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Identification of novel biomarkers of response to chemotherapy and chemoradiotherapy in oesophageal cancer

Dr. Stephen Maher, Postdoctoral Scientist
Dr. Stephen Maher, Postdoctoral Scientis

Oesophageal cancer is an aggressive disease with increasing annual incidence and an extremely poor prognosis.  Chemoradiotherapy (CRT) before surgery is the standard of care for oesophageal cancer patients. Unfortunately, only one third of patients have a good response to CRT, while the remaining patients receive little or no benefit. Indeed, evidence suggests that those patients who fail to respond to CRT ultimately have a worsened outcome due to the increased wait time to surgery as a result of receiving the CRT.

Presently, there are no reports describing microRNA studies to determine markers of resistance to therapy in this cancer. Studies to determine molecular predictors of response to chemoradiotherapy are essential to improve patient selection and ultimately therapeutic efficacy. In this proposal, we will examine, by microRNA microarray, the differential microRNA profiles in pre-treatment tumour samples from responder and non-responder patients receiving neoadjuvant chemoradiotherapy for oesophageal adenocarcinoma. Recent studies have shown that microRNAs are readily detected in plasma and serum. We shall also assess matched serum samples from these patients for the levels of differentially-expressed array-associated microRNAs, and critique it as a relatively non-invasive alternative to biopsy. The microRNA data will also be incorporated into a prediction model algorithm based on patient response to treatment, to establish the ‘microRNA signature’. We will validate the microRNA signature in an independent cohort of patients, and establish its positive and negative predictive values. Additionally, we will examine the combined power of both microRNA and gene expression profiles (previously published by this unit) in predicting patient response to therapy. Functionally, we will assess, using isogenic models of chemo- and radio-resistance, the relative contributions of specific signature microRNAs to tumour cell sensitivity to chemotherapeutics and radiation. This will be achieved via overexpression with pre-microRNA molecules. This work has important implications for oesophageal cancer therapy, in that the identification of microRNA signatures predictive of patient response to treatment will provide a platform for the development of a new diagnostic test. This may ultimately improve patient selection, treatment benefit, and survival. Moreover, understanding the contributions of microRNAs to therapeutic sensitivity may highlight new targets for future drug development.

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Last updated 23 November 2016 Surgery - Web Administrator (Email).