Mouse models of colon cancer are a critical experimental tool for determining the role of specific genes in carcinogenesis, studying tumor initiation and progression, and testing potential chemopreventive and therapeutic compounds. Typically, mouse study outcomes are determined by sacrifice and colon tissue harvesting for procedures such as tumor count, immunohistochemistry, and various assays. Since each animal can only be analyzed once, comparison across timepoints must be done statistically. With this method, it is impossible to know the progression (and possible regression) history of a lesion. We are changing the current destructive paradigm through the use of miniaturized combined reflectance and fluorescence endoscopes. Our current endoscopes contain optical coherence tomography and laser induced fluorescence to enable non-destructive, high resolution and high sensitivity imaging for time-serial visualization of an individual animal's disease. In the current funding period, we performed several studies to prove the utility of dual-modality imaging to visualize disease progression, with and without targeted fluorescence and scattering contrast agents. In this renewal, we will refine the imaging instrumentation and contrast agents based on our experience and the needs of the mouse imaging community. We will then utilize this technology for scientifically-compelling studies of carcinogenesis and chemoprevention/therapy. Our technology will enable questions regarding disease progression and regression to be answered that are difficult, if not impossible, to do with the current (sacrifice and tissue harvest) paradigm.
The specific aims are: 1. Enhance the capability of the reflectance/fluorescence endoscopic systems. We will modify our endoscope to add a magnifying surface view for chromoendoscopy, to view the earliest putative lesion, aberrant crypt foci (ACF). Other system improvements include speed and automation enhancements. 2. Develop novel targeted contrast agents. We will continue to develop targeted contrast agents, focusing on the targets VEGFR and EGFR. Gold nanoparticles will be used as OCT reporters. LIF reporters will include cyanine dyes, cadmium-free nanodots, and upconverting lanthanide particles. 3. Perform chemoprevention and chemotherapeutic studies. We will perform four studies: a) How do ACF and gastrointestinal neoplasias progress to adenoma and/or adenocarcinoma? b) Can treatment with ?-difluoromethylornithine (DFMO) and/or sulindac regress adenoma and prevent adenocarcinoma? c) What role does the RAS oncogene play in sulindac prevention of azoxymethane-induced cancer? d) Can an alternative scheduling of sulindac provide effective chemoprevention at a lower dose? At the conclusion of this next funding period, we expect to have developed a powerful endoscopy system and to have made significant advances in the basics science of chemoprevention/chemotherapy, which can be applied to the prevention and treatment of colon cancer in humans.

Public Health Relevance

The fight against colon cancer requires better tools to understand the origin and progression of this disease, and evaluate possible preventive and therapeutic drugs. We will continue to develop our novel optical endoscope and contrast agents, and employ them to image a mouse model of the colon cancer. We will address critical questions regarding cancer growth and how preventive and therapeutic drugs work.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109385-09
Application #
8305066
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Nordstrom, Robert J
Project Start
2004-07-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$320,089
Indirect Cost
$92,547
Name
University of Arizona
Department
None
Type
Organized Research Units
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Harpel, Kaitlin; Leung, Sarah; Rice, Photini Faith et al. (2016) Imaging colon cancer development in mice: IL-6 deficiency prevents adenoma in azoxymethane-treated Smad3 knockouts. Phys Med Biol 61:N60-9
Keenan, Molly R; Leung, Sarah J; Rice, Photini S et al. (2015) Dual optical modality endoscopic imaging of cancer development in the mouse colon. Lasers Surg Med 47:30-9
Welge, Weston A; Barton, Jennifer K (2015) Expanding Functionality of Commercial Optical Coherence Tomography Systems by Integrating a Custom Endoscope. PLoS One 10:e0139396
LeGendre-McGhee, Susan; Rice, Photini S; Wall, R Andrew et al. (2015) Time-serial Assessment of Drug Combination Interventions in a Mouse Model of Colorectal Carcinogenesis Using Optical Coherence Tomography. Cancer Growth Metastasis 8:63-80
Leung, Sarah J; Rice, Photini S; Barton, Jennifer K (2015) In vivo molecular mapping of the tumor microenvironment in an azoxymethane-treated mouse model of colon carcinogenesis. Lasers Surg Med 47:40-9
Wall, R Andrew; Barton, Jennifer K (2014) Oblique incidence reflectometry: optical models and measurements using a side-viewing gradient index lens-based endoscopic imaging system. J Biomed Opt 19:067002
Carbary-Ganz, Jordan L; Barton, Jennifer K; Utzinger, Urs (2014) Quantum dots targeted to vascular endothelial growth factor receptor 2 as a contrast agent for the detection of colorectal cancer. J Biomed Opt 19:086003
Gainer, Christian F; Romanowski, Marek (2013) Multiphoton Imaging of Upconverting Lanthanide Nanoparticles in Three Dimensional Models of Cancer. Proc SPIE Int Soc Opt Eng 8595:
Gainer, Christian F; Joshua, Gihan S; Romanowski, Marek (2012) Toward the Use of Two-Color Emission Control in Upconverting NaYF4:Er(3+), Yb(3+) Nanoparticles for Biomedical Imaging. Proc SPIE Int Soc Opt Eng 8231:
Gainer, Christian F; Utzinger, Urs; Romanowski, Marek (2012) Scanning two-photon microscopy with upconverting lanthanide nanoparticles via Richardson-Lucy deconvolution. J Biomed Opt 17:076003

Showing the most recent 10 out of 23 publications