven that cancer cells may be using to survive current therapies. As there are already several approved drugs on the market that could inhibit GS formation, the results of this project could directly influence new clinical trials.

Who will it help?

This work has the most direct potential to help people diagnosed with a GBM in the future. But because they are studying the effect of current radiotherapy and surgical treatments on the TME, which is made up of non-tumour cells in the brain, their results may also help to understand other brain tumours that recur.

Milestones

• The project successfully met its goals, characterising the composition of glial scars and deciphering their organisation.
• Advanced microscopy techniques were developed to study the reorganisation of cells and structures in the tumour microenvironment after treatment.
• A new type of cell was discovered that normally resides on blood vessels in the brain and plays a role in scar formation.
• By investigating the signals driving scar formation, the project identified a combination of two drugs that could block this activity and improve the response to glioblastoma treatment.
• The results supported the hypothesis that inhibiting glial scarring can enhance the response to anti-glioblastoma treatment, resulting in two major publications currently in preparation.

Further Research

Dr Spencer Watson has recently been awarded the Junior Fellows Award.