Targeting glioblastoma cell metabolism

Fast Facts

• Title: Exploiting passenger synthetic lethality for the treatment of aggressive glioblastomas
• Lead Researchers: Dr Vincenzo D’Angiolella
• Where: Oxford Institute for Radiation Oncology
• When: July 2019 – June 2021
• Cost: £120,000 over a 2 year period
• Research type: Adult, Glioblastoma (High Grade), Academic, Expanding Theories
• Grant round: Expanding theories

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What is the purpose of this study?

This grant aims to explore and target the increased metabolism of glioblastoma (GBM) cells which allow them to grow so quickly. In normal, healthy cells a lot of genes can cause metabolism to increase or decrease, speeding up or slowing down the cell’s growth. In all cancers there are metabolic genes lost called tumour suppressors which would normally slow growth. In GBM specifically, a gene called MTAP has been lost along with the tumour suppressors. This loss of MTAP is key to this project because it makes the GBM cells different to normal cells in a way that the researchers can target. In the absence of MTAP, tumour cells have to rely on alternative methods to survive.

Do the siRNAs stop GBM growth?

The first aim of this project is to grow GBM cells, which are missing MTAP, in the lab. The team will then test chemicals called siRNAs which should block the alternative pathways and see if the cells die. To confirm that these drugs will only harm GBM cells, and not normal brain cells, the scientists will then cause the cells to start making MTAP again, and they should be resistant to the drug.

How do the siRNAs work?

Following on from the work in Aim 1, the second part of the grant is to look at what specific changes the siRNAs cause in the cells. The team will look at levels of different metabolites to see how the siRNAs are stopping GBM growth.

Why is it important?

Glioblastomas are the most common and aggressive types of brain cancer found in adults. The current standard treatment involves surgery to remove as much of the tumour as possible, followed by radiotherapy and chemotherapy. Despite aggressive treatment, tumour recurrence is often inevitable, highlighting the urgent need to understand why these treatments are failing.

This research project will help to improve our knowledge of the differences between healthy brain tissue and tumour cells. It will help us better understand the underlying mechanisms driving aggressive glioblastomas, and identify ways in which we can disrupt these interactions with drugs to slow tumour growth. GBMs lacking the MTAP gene represent a subset of tumours with significantly poor survival. So it’s a priority to identify novel targets in this subset. The test for the presence or absence of MTAP in GBM could become an important biomarker test for these patients, and potentially steer the type of treatment people receive in the future.

Importantly, the research will also test how the drugs are working in the lab. Unfortunately a large number of drugs that work in the lab are not effective in the clinic. By understanding how the siRNA is changing the GBM cells, new drugs could be developed sooner by expanding on this knowledge.

Who will it help?

This research has the potential to help anyone with a glioblastoma which does not have MTAP. It could provide a new test to help clinicians predict the prognosis of their patients, and could even provide a new class of drugs to use to defeat GBM.

Understanding the biological mechanisms underlying the weakness of cancer cells will help to properly translate the approach to the clinic and suggest potential mechanisms of resistance to therapy.

Dr Vincenzo D’Angiolella

Milestones

When this grant starts in early 2019, the first aims will be to grow GBM cells that lack MTAP and then test the siRNA to stop growth. Next, they will assess the cells to find out what the siRNA is changing which leads to cell death.