Understanding medulloblastoma subtypes
- Official title: Refining the definition and clinical significance of medulloblastoma subtypes
- Lead researcher: Dr Paul Northcott
- Where: St. Jude Children’s Research Hospital
- When: January 2019 - December 2023
- Cost: £397,199 over a four-year period
- Research type: Paediatric, Medulloblastoma (High Grade), Clinical Biomarkers, Academic
What is it?
Medulloblastoma is the most common high-grade brain tumour in children. Based on clinical and biological characteristics medulloblastomas are divided into four subgroups: WNT, SHH, Group 3 and Group 4.The four subgroups are linked to very different outcomes and need different levels of treatment.
The 2016 revision of brain tumour classifications from the World Health Organisation (WHO) included, for the first time, the four consensus subgroups. Following this WHO revision they are now considered an essential diagnostic, prognostic and treatment indicator.
Bringing clinical trials up to date
Two children’s medulloblastoma clinical trials in North America (called ACNS0331 and ACNS0332) were designed before information about the medulloblastoma subgroups had been generally accepted, effectively making all the data they have collected to-date obsolete. However, these clinical trials are still relevant today as they are testing the effectiveness of reduced radiation (ACNS0331) and different chemotherapies (ACNS0332).
This research grant will mean that all the stored tumour samples (from about 800 children) collected during these trials will be analysed in the lab and assigned one of the four consensus subgroups. The results of the clinical trials will then be reassessed incorporating the new subgroup information and will help shape treatments and clinical trials.
Finding subtypes within Group 3 and Group 4
So far, medulloblastomas in Groups 3 and 4 have been notoriously difficult to treat because they have many different and unpredictable responses to treatment. Some researchers think this is because Groups 3 and 4 include more than just two different types of tumour. To investigate this possibility, information about the Group 3 and Group 4 samples from ACNS0331 and ACNS0332 will be combined with the data from the same subgroups in two other North American clinical trials, namely SJMP03 and SJYC07 (for which Group 3 and Group 4 analysis is already complete).
Dr Northcott’s team will use sophisticated statistical analysis, on over 1200 samples, to determine if there are further subtypes within these subgroups. Learning more about the different subgroups within ‘medulloblastoma’ will guide research and help to target treatments at the tumours more effectively.
Why is it important?
Without this work the information collected about treatment response from children on ACNS0331 and ACNS0332 will not be brought up to the current standard and any results from the trials will be confused by the lack of subgroups. It could mean that important treatment responses in one subgroup are lost in the ‘noise’ of the other subgroups.
Having this vital information on these older trials will mean that the next trials that are designed for children with medulloblastoma have the best possible starting point and that better treatments can be given to children sooner.
The second part of the study (further subdividing Groups 3 and 4) will lead to better understanding of the tumours within these subgroups. Better understanding will mean that dedicated time and effort can be given to each subtype of tumour and that development of new targeted treatments will be possible.
Who will it help?
This study will benefit all children who are diagnosed with medulloblastoma in the future.
The most immediate impact will be that the clinical trials ACNS0331 and ACNS0332 will be able to report more meaningful results because of the inclusion of the 4 subgroups in their analysis. Publication of the results of these large trials will mean that clinicians treating children with a medulloblastoma, even if they’re not on a trial, will have the most up-to-date information to inform their care.
A longer term impact is that the results of these trials will help shape the next generation of clinical trials in North America. They will also influence the next European trials by linking with trial data from existing trials, like PNET5, to make sure the field is moving forward and not duplicating work.
Aim 2, discovering more subtypes of medulloblastoma within Groups 3 and 4, will give hope for better treatments for children with these subgroups of tumour. Better understanding of the tumours will make it easier to test more tailored treatments, with the ultimate aim of defeating them with minimal detriment to quality of life.
The results of these studies will have a direct impact on the design of forthcoming clinical trials and lead to better treatment outcomes for medulloblastoma patients in the future.
In the first year of this grant the team have been concentrating on defining the molecular subgroups from the clinical trials ACNS0331 and ACNS0332. Their analysis means that 400 tumours from ACNS0331 and 255 tumours from ACNS0332 are now classified according to the four consensus subgroups.
Now that they know which subgroup each tumour belongs to, they can link this to how the tumour responded to treatments tested in the clinical trials. We hope that this will show which treatments are best at killing the different subgroups of tumour, and kindest for the children.
The team are now beginning to write up their results to share with the research community.
Once the initial results are shared, Dr Northcott’s team will continue on to Aim 2. This will see them combine the information about the tumours in subgroups ‘Group 3’ and ‘Group 4’ from ACNS0331 and ACNS0332 with those from two additional clinical trials (SJMP03 and SJYC07) and determine if there are any further subtypes within the subgroups.
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