Childhood Brain Tumours

Question 1

Child Brain Tumours: overview.

Answer 1

• Paediatric oncology is on of the medical success stories of the 80’s-90’s.
• Steady improvement on the overall survival of children with cancer but not CNS tumours - only 50% survive.
• 10,000 life years lost and considerable morbidity - 12,000 disability life years.
• Plateau and Stasis: More recently small advances only are being made and for some tumours little progress at all.
• Fight fire with fire - i.e. unpleasant treatments to try and cure cancer.

Question 2

What is the challenge for any translational biology coming into cancer treatment?

Answer 2

• Optimisation and individualisation of current therapies - tumours are clonal and may need different treatments depending on specific clones present.
• Maximise efficacy.
• Minimise side-effects.
• Development of new therapeutic approaches.

Question 3

What may lead to complexity in treating childhood CNS tumours?

Answer 3

Interaction of:

• Age of onset
• Location / surgical accessibility
• Histological type and grade
• Post surgical stage
• Biology
• Impact of treatment
• Drug resistance

Question 4

What are some of the particular issues we face when dealing with brain tumours?

Answer 4

• Brain tumours are relatively rare - there is a poor understanding of disease biology - there is no accurate disease stratification and the treatment strategies are broadly based. Because of this there is a high mortality / morbidity - likely because treatments are sometimes unnecessarily harsh and perhaps not always that effective.
• Brain tumours used to be of low priority for molecular research.
• Currently there are a lack of molecular targets for new treatment approaches for brain tumours because we don’t understand the biology well enough to identify new targets. Again this results in increased morbidity and mortality.

Question 5

How can we improve outcomes for brain tumours through biology?

Answer 5

There are 2 strands to this.

1) . Developing robust markers which you can use to stratify patients into treatment groups and/or help understand how to treat certain patients. Have to validate any prospective biological marker in a group of patients that are treated in the same way.
e. g. Markers for patient management > Validation / clinical trials > patient stratification > Individualised therapy based on biological data
2) . Identifying targets for therapeutic intervention.

Targets for therapeutic intervention > Mechanistic studies - evaluate biological roles (models) > Drug development > Clinical trials > New rationally-designed therapies.

• Build up models based on tumour markers etc that allow you to accurately predict whether you can reduce therapy or not.

Question 6

What is a marker of outcome in Medulloblastoma?

Answer 6

• Markers can help to assess when we can reduce radiotherapy in treatment of young children - use of radiotherapy in very young children affects normal cognitive development.
• TrkC predicts good clinical outcome in medulloblastoma.
• Overall survival is higher in B-cat nucleopositive tumours than neg tumours.

Question 7

What is a good marker for identifying those with better prognosis in Ependymoma?

Answer 7

• PRUNE

Question 8

Childhood Brain Tumours: Key Hypotheses.

Answer 8

Key Hypotheses:

• Genetic markers can predict outcome in childhood CNS tumours.
• Tumours arising in different age groups have distinct genetic aberrations.
• Tumours of different histological grade have distinct genetic fingerprints.
• Development of large data sets linked to clinical parameters will enable the discovery of novel targets for therapy.
• Tumourigenesis arises from disordered neural development and involves distinct tumour specific pathways.

Question 9

What pathway can we develop antagonists for to treat certain medulloblastomas?

Answer 9

Sonic Hedgehog Pathway inhibitors.

Question 10

What culture system can be used to more accurately research tumours?

Answer 10

• 3D culture using 0G methods.

Question 11

Outline appropriate clinical trial structure for molecular targeted therapy.

Answer 11

Clinical trial structure:

• Designed to assess toxicity and efficacy of combinations of chemotherapy and radiotherapy.
• No ubiquitous mandate for collecting biological samples.
• Molecular subdivisions of CNS tumours will convert an uncommon disease to an extremely rare one.
• Procurement and appropriate storage and development of fresh samples on an international scale presents the greatest challenge.

Question 12

Watch the lecture on Childhood Brain Tumours again.

Answer 12

Watch it.