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Integrated genome-wide analyses of glioblastoma intra-tumour heterogeneity: a framework for personalised medicine

Project fact file

Supervisor(s)
Dr Ruman Rahman
School / Division
Children's Brain Tumour Research Centre
Keywords
brain cancer tumour heterogeneity next-generation sequencing patient-tailored pharmacology
Fee band
High cost laboratory-based research
Date posted
October 2017

Project description

Background

Glioblastoma (GBM) is among the most aggressive and treatment-resistant primary adult cancers with a median survival of 14 months. Biological differences within each GBM (intra-tumour heterogeneity) resulting from divergent tumourigenic clones, likely accounts for therapy failure. There is an urgent need for more specific therapies based on an understanding of the evolutionary progression of GBM subclones within individual patients.

Aims

1) Reconstruct GBM dynamics using next-generation sequencing

2) Target patient-derived GBM cells via tailored pharmacology.

Methodology

(Year 1): Through collaboration with the Queen’s Medical Centre Neurosurgery Department, GBM fragments from five spatially distinct regions and based upon clinical scans will be collected. Genome-wide cytogenetic analyses (Affymetrix CytoScan™) will determine the mutation spectra (copy number alterations) across tumour regions, relative to patientmatched blood. Genome-wide gene expression analysis (Affymetrix Transcriptome Array 2.0™) will enable a precise measurement of both coding, non-coding and splice variant transcripts in distinct GBM regions, normalised to cerebral cortex gene expression. Abnormal gene expression will be matched to the underlying mutation previously determined. Ultimately, integrative genomics that combines genetic mutation and gene expression from different tumour regions, will be used to identify common, shared and unique genetic signatures and thereby identify the dynamics within each tumour.

(Year 2): Overexpressed genes with associated mutations and which are common to all five GBM regions will be targeted therapeutically in vitro using patient-derived cells grown in the 3-Dimensional Rotary Cell Culture System (RCCS) [1]. For each GBM, 2-3 candidate genes will be targeted therapeutically with novel chemotherapy drugs.

(Year 3): The single most efficacious treatment regime will be validated and characterised in vivo using patient-derived GBM tumours in mice, in collaboration with the Department of Pre-Clinical Oncology, University of Nottingham. This overall strategy represents a framework for personalised medicine using next-generation chemotherapy. The immediate beneficiaries of this research will be healthcare professionals engaged in the diagnosis and treatment of GBM and other malignant brain tumours.

Training

The project will ensure that a high calibre PhD student develops advanced research skills in a translational neuro-oncology setting. The student will gain expertise in computational and statistical methodologies applied to the field of genomics in addition to molecular and cellular biology approaches to evaluate drug targets in vitro and in vivo. Close interaction with neurosurgeons and neuro-oncologists throughout the project will ensure training in the dynamic interface of basic-translational science.

References

[1] Smith SJ……, Grundy RG, Rahman R. A dynamic 3D brain cancer model recapitulates neoplastic phenotypes and molecular signatures with decreased sensitivity to histone deacetylase inhibition. PLoS One 7(12): e52335 (2012).

Please email a CV with a covering letter to Dr Ruman Rahman, who can also supply more information to interested candidates.

 

 

 

School of Medicine

University of Nottingham
Medical School
Nottingham, NG7 2UH

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