BETRNet

Project 1: DG Beer and his team will perform Affymetrix expression analysis of genes overexpressed in both EAC and GEJAC relative to normal gastric or esophageal mucosa to identify potential candidates for development of new peptide imaging agents to detect either cancer regardless of the presence of BE. Promising cell surface targets will be validated by both qRT-PCR and IHC for validation of overexpressionin both EAC and GEJAC.

Institutions: The University of Michigan, University of Washington, and Harvard Medical School forms a Research Center in the NIH-funded BETRNet program. This Center aims to advance new methods of imaging to visualize the spatial distribution of genetic mutations in Barrett's esophagus, evaluate tumor heterogeneity, and assess impact on progression toward cancer.

Project 2: TD Wang and his team will develop a panel of monomer peptides that are specific for early targets found in Project 1 that arise during progression from BE to EAC. We expect early targets to be expressed at low levels, thus we will arrange monomers in a dimer configuration. By visualizing target overexpression in vivo over time, we can study the biology of EAC and its precursor lesion BE.

Goals: We aim to develop novel methods for in vivo imaging to visualize molecular processes that drive cancer progression in the esophagus over time. Because cancer is a heterogeneous process, a panel of targets is needed for early cancer detection in the general patient population. Known genetic mechanisms that drive disease progression include loss of heterozygosity (LOH), changes in DNA methylation, abnormalities in tumor suppressor loci, changes in cell cycle regulation, dysregulation of cell signaling, and focal gene amplifications and deletions.

PI's: DG Beer leads Project 1 to identify early targets in progression of BE to EAC. TD Wang develops novel molecular probes using peptide heterodimer structures that bind these early targets. EJ Seibel leads Pilot Projects that infuse new ideas and technologies to advance this multiplexed imaging strategy. DK Turgeon leads the clinical validation effort in human subjects. JM Taylor provides bioinformatics and biostatistics support. JH Rubenstein supports the Patient Registry and BETRNet virtual repostory.

Technology: Multiplexed imaging instruments are being developed by EJ Seibel at the University of Washington. Excitation is delivered by a single flexible optical fiber that is scanned in spiral pattern and focused onto the mucosa by a lens assembly while a ring of fibers collects the return light. White light image is shown from colon of CPC;Apc mouse genetically engineered to sporadically delete APC and spontaneously develop polypoid and flat adenomas.

Key publications

    • Stachler MD, Taylor-Weiner A, Peng S, McKenna A, Agoston AT, Odze RD, Davison JM, Nason KS, Loda M, Leshchiner I, Stewart C, Stojanov P, Seepo S, Lawrence MS, Ferrer-Torres D, Lin J, Chang AC, Gabriel SB, Lander ES, Beer DG, Getz G, Carter SL, Bass AJ. Paired exome analysis of Barrett's esophagus and adenocarcinoma. Nature Genetics 2015;47:1047-55. PMC4552571
    • Dulak AM, Stojanov P, Peng S, Lawrence MS, Fox C, Stewart C, Bandla S, Imamura Y, Schumacher SE, Shefler E, McKenna A, Carter SL, Cibulskis K, Sivachenko A, Saksena G, Voet D, Ramos AH, Auclair D, Thompson K, Sougnez C, Onofrio RC, Guiducci C, Beroukhim R, Zhou Z, Lin L, Lin J, Reddy R, Chang A, Landrenau R, Pennathur A, Ogino S, Luketich JD, Golub TR, Gabriel SB, Lander ES, Beer DG, Godfrey TE, Getz G, Bass AJ. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nature Genetics 2013;45:478-86. PMC3678719
    • Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202-9. PMC4170219
    • Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature 2017;541:169-75. PMID 28052061
    • Sturm MB, Joshi BP, Lu S, Piraka C, Khondee S, Elmunzer BJ, Kwon RS, Beer DG, Appelman HD, Turgeon DK, Wang TD. Targeted imaging of esophageal neoplasia with a fluorescently labeled peptide: first-in-human results. Sci Transl Med 2013;5:184ra61. PMC3859345
    • Joshi BP, Duan X, Kwon RS, Piraka C, Elmunzer BJ, Lu S, Rabinsky EF, Beer DG, Appelman HD, Owens SR, Kuick R, Doguchi N, Turgeon DK, Wang TD. Multimodal endoscope can quantify wide-field fluorescence detection of Barrett's neoplasia. Endoscopy. 2016 Feb;48(2):A1-A13. PMC5011967
    • Sturm MB, Wang TD. Emerging optical methods for surveillance of Barrett's oesophagus. Gut 2015;64:1816-23. PMC5019028