Identification of Cell Surface Markers for Risk Stratification of Barrett's Esophagus Patients

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

? DESCRIPTION (provided by applicant): The incidence of esophageal adenocarcinoma (EAC) has risen for the past several decades at an alarming rate that is higher than that for any other cancer. Diagnosis of this cancer often occurs when it is at an advanced stage and when current treatment options are limited, resulting in extremely poor patient survival. Identification of patients with the metaplastic condition of Barrett's Esophagus (BE) allows patients to undergo surveillance endoscopic biopsy to help identify cancer. Unfortunately this approach is random, and may not identify the patients at greatest risk for cancer development by missing focal areas of dysplasia. Currently there is a lack of understanding of the molecular events associated with the progression of Barrett's mucosa to dysplasia and cancer as well as useful biomarkers that identify patients that are at greatest risk for development of EAC. Therefore, it is critically important that current trainees for the next generation of research scientists both understand and help develop strategies to diagnose cancer at its earlier stages and develop the most effective treatments. Towards this end, the purpose of this training proposal is to provide training in molecular biology and cancer biology to an accomplished pre-doctoral candidate in the Cancer Biology program with previous experience in human genetics and genomics. This training will include didactic, small group, and bench research training overseen by a mentorship team of established investigators in cancer biology research. The scientific training will involve investigating the molecular events that are frequently dysregulated at the transcriptome and protein levels in patient's tissue representing Barrett's metaplasia, dysplasia and EAC. Preliminary studies carried out by the applicant have provided insight into the most frequently observed transcript variants and identified candidate genes that encode for cell surface proteins over-expressed in the highly dysplastic precancerous and EAC tissues. We observe that highly dysplastic and cancer cells have a different transcription profile than non-dysplastic BE cells. We have identify candidates that show significant over-expression in HGD, and once validated, could be developed for our endoscopic-based targeting using specific target peptides directed again these cell surface proteins (Sturm et al, Sci. Transl Med, 2013). Therefore, three scientific aims will be addressed in this training proposal: 1) to validate the over- expression at the (mRNA) transcription level of cell surface coding proteins in BE that define the high-risk BE patient. 2) To validate the protein expression of the top high-risk candidate markers using tissue microarrays of BE and HGD mucosa. 3) To interrogate the processes and pathways that are dysregulated in the progression of BE to EAC. At the end of this training period, the trainee will have defined potential cell surface markers that can identify patients that at greatest risk fr development of EAC. Also she will elucidate the mechanisms and cellular processes involved in the progression of BE to dysplasia and cancer. Most importantly, this research program will significantly advance the training of a promising pre-doctoral student poised to be a future leader at the interface of cancer biology and early cancer detection.