(MRC CASE) Liquid biopsies to support management of Ewing sarcomas

Ewing sarcoma (ES) is a primary bone and soft tissue cancer of children and young adults driven by oncogenic gene fusions including EWSR1/FLI1 and EWSR1/ERG. Small pilot studies demonstrated that circulating tumour nucleic acids (ctDNA and ctRNA) are detectable in patient plasma at diagnosis. ctDNA correlates with tumour volume and is more abundant at recurrence. ctRNA has theoretical advantages over ctDNA as a circulating biomarker being restricted to a smaller genetic footprint with less inter-patient variability and greater abundance per tumour cell. However, ctRNA is less well studied. This project, a collaboration between the CRUK Manchester Institute’s Cancer Biomarker Centre (CBC), University of Manchester and ThermoFisher will explore the potential utility of EWSR1/FLI1 and related fusion transcript ctRNAs circulating in plasma as biomarkers of response and progression in ES. 

The CBC Nucleic Acids Biomarkers Team (>20 staff) with established expertise in the development and validation of nucleic acid based liquid biopsy assays with host this student.

The project will involve:

(i) evaluation and optimisation for ctRNA in plasma of an existing commercial assay, Thermofisher's Oncomine Childhood NGS panel that reliably detects ES fusion transcripts in tumour tissue, using their Ion Torrent platform;

(ii) detection of ES fusions in serial clinical samples using this assay from a pilot cohort of standard and high risk Manchester ES patients at diagnosis and recurrence to evaluate the assay's clinical utility;

(iii) quantification of ctRNA fusions at baseline from patients recruited to two international ES trials: EE2012 and rEECur, and correlation of transcript abundance with established clinical risk factors;

(iv) investigation of the biology of ctRNA in ES including exploration of how ctRNA is shed into the blood, specifically whether it is transported as cargo in extracellular vesicles or as free ctRNA, and

(v) analysis of the phenotypic and functional effects on non-neoplastic cells of exposure to free or vesicle-bound ES cell-derived EWSR1/FLI1.

The unique fusion genes that define ES make an attractive approach for serial liquid biopsies to monitor response to chemotherapy and screen for asymptomatic disease relapse prior to the development of clinical symptoms, and may predict outcome. This collaborative project, led from the clinic by Dr McCabe, uses state-of-the-art and scalable technologies with potential for rapid clinical adoption. The supervisory team, through its links with the EuroEwing Consortium, is ideally placed to translate pre-clinical research into clinical research and drive a step change in clinical ES management.

https://www.cruk.manchester.ac.uk/Our-Research/Cancer-Biomarker-Centre/CEP-Home

Entry Requirements

Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or overseas equivalent) in a relevant subject.

Applicants interested in this project should make direct contact with the Primary Supervisor to arrange to discuss the project further as soon as possible.

To be considered for this project you MUST submit a formal online application form - full details on how to apply can be found on the MRC Doctoral Training Partnership (DTP) website http://www.manchester.ac.uk/mrcdtpstudentships

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