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1 NAME: Wang, Thomas D. OMB No /0002 (Rev. 08/12 Approved Through 8/31/2015) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. era COMMONS USER NAME: Wang.Thomas POSITION TITLE: Associate Professor of Medicine, Biomedical Engineering, and Mechanical Engineering EDUCATION/TRAINING: INSTITUTION AND LOCATION DEGREE (if applicable) Completion Date MM/YYYY FIELD OF STUDY Harvey Mudd College; Claremont, CA BS 03/1985 Mathematics/Physics MIT; Cambridge, MA MSEE 06/1987 Electrical Engineering MIT; Cambridge, MA PhD 06/1996 Medical Engineering Harvard Medical School; Boston, MA MD 06/1998 Medicine A. Personal Statement I am a physician scientist and have developed a number of novel methodologies for in vivo imaging in the digestive tract for early cancer detection and staging. I have pioneered the use of fluorescence-labeled peptides to detect overexpressed cell surface targets in vivo to identify pre-malignant mucosa. Furthermore, I have developed the first video endoscope that is sensitive to fluorescence for rapidly identifying pre-malignant lesions over large mucosal surface areas. This approach has been patented, commercialized, and developed for clinical use, and is widely cited as a major impetus for the accelerated convergence of fluorescence spectroscopy and endoscopy. I have mentored a total of 2 junior faculty (research investigators), 21 post-docs (research fellows), 3 M.D. (clinical) fellows, 6 Ph.D. graduate students, 1 medical resident, 2 medical students, and 6 undergraduates. In addition, I have filed 12 patents with the USPTO on novel optical imaging technologies. I have partnered with Olympus Medical Systems Corporation for over 9 years, and we have codeveloped the first multi-modal visible endoscope that collects white light, fluorescence, and reflectance images concurrently. This novel medical instrument was successfully introduced into the clinic for early detection of cancer in esophagus in a clinical study using a monomer peptide. B. Positions and Honors Positions Research Scientist, Dynamics Technology, Inc, Torrance CA Research Assistant, G.R. Harrison Spectroscopy Lab, MIT, Boston MA Post-Doctoral Fellow, Wellman Laboratory of Photomedicine, Boston MA Resident, Internal Medicine, Boston Medical Center, Boston, MA Fellow, Gastroenterology, Stanford University, Stanford, CA Instructor of Medicine, Stanford University, Stanford, CA Assistant Professor, Medicine and Biomedical Engineering, Univ of Michigan, Ann Arbor, MI 2011-current Associate Professor, Medicine and Biomedical Engineering, Univ of Michigan, Ann Arbor, MI 2013-current Associate Professor, Mechanical Engineering, University of Michigan, Ann Arbor, MI Honors 2006 Doris Duke Charitable Foundation Clinical Scientist Development Award

2 2006 Research Excellence in GI and Liver (REGAL) Award 2009 Member, American Society for Clinical Investigation (ASCI), elected 4/ University of Michigan League of Research Excellence 2011 University of Michigan Jerome W. Conn Award for Excellence in Research 2012 Fellow of the American Gastroenterological Association (AGA) 2014 H. Marvin Pollard Collegiate Professor of Endoscopy Research 2015 Senior Member, Society of Photo-Optical Instrumentation Engineers (SPIE) C. Contributions to Science 1. Peptide-based imaging agents. Current methods of clinical cancer screening in the digestive tract with white light endoscopy is limited by low contrast and poor sensitivity to flat lesions that are easily missed and may lead to preventable cancers. As an academic physician, I have led a team of investigators in two separate first-in-humans studies to demonstrate use of fluorescently-labeled peptides that bind in vivo to premalignant disease in 1) colon and 2) esophagus. We demonstrated the first clinical use of topical administration to deliver peptides to the mucosal surface in high concentrations, maximizing target interactions and achieving rapid binding with minimal risk for toxicity. Compared with systemic delivery, this approach localizes distribution of an exogenous imaging agent to target tissues only, minimizing background, and maximizing contrast. Peptides have large diversity, and can be developed to achieve high specificity with binding affinities approaching that of antibodies with low manufacture costs. These properties are well suited for clinical imaging in high volume procedures. a. Zhou J, Joshi BP, Duan X, Pant A, Kuick R, Owens SR, Wang TD. EGFR overexpressed in colonic neoplasia can be detected on wide-field endoscopic imaging, Clinical Translational Gastroenterology 2015;6:e102. PMID: b. Joshi BP, Zhou J, Pant A, Duan X, Zhou Q, Kuick R, Owens SR, Appelman HD, Wang TD. Design and Synthesis of Near-Infrared Peptide for In Vivo Molecular Imaging of HER2, Bioconjugate Chemistry 2016, in press. c. Rabinsky EF, Joshi BP, Zhou J, Duan X, Pant A, Kuick R, Fan S, Nusrat A, Owens SR, Appelman HD, Wang TD. Claudin-1 peptide can detect colonic neoplasia in vivo on endoscopic imaging, Cellular and Molecular Gastroenterology and Hepatology 2016, in press. 2. Vertical cross-sectional imaging. Current methods of confocal fluoresecence endomicroscopy collect images in horizontal planes only. In this orientation, pathology is often fairly similar across the image field-ofview. As an electrical engineer, I have led a team of investigators to develop a novel optical design using the dual axes configuration. Illumination and collection of light is performed off-axis to minimize effects of tissue scattering and significantly improve the dynamic range of detection. Fluorescence images can then be collected in vertical planes. This orientation allows for the natural direction of disease progression (luminal-tobasilar) to be viewed, and shows the relationship among tissue microstructures with depth relative to the mucosal surface. This innovation can be clinically translated to improve methods for early staging of epithelial-derived cancers. The depth of early cancer invasion (T1a versus T1b) can then be assessed to determine if local resection can be performed. Cancer invasion below this landmark (stage T1b) significantly increases risk for micrometastasis into lymphatics in the lamina propria. a. Liu JTC, Mandella MJ, Crawford JM, Friedland S, Soetikno R, Contag CH, Kino GS, Wang TD. A dualaxes confocal reflectance microscope for distinguishing colonic neoplasia. J Biomedical Optics 2006;11: PMC b. Liu J, Mandella MJ, Crawford JM, Contag CH, Wang TD, Kino GS. Efficient rejection of scattered light enables deep optical sectioning in turbid media with low-na optics in a dual-axes confocal architecture. J Biomedical Optics 2008;13: PMID: c. Qiu Z, Liu Z, Duan X, Khondee S, Joshi BP, Mandella MJ, Oldham KR, Kurabayashi K, Wang TD. Targeted vertical cross-sectional imaging with handheld near-infrared dual axes confocal fluorescence endomicroscope. Biomedical Optics Express 2013;4: PMC Multiplexed imaging methods. Because cancer biology is heterogeneous, an approach that can detect multiple targets (multiplexing) is needed for clinical use in a broad patient population. Current methods of molecular imaging, such as PET and SPECT, can detect only one target at a time. As an electrical engineer, I have led a team of investigators to demonstrate the first use of multiplexed methods, including 1) wide-field

3 endoscopy and 2) confocal endomicroscopy, to detect fluorescence images in multiple channels concurrently. On wide-field endoscopy, we took advantage of the flexibility of peptide-based imaging agents to be labeled with a broad range of fluorophores to detect pre-malignant lesions in vivo in mouse colon. This comprehensive imaging approach can be clinically translated, and is needed for cancer surveillance in the general patient population. On confocal endomicroscopy, we registered molecular and anatomic images collected concurrently to help with interpretation of target expression patterns. Multiplexing can also be used to observe ligand-receptor interactions and cell tracking behavior. a. Miller SJ, Lee CM, Joshi BP, Gaustad A, Seibel EJ, Wang TD. Targeted detection of murine colonic dysplasia in vivo with flexible multi-spectral scanning fiber endoscopy. J Biomedical Optics 2012;17: PMC b. Joshi BP, Miller SJ, Lee CM, Seibel EJ, Wang TD. Multispectral endoscopic imaging of colorectal dysplasia in vivo. Gastroenterology 2012;143: PMC c. Qiu Z, Khondee S, Duan X, Li H, Mandella MJ, Joshi BP, Zhou Q, Owens SR, Kurabayashi K, Oldham KR, Wang TD. Vertical cross-sectional imaging of colonic dysplasia in vivo with multi-spectral dual axes confocal endomicroscopy. Gastroenterology 2014;146: PMC Clinical translation of targeted imaging agents. As a P.I. in the NCI Network for Translational Research (NTR), I made key contributions to the development of a regulatory roadmap for clinical translation of new targeted contrast agents for optical imaging. I teamed with a collaborative network of investigators from the NIH, FDA, academia, and industry to develop a successful multi-disciplinary approach to navigate the long and complex regulatory path for FDA approval of these fluorescently-labeled imaging agents. We described standardized methods by which optical imaging agents are synthesized, qualified, and validated for preclinical testing, and ultimately translated for first-in-humans studies using investigational optical imaging instruments. By identifying and adopting consensus approaches for seemingly disparate optical imaging modalities and clinical indications, we established a systematic method for navigating the ever-changing roadmap to most efficiently arrive at the destination for clinical adoption and improved outcomes for cancer patients. a. Hsiung P, Hardy J, Friedland S, Soetikno R, Du CB, Wu AP, Sahbaie P, Crawford JM, Lowe AW, Contag CH, Wang TD. Detection of colonic dysplasia in vivo using a targeted heptapeptide and confocal microendoscopy. Nature Medicine 2008;14: PMC b. Sturm MB, Joshi BP, Lu S, Piraka C, Khondee S, Elmunzer BJ, Kwon RS, Beer DG, Appelman HD, Turgeon DK, Wang TD. Targeted endoscopic imaging of Barrett's neoplasia with specific fluorescentlabeled peptide: first in-human results. Science Translational Medicine 2013;5:184ra61. PMC c. Joshi BP, Duan X, Rabinsky EF, Piraka C, Elmunzer BJ, Kwon RS, Lu S, Beer DG, Appelman HD, Owens SR, Kuick R, Doguchi N, Turgeon DK, Wang TD. Multi-modal endoscopy can quantify wide-field fluorescence detection of Barrett s neoplasia. Endoscopy 2016;48:1-15. PMID: Miniature thin-film PZT actuators. Current technologies for performing axial scanning in miniature imaging instruments do not have sufficient scan speeds and axial displacement to image the epithelium of hollow organs in real time. As an electrical engineer, I have collaborated with Dr. KR Oldham in Mechanical Engineering at the University of Michigan to develop thin-film piezoelectric (PZT) actuators. Because of unusually high work density, we have developed these devices to achieve unprecedented scan speeds and axial displacements in a miniature form factor. The high work density of these materials allows for large vertical depth focusing (>500 m axial displacement) with real time imaging speeds in a small, low weight package. Individual legs can be independently controlled to perform random access scanning of arbitrary volumes within the image field of view to optimize signal-to-noise, temporal resolution, and frame rate and to track cell trajectories. a. Qiu Z, Pulskamp JS, Lin X, Rhee CH, Wang TD, Polcawich RG, Oldham K. Large displacement vertical translational actuator based on piezoelectric thin films. J Micromechanics and Microengineering 2010;20:1-10. b. Choi J, Qiu Z, Rhee CH, Wang TD, Oldham KR. A three-degree-of-freedom thin-film PZT-actuated microactuator with a large out-of-plane displacement, J Micromechanics and Microengineering 2014:24: c. Qiu Z, Rhee CH, Choi J, Wang TD, Oldham KR. Large Stroke Piezoelectric Vertical Microactuator with High-Speed Rotational Scanning Mirror. J Microelectromechanical Systems 2014;23:

4 Complete List of Published Work in MyBibliography: cending Patents 1. Wang TD, Joshi BP. "Her2 peptide reagents and methods," US Patent Application No 62/262,159, filing date 12/02/ Wang TD, Khondee S. Targeted Micelles with Lipophilic Drugs for Treating Cancer US Provisional Patent Application No 13/329, Wang TD, Rabinsky EF, Joshi BP. "Claudin-1 peptide reagents and methods," US Patent Application No 62/121,663, filing date 02/27/ Wang TD, Zhou J, Joshi BP, "Peptide Reagents and Methods for Detection of Dysplasia and Early Cancer," US Patent Application No 62/040,590, filing date 08/22/ Wang TD, Miller SM, Joshi BP. "Peptide Reagents and Methods for Detection of Colon Dysplasia," US Patent No. 8,901,276, issued 09/02/ Oldham KR, Wang TD, Liu Z, Ye J. Two-Photon Endoscopic Scanning Assembly for Inflammatory Disease Detection, US Patent No 8,807,801, issued 08/19/ Wang TD, Kurabayashi K, Oldham KR, Qiu Z. Targeted Dual Axes Confocal Imaging Apparatus with Vertical Scanning Capabilities, US Patent Application No 12/916,159, filing date 10/29/2010, publication date 05/26/ Wang TD, Lu S. Neoplasia Targeting Peptides and Methods of Using the Same, US Patent No. 8,247,529, filing date 05/15/2009, issued 08/21/ Wang TD, Li M. Targeted Detection of Dysplasia in Barrett's Esophagus with a Novel Fluorescencelabeled Polypeptide, US Patent Application No 12/763,033, filing date 04/19/2010, publication date 12/09/ Kino GS, Mandella MJ, Wang TD, Two Beam Fluorescence Microscope, US Patent No: 7,130,042, filing date 03/05/2004, publication date 10/31/ Wang TD, Feld MS, Wang Y, Van Dam J, Fulghum SF. Fluorescence Imaging Endoscope, US Patent No: 7,235,045, filing date 03/20/2003, issue 06/26/ Wang TD, Feld MS, Wang Y, Van Dam J, Fulghum SF. Fluorescence Imaging Endoscope, US Patent No: 6,537,211, filing date 01/26/1999, issued 03/25/03. D. Research Support Ongoing U54 CA P.I. TD Wang 09/21/11 08/31/16 NIH/NCI (Barrett s Esophagus Translational Research Network) Multi-Spectral Targeted Imaging for Early Detection of Cancer in Barrett s Esophagus The Barrett s Esophagus Translational Research Network (BETRNet) is a network of academic institutions that forms a multi-institutional, multi-disciplinary Specialized Research Resource to accelerate clinical translation of research in Barrett s esophagus with improved access to biospecimens through a network-wide virtual biorepository, collective leveraging of novel animal and cellular models, genomics, proteomics and imaging. U01 CA P.I. TD Wang 07/01/15 06/30/19 NIH/NCI (Imaging and Biomarkers for Early Cancer Detection) Multiplexed Multi-Modal Endoscopic Imaging of Cancer Biomarkers The goal of this project is to develop a novel, multi-modal imaging strategy that uses the principle of multivalency to perfrom multiplexed detection with a NIR-labeled peptide multimer to improve methods for early detection of esophageal adenocarcinoma. R01 CA P.I. TD Wang 07/14/15 06/30/20 NIH/NCI (Imaging and Biomarkers for Early Cancer Detection) Multiplexed Imaging of Biliary Intra-Epithelial Neoplasia

5 The goal of this project is to develop a novel, multi-spectral imaging strategy that uses multiplexed detection with a panel of peptide monomers to improve methods for early detection of intra-epithelial neoplasia in the biliary tract. R01 EB P.I. KR Oldham 07/18/15 04/30/19 NIH/NCI (Bioengineering Research Grant) Multi-Photon Endomicroscope for Real-Time In Vivo Vertical Sectioning Role: Co-Investigator The goal of this project is to develop a novel scanning actuator that performs high speed random access interrogation of intra-epithelial biological behavior with large axial and lateral displacements in a multi-photon endomicroscope. Pending R01 CA P.I. TD Wang 03/01/16 02/28/20 NIH/NCI (Academic-Industrial Partnerships for Translation of In Vivo Imaging Systems) Early Detection of Colorectal Cancer on Near-Infrared Molecular Endoscopy The goal of this project is to develop an academic-industrial partnerships for translation of in vivo imaging systems for cancer investigations for early detection of colorectal cancer. Completed R01 CA P.I. TD Wang 02/25/10 12/31/14 NIH/NCI (Bioengineering Research Partnership) Targeted Multi-Spectral Dual Axes Confocal Imaging of In Vivo Molecular Expression The goal of this collaboration between the College of Engineering and School of Medicine at the University of Michigan is to develop a novel intra-vital imaging strategy that provides vertical cross-sectional images to study molecular changes in the epithelium of small animal models of cancer. U54 CA PI TD Wang 09/29/08 08/31/13 NIH/NCI (Network for Translational Research) In Vivo Detection of Neoplasia in the Digestive Tract The Network for Translational Research (NTR) is a multi-institutional, multi-disciplinary Specialized Research Resource Center that aims to optimize and validate novel, multi-modal methodologies using optical imaging platforms for early cancer detection. P50 CA93990 PI BD Ross 09/22/08 03/30/13 NIH/NCI (In Vivo Cellular and Molecular Imaging Center) Title: In Vivo Imaging of Neoplasia Goals: The aim of this project is to develop novel peptide probes and high resolution optical imaging instruments for longitudinal study of colorectal cancer in the pre-clinical and clinical setting. Role: Leader, Project 1