Identifying and validating molecular targets in nervous system tissue
Research type
Research Study
Full title
Identifying and validating molecular targets in brain tumour and control nervous system tissue
IRAS ID
264520
Contact name
Kathreena Kurian
Contact email
Sponsor organisation
North Bristol Trust
Duration of Study in the UK
5 years, 0 months, 0 days
Research summary
Currently low grade (benign) and high grade (malignant) brain tumours are treated by surgery or radiation therapy plus or minus chemotherapy. The aim of the study is to discover and validate new molecular biomarkers and drug targets for brain tumours (low and high grade) using laboratory research and comparing the findings with control tissue. The control tissue will come from operations of non-tumour central nervous system abnormalities for example arteriovenous malformations and hippocampal epilepsy resections.
This includes also using tissues, blood fractions and cell culture from patients with brain tumours. We hope that in vitro research will reveal biomarkers for these tumours which in the future could indicate successful drug action or are specific for a genetic subtype of tumour. In addition we hope that these biomarkers could aid early diagnosis of CNS tumours.
Hypothesis-driven approach:
1) We hypothesise that our NGS biomarker panel (including IDH1/IDH2 • ATRX, 1p/19q co-deletion, BRAF fusion, Histone H3.3 K27M mutation, MGMT promoter methylation,TERT) will identify subtypes of CNS tumour which are amenable to targeted therapies including (PD1 inhibitors) checkpoint inhibitors
2) We hypothesis that proteomic/metabolomic analysis may identify dysregulated cellular function within CNS tumours, which are potential molecular drug targets
3) We hypothesise that GFAP and other proteins in blood may be a biomarker to aid early diagnosis of CNS tumours in blood samples
Based on our previous results, we will analyse expression and activation of growth factor receptors and downstream signalling pathways, via Western blots, pull downs, shRNA as previously published (1-17). Functional relevant readouts, such as immunophenotyping, proliferation and cell death assays, have been established. Relevant signalling pathways will be inhibited with drugable compounds in cell culture.Systematic unbiased approach:
1. Assessment of the protein, gene expression activation network
2. Identification and validation of common and differential therapeutic targets in tumours of a certain genotype
3. Further understanding of the mechanisms of drug action in vitro.
We expect to identify a group of common and differentially activated (phospho) proteins in these tumours. We plan to compare alterations of protein expression and phosphorylation/activation in tumours by analysing the phosphoproteome of different human primary tumour cell cultures from brain tumours including gliomas, schwannomas, meningiomas and ependymomas.REC name
South West - Cornwall & Plymouth Research Ethics Committee
REC reference
19/SW/0194
Date of REC Opinion
31 Dec 2019
REC opinion
Further Information Favourable Opinion