Medulloblastoma Epigenome Regulation in Treatment (MERIT)

Fast facts

• Official title: Medulloblastoma Epigenome Regulation in Treatment (MERIT)
• Lead researcher: Dr Paul Northcott
• Where: St Jude Children’s Research Hospital
• When: September 2018 – August 2024
  
• Cost: £1.5 million over a period of five years
  
• Research type: Paediatric, Medulloblastoma (High Grade), Academic
• Grant round: Quest for Cures

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Medulloblastoma is the most common high-grade brain tumour in children. Medulloblastomas are divided into the following sub-groups based on different clinical and biological characteristics: WNT, SHH, Group 3 and Group 4. Children diagnosed with Group 3 medulloblastomas have the worst outcomes due to a high rate of recurrence. This pattern of recurrence suggests that changes occurring in the tumour during the course of treatment may be driving resistance to treatment, leading to tumour progression. It is therefore important to understand these changes and how they contribute to the failure of current treatments.

What is it?

Previous research has shown that epigenetic changes or changes to the structure of DNA which alter the way DNA is ‘read’ contribute to the treatment resistance in medulloblastomas. The research team, led by Dr Paul Northcott, is to identify these epigenetic changes occurring in Group 3 medulloblastomas in response to treatment.

To accomplish this aim, the research team will analyse tumour samples to map the various epigenetic changes occurring in Group 3 medulloblastomas, as well as identify changes occurring in response to chemotherapy and/or radiation therapy. They will then follow-up by finding treatments that have the ability to reverse resistance to treatment and then translate their work into pre-clinical models.

Why is it important?

Medulloblastoma is the most common high-grade brain tumour in children. Medulloblastomas are divided into the following sub-groups based on different clinical and biological characteristics: WNT, SHH, Group 3, and Group 4. Children diagnosed with Group 3 medulloblastomas have the worst outcomes due to a high rate of recurrence. This pattern suggests that the changes occurring in the tumour during the course of treatment may be driving resistance to treatment, and leading to tumour progression. It is therefore important to understand what these changes are and how they contribute to the failure of current treatments.

Who will it help?

This research will help children diagnosed with Group 3 medulloblastomas and their family members.

Milestones

• The team analysed the transcriptional and epigenetic changes that occur in 58 primary tumour samples, including 19 Group 3 medulloblastomas.
• They also created a mouse model of Group 3 medulloblastoma using parts of Group 3 medulloblastoma from children’s surgeries.
• They used these models to complete 2 pre-clinical studies. These studies investigated how combination therapy with different doses of radiotherapy and chemotherapy affected tumour growth and also, what changes occurred during treatment.
• Additionally they generated a library of potential ‘master regulators’ which they think could be controlling the initiation and growth of the tumours. They have then worked to confirm the effect of these ‘master regulators’ in medulloblastoma cells. The researchers are now analysing the results from these experiments to help them identify which regulators are key.